Progress in Neurobiology 85 (2008) 1–74

www.elsevier.com/locate/pneurobio

Neurotransmitter, peptide and cytokine processes in relation to

depressive disorder: Comorbidity between depression and
neurodegenerative disorders
Hymie Anisman a,*, Zul Merali b, Shawn Hayley a
a
Institute of Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada
b
University of Ottawa, Institute of Mental Health Research, Canada
Received 22 August 2007; received in revised form 4 December 2007; accepted 18 January 2008

Abstract
Given the array of biological changes induced by stressors, it is not surprising that these experiences may provoke a variety of illnesses.
Among others things, stressors promote functional changes of neuropeptide and classical neurotransmitter systems. The peptidergic changes, for
instance, include alterations of corticotropin releasing hormone, arginine vasopressin, and bombesin-like peptides at specific brain sites.
Similarly some of the neurotransmitter systems influenced by stressors include GABAergic and monoamine functioning. Variations of these
processes may limit neurogenesis (and dysregulation of growth factors such as BDNF) and influence cellular viability (through NFkB and MAP
kinase pathways). As well, stressors activate the inflammatory immune system, notably the release of signaling molecules (cytokines), which
may provoke many of the same neuropeptide (and other neurotransmitter) changes. By virtue of their actions on neuronal functioning,
inflammatory processes may influence stress-related illness, such as depression, and may be a common denominator for the comorbidity that
exists between depression and neurological conditions, including Parkinson’s and Alzheimer’s diseases, as well as cardiovascular-related
pathology. The present report provides an overview of biological endophenotypes associated with stressors that are thought to be related to major
depressive disorder and related comorbid conditions. The view is taken that synergy between stressors and inflammatory factors may promote
pathological outcomes through their actions on neuropeptides and several neurotransmitters. As well, stressful events may result in the

Abbreviations: 5-HT, serotonin; 5-HT1A, HT1B, 5-HT2A, and 5-HT2C, serotonin receptor subtypes; 5-HTT, serotonin transporter; 5-HTTLPR, 5-HTT gene
promotor polymorphism; ACTH, adrenocorticotropic hormone; AD, Alzheimer’s disease; AGII, angiotensin II; a-MSH, a-melanocyte stimulating hormone; APAF,
apoptotic protease-activating factor ( ); APP, amyolid precursor protein; AVP, arginine vasopressin; BB, bombesin; BB1, BB2, bombesin receptor subtypes; BBB,
blood brain barrier; BDNF, brain-derived neurotropic factor; BDZ, benzodiazepine; BNST, bed nucleus of the stria terminalis; BSA, basolateral amygdala; CeA,
central amygdala; CGRP, calcitonin gene-related peptide; CNS, central nervous system; COX-2, cyclooxygenase-2; CREB, cAMP response element-binding
protein; CRH, corticotropin releasing hormone; CRH1, CRH2, corticotropin releasing hormone receptor subtypes; CRP, C-reactive protein; CSF, cerebrospinal fluid;
DA, dopamine; DEAF-1, nuclear deformed epidermal auto-regulatory factor; DRN, dorsal raphe nucleus; DVC, dorsal vagal complex; ERK, extracellular signal-
regulated kinase; FGF, fibroblast growth factor; FPC, frontopolar cortex; GABA, gamma-aminobutyric acid; G-CSF, granulocyte colony-stimulating factor; GDNF,
glial derived neurotrophic factor; GR, glucocorticoid receptor; GRP, gastrin releasing hormone; GRPR, gastrin releasing hormone receptor; HPA, hypothalamic-
pituitary-adrenal; HPG, hypothalamic–pituitary–gonadal; IDO, indoleamine-2,3-dioxygenase; IFN, interferon; IGF-I, insulin-like growth factor I; IkB, inhibitory
factor kappa B; IL, interleukin; IL-1ra, IL-1 receptor antagonist; INOS, inducible nitric oxidase synthase; IP3, inositol triphosphate; Ir, immunoreactivity; IRS-1,
insulin receptor substrates 1; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LIF, leukemia inhibitory factor; LPS, lipopolysaccharide; MAPK, mitogen-activated
protein kinase pathways; MAO-A, monoamine oxidase A; MAOI, monoamine oxidase inhibitor; MAP, mitogen-activated protein; MCAO, middle cerebral carotid
artery occlusion; MDD, major depressive disorder; MnSOD, manganese superoxide dismutase; MR, mineralocorticoid receptor; MS, multiple sclerosis; NE,
norepinephrine; NFkB, nuclear factor kappa B; NK, natural killer cell; NMB, neuromedin B; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NSAID, non-steroidal
anti-inflammatory; NT-3, neurotrophin-3; NTS, nucleus of the solitary tract; OCD, obsessive compulsive disorder; OXT, oxytocin; PI3K, phosphatidylinositol 3-
kinase; PACAP, pituitary adenylate cyclase-activating polypeptide; PD, Parkinson’s disease; PET, positron emission tomography; PFC, prefrontal cortex; PGE2,
prostaglandin; PKC, protein kinase C; PR, progressive ratio; PVN, paraventricular nucleus; sICAM-1, soluble intracellular adhesion molecule; sIL-R, soluble IL
receptors; sIPSC, spontaneous inhibitory postsynaptic currents; SNc, substantia nigra pars compacta; SP, substance P; SSRI, selective serotonin reuptake inhibitor;
STAT, signal transducer and activator of transcription; THDOC, tetrahydrodeoxycorticosterone; TLR4, toll-like receptor 4; TNF, tumor necrosis factor; TNF-R1,
TNF-R2, TNF receptor subtypes; TrkB, tyrosine kinase B; VIP, vasoactive intestinal peptide.
* Corresponding author. Tel.: +1 613 520 2699; fax: +1 613 520 4042.
E-mail address: hanisman@ccs.carleton.ca (H. Anisman).

0301-0082/$ – see front matter # 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2008.01.004
2 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74

sensitization of neurochemical and cytokine processes, so that later re-exposure to these stimuli may promote rapid and exaggerated responses
that favor illness recurrence.
# 2008 Elsevier Ltd. All rights reserved.

Keywords: Depression; Neurodegeneration; Comorbidity; Endophenotype; Cytokine; Neuropeptide

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Stress and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1. Moderators of the stress response in relation to pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2. Stressor appraisals and coping in relation to pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Biological correlates of depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Stressors induce biogenic amine changes akin to those associated with depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.1. Biogenic amines: acute stressor effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.2. Sensitized biogenic amine variations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.3. Impact of chronic stressor on biogenic amine activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Serotonin signaling and depression in stress-based models of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1. 5-HT manipulations influence depressive-like behavioral impairments in animal models . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2. Serotonin correlates of depression: human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.3. Serotonin variations in depression and among depressed suicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.4. Genetic links between serotonin functioning and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6. Corticotropin releasing hormone (CRH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1. Stressor-induced CRH functioning: animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.2. CRH and CRH receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.3. CRH in depression/suicide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.4. CRH has multiple actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
7. Arginine vasopressin (AVP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
7.1. Arginine vasopressin in relation to depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
7.2. Arginine vasopressin and CRH synergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
8. Bombesin (neuromedin B and gastrin-releasing peptide). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.1. Bombesin and CRH interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.2. Bombesin and 5-HT interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
8.3. Bombesin and anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
9. Leptin, feeding and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
9.1. Leptin and cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
9.2. Leptin and reward processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
9.3. Relation to stress processes and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
9.4. Leptin involvement in atypical depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
9.5. Ghrelin, food consumption and motivational processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
10. Gamma-aminobutyric acid (GABA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
10.1. GABAA variations associated with suicide/depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
10.2. GABA and CRH inter-relations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
10.3. GABA, CRH and 5-HT inter-relations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
11. Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
11.1. Cytokines as signaling molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
11.2. Paracrine and autocrine actions of cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
11.3. Cytokines influence CNS processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
11.4. Neurochemical effects of cytokines: implications for depressive illness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
11.5. Neurochemical consequences of IL-1b, IL-6 and TNF-a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
11.6. Cytokine-induced behavioral changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
11.7. Proactive effects of cytokines and stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
11.8. Cytokines in relation to depression in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
11.9. Immune activation provokes depressive mood state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
11.10. Mechanisms linking cytokine activation and depressive illness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
12. Morphological correlates of major depressive illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
12.1. Stressor and corticoid actions in relation to morphological changes associated with MDD . . . . . . . . . . . . . . . . . . . . . . . 32
13. Growth factors in relation to stressors and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
13.1. BDNF involvement in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
13.2. Neurogenesis, growth factors and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
13.3. Neurodegeneration and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74 3

13.4. Downstream growth factor signaling pathways in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

14. Neuropeptide and cytokine influences on neurodegeneration: Contribution of the inflammatory immune system . . . . . . . . . . . . . 37
14.1. Anti-inflammatory properties of CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
14.2. Anti-inflammatory properties of a-MSH, VIP, PACAP and IGF-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
14.3. Proinflammatory effects of peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
15. Neuropeptide and cytokine interactions in the modulation of neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
15.1. Role of cytokines and CRH in stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
15.2. Role of cytokines and CRH in sequelae of acute head injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
15.3. Role of cytokines, VIP, and PACAP in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
15.4. Role of IGF-I and cytokines in Alzheimer’s disease (AD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
16. Cytokines mediate the comorbidity between depression and neurodegenerative conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
16.1. Depression and comorbid cardiovascular (heart and stroke) disturbances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
16.2. Depression and comorbid Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
16.3. Depression and comorbid Alzheimer’s disease (AD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
17. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

1. Introduction depression to comorbid illnesses, including those associated

Stressful events engender multiple neurochemical and
hormonal alterations, presumably as an adaptive response to
meet environmental demands. Yet, pathological outcomes are
frequent sequelae of stressful experiences, which might not be
surprising given the wide range of biological changes that are
engendered. The specific illness that emerges in response to
stressors might reflect vulnerability to particular biological
alterations and ‘‘weak links’’ in endogenous buffering
mechanisms. Evidently, in some individuals the neurochemical
alterations are insufficient to deal with the insults (varying with
the nature of the stressor, or the individual’s genetic or
experiential disposition) or may become overly taxed (allostatic
overload), culminating in adverse outcomes (McEwen, 2006;
Schulkin et al., 1998). As well, in some instances the
‘‘adaptive’’ biological changes themselves may have secondary
adverse consequences.
It seems that illnesses frequently do not occur in isolation of
one another, and comorbid conditions are common, particularly
in chronic illnesses. In the case of depression, comorbidities
have been reported with respect to anxiety (Nutt and Stein,
2006), cardiovascular disease and stroke (Bondy, 2007;
Frasure-Smith and Lesperance, 2005) as well as neurodegen-
erative disorders such as Parkinson’s and Alzheimer’s diseases,
and multiple sclerosis (Griffin et al., 2006; Lieberman, 2006;
Mohr, 2007; Owens, 2002; Wheeler and Owens, 2005). The
presence of comorbid illnesses may complicate treatment, and
there is reason to believe that depression itself (and the
antecedent or concurrent distress) may limit recovery from co-
occurring pathologies (Rosenthal, 2003).
The present report describes the contribution of stressful
events to the emergence of various endophenotypes that
comprise depression, including the possible biological pro-
cesses (neurotransmitter, hormone, neuropeptide, growth factor
and cytokine) that might be responsible for the disorder. In so
doing, we will outline some of the moderating conditions that
influence these biological changes, and will relate stress and
with the aftermath of stroke (and head injury) and those of a
neurodegenerative nature (Parkinson’s disease and Alzheimer’s
disease), with the aim of defining some of the shared processes
that subserve them. Understanding these common processes
may offer insights into the mechanisms subserving these
disease states, might provide important clues for effective
prophylactic and therapeutic treatment, and will reinforce the
view (Martin, 2002) that barriers between psychiatry and
neurology are counterproductive.
2. Stress and depression
Studies in animals have shown that stressors markedly
influence central neurochemical processes that may be pivotal to
the provocation of depressive illness. These neurochemical and
hormonal changes are thought to serve in an adaptive capacity
(de Kloet et al., 1999; Kovacs and Sawchenko, 1996; Sapolsky
et al., 2000; Sato et al., 1997; Sawchenko et al., 1996), being
fundamental in maintaining allostasis (i.e., homeostasis pertain-
ing to the stress response). Among other things, these
neurochemical changes may prepare the organism to deal (cope)
with the stressor, blunt its psychological impact, and stimulate
processes that preclude excessive physiological activation, such
as immune over-reaction (de Kloet et al., 1999; McEwen, 2000;
Sapolsky et al., 2000). Yet, if the stressor experience is
sufficiently severe and/or long lasting (i.e., chronic strain), then
the load placed on biological systems may become excessive
(allostatic overload), ultimately resulting in increased vulner-
ability to pathology (McEwen, 2000). Of course, genetic or
experiential factors might influence the organism’s adaptive
capacity (or hardiness) in dealing with such insults and it is likely
that these factors, among others, moderate the stress response
(Tannenbaum and Anisman, 2003).
Paralleling the animal studies, there is considerable evidence
from human research confirming that stressful experiences
promote or exacerbate depressive symptoms (Kessler, 1997;
Paykel, 2003) and may elicit or aggravate several other
4 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
psychological and physical disorders. In evaluating the impact
of stressors on pathology, however, it ought to be considered
that there is appreciable variability in how stressors are
perceived, the emotional reactions to them, as well as the
peripheral and central neurochemical changes elicited. Thus,
individuals may differ with respect to the adverse effects
elicited by stressful events. Indeed, it is generally thought that
major depressive disorder (MDD) is biochemically hetero-
geneous, wherein symptoms as well as the processes leading to
depression, may vary across individuals; consequently, the
treatments effective in alleviating the disorder may vary
accordingly. This, coupled with the limited success in defining
the genetic compliments associated with depression, has lead to
the suggestion that analysis of MDD might not always be best
served when viewed as a syndrome or phenotype. Instead, it
might be more profitable to evaluate endophenotypes that make
up the disorder (i.e., focusing on genetic factors and specific
neurochemical processes related to particular symptoms of
illness) (e.g., Cryan and Slattery, 2007; Gottesman and Gould,
2003; Hasler et al., 2004). In this regard, the neurochemical
disturbances associated with depressive disorders have been
considered endophenotypes that might be responsible for
different aspects or symptoms of the illness (Hasler et al.,
2004). Analyses of endophenotypes likely represent a highly
effective and valid approach, so long as it is appreciated that the
constellation of symptoms and neurochemical characteristics
associated with psychiatric illnesses likely reflect complex
interactions between several biological systems. Essentially, it
may be that a concatenation of neurotransmitter alterations is
fundamental to the emergence of pathology.
2.1. Moderators of the stress response in relation to
pathology
Analyses of stressor effects on pathology based exclusively on
animal studies can only go so far in predicting pathological
outcomes. Although animal studies can be instrumental in
defining many of the neurochemical mediators and consequences
of stressor outcomes, some of the variables influencing
vulnerability to pathology cannot readily be assessed in animal
models. Considerable animal research has focused on the
contribution of genetic factors and early life experiences (as well
as those related to aging) and the nature of the stressor
experienced (including specific characteristics of the stressor
such as its predictability, ambiguity, controllability and
chronicity) in promoting pathological outcomes. Other pro-
cesses, such as appraisal and coping mechanisms that moderate
the impact of stressful experiences on the evolution and
exacerbation of pathology are more difficult to assess in animals
(Anisman and Matheson, 2005). Likewise, several factors have
been identified that limit the impact of stressors (i.e., promote
stressor resilience), and although some of these can be evaluated
in animal models, others cannot. Charney (2004), for instance,
suggested that neural mechanisms related to reward and
motivation (hedonia, optimism, and learned helpfulness),
responsiveness to fear and fear-related situations, and adaptive
social behaviors (altruism, bonding, and teamwork) all acted to
influence character traits that affected resilience to severely
traumatic events. No doubt, a set of resiliency factors, including
early experiences and genetic factors, likewise contribute to the
emergence of depression in the face of stressors.
2.2. Stressor appraisals and coping in relation to
pathology
The endorsement of inappropriate or ineffective coping
strategies to deal with stressors has been implicated as being
fundamental in the promotion of psychological illnesses such as
MDD. It is thought that when confronted with a stressor,
individuals make appraisals regarding the threat, and this
subjective interpretation influences the coping methods
endorsed (Lazarus and Folkman, 1984). Appraisals comprise
a constellation of evaluative dimensions, including the threat or
risk associated with the event, its severity, controllability,
predictability, ambiguity, and the meaning imposed. Variations
along each of these dimensions are associated with perceived
distress and may govern the coping methods selected to deal
with the stressor (Anisman and Matheson, 2005).
Coping strategies are often classified into two general types;
problem-focused and emotion-focused (Billings and Moos,
1985; Lazarus and Folkman, 1984), which subsume multiple
strategies (e.g., emotion-focused coping may comprise emo-
tional expression, emotional containment, self- or other-blame,
withdrawal, denial, and passive resignation). In addition, several
alternative coping methods can be used, including cognitive
restructuring (re-evaluating the threat), social support seeking,
active distraction, religion, humor, wishful thinking and
rumination (Carver et al., 1989; Endler and Parker, 1990;
Matheson and Anisman, 2003; Nolen-Hoeksema, 1998). It is
often taken as axiomatic that in situations in which the individual
has control, problem-focused strategies (e.g., problem solving,
cognitive restructuring or positive growth) are adaptive, whereas
those strategies that encourage undue focus on emotions (e.g.,
rumination, emotional venting, self-blame) are not (Carver et al.,
1989; Lazarus and Folkman, 1984). This said, it was suggested
that in emotionally charged situations, emotional-approach
coping might facilitate the individuals ability to come to terms
with their feelings and in so doing, distress may be reduced
(Stanton et al., 1994). Likewise, although avoidance often works
against individuals’ well-being in the long-run, it may provide
temporary relief from an ongoing stressor, allowing the
individual the opportunity to adopt or develop more effective
strategies (Suls and Fletcher, 1985).
Any given coping strategy may serve different functions, or
operate to facilitate or inhibit other strategies. For instance,
social support can be used for a variety of purposes, including a
source of information, a shoulder to cry on, a means of
distracting oneself, and so forth. However, it is important to
note that as much as social support may provide an effective
buffer against ongoing stressors (Underwood, 2000), the
perception of unsupport (e.g., not receiving support when it
was reasonably expected) may have marked repercussions on
depressive state (Ingram et al., 1999). Further to the same point,
although rumination has been associated with depressive illness
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74 5

(Nolen-Hoeksema, 1998), this method of dealing with stressors
does not occur in isolation of other coping strategies.
Interestingly, it was observed that rumination ordinarily co-
occurred, in controls, with a broad constellation of problem- and
emotion-focused strategies, as well as cognitive disengagement.
In contrast, among dysthymic patients, rumination was
associated with a limited array of strategies related to
emotion-focused coping, and inversely related to efforts to
disengage (Kelly et al., 2007). Thus, the effectiveness of a given
strategy may be determined by how it is used in conjunction with
other strategies, and perhaps in how flexible individuals are in
their selection of these strategies. This said, it appears, as well,
that the specific coping strategies endorsed may vary over time
and across situations (Delongis and Holtzman, 2005; Tennen
et al., 2000), and might also serve different functions as the
stressor evolves. Of course, individuals bring with them certain
coping dispositions or styles that influence the strategies adopted
most readily across different situations (e.g., Carver et al., 1989).
Typically, depressive mood is accompanied by the use of
emotion-focused coping and rumination, at the expense of
problem-oriented coping and social support seeking (Carver
et al., 1989; Matheson and Anisman, 2003; Ravindran et al.,
1999). However, this still begs the question, as to how certain
coping styles came to predominate. For example, is there a
genetic disposition to endorse one style over another, or are the
styles developed during early childhood subsequently main-
tained? Likewise, are particular coping styles secondary to
personality factors such as poor self-esteem? Ultimately, it is
likely that appraisals, coping, and the many factors that moderate
these responses, may influence the neurochemical alterations
associated with stressors (and the converse is no doubt the case,
as well), thereby favoring the development of depressive illness.
3. Biological correlates of depression
It is clear from various studies assessing neurotransmitter
alterations associated with MDD, that multiple processes may be
perturbed and could potentially subserve depressive illness.
These have included variations of brain levels and turnover of 5-
HT, alterations of the 5-HT transporter (5-HTT) and several 5-HT
receptors (5-HT1A, HT1B, 5-HT2A, and 5-HT2C), DA auto-
receptors, and a1-NE or b-NE receptors (Maes and Meltzer,
1995; Nestler et al., 2002; Nutt, 2002; Wong et al., 2000).
Moreover, depression has been associated with alterations of
peptidergic functioning (e.g., corticotropin releasing hormone;
CRH), including neuronal release or the number and sensitivity of
peptide receptors (Mitchell, 1998; Nemeroff, 1996; Reul and
Holsboer, 2002), as well as alterations of growth factors (e.g.,
brain-derived neurotrophic factor; BDNF) (Duman and Mon-
teggia, 2006; Duman et al., 2000, 2001; Manji et al., 2001) and
cytokines that are more typically considered as immune system
signaling molecules (e.g., interleukin-1, -2 and -6, interferon-a,
tumor necrosis factor-a (Hayley et al., 2005; Maes, 1999)).
Moreover, the downstream signaling factors associated with
several of these signaling molecules, such as cAMP, CREB and
protein kinase A, have been implicated in depressive illness

Fig. 1. Schematic representation depicting potential routes by which stressors and cytokines could influence depressive state. A stressor could potentially influence
major depression through two major routes that feed into several interconnected loops. Stressors and cytokines both increase hypothalamic (and extra-hypotalamic)
CRH release, although in the case of stressors this outcome may involve activation of bombesin-like peptides (neuromedin-B and gastrin releasing peptide; NMB and
GRP, respectively). In addition to activating HPA functioning, CRH may influence 5-HT processes, and GABAA activity may act as a mediator in this regard. This, in
turn may influence depression directly, or may do so by impairing neuroplastic processes. An alternative, although not necessarily mutually exclusive pathway
involves cytokine/stress activation of either NFkB, MAP kinases, or JAK/STAT signaling. These would influence oxidative or apoptotic mechanisms, leading to
altered growth factor expression (e.g., BDNF), hence again favoring impaired neuroplastic processes, culminating in major depression.
6 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
(Dwivedi et al., 2002). To this point, however, it is uncertain
whether specific features of depression correspond to particular
neurochemical changes (e.g., are the DA changes related to
anhedonic features of depression, or are 5-HT reductions in
frontal regions related to impulsivity among depressed
suicides?).
The multiple neurochemical alterations that have been
presumed to be associated with depression likely do not act
independently of one another. Some may reflect serial variations
(induction of a cascade of neuronal changes), whereas others may
reflect parallel processes stemming from common instigators
(e.g., stressful experiences). As will be described in the ensuing
sections (depicted in Fig. 1), it is our view that stressful events
favor the development of several neurochemical disturbances that
ultimately come to promote the emergence of depressive
symptoms (or exacerbate the symptoms of an already existent
depression). In addition to monoaminergic neurotransmitter
system involvement, we propose that stressors promote variations
of several neuropeptidergic (serving as neurotransmitters and/or
neuromodulators) systems (e.g. bidirectional interactions
between neuromedin B (NMB), gastrin releasing hormone
(GRP) and CRH systems). In addition, many of these peptidergic
systems modulate classical neurotransmitter systems. Illustra-
tively, CRH and NMB variations influence 5-HT functioning,
possibly being moderated by GABAA neuronal activity
(Brambilla et al., 2003; Shiah and Yatham, 1998; Tunnicliff
and Malatynska, 2003; Merali et al., 2004a,b). Further, stressors
may come to affect processes associated with neurogenesis and
cell survival (possibly involving growth factors such as BDNF),
which likewise might contribute to major depressive disorder. In
this regard, a major focus of the model provided in Fig. 1 is that
certain stressors, like immunogenic challenges, may provoke
activation of the inflammatory immune system, and the ensuing
release of immune signaling molecules (cytokines). These
cytokines, in effect, function like stressors in affecting
neurochemical processes, and may act synergistically with
traditional stressors in provoking these outcomes. As well,
sensitization of neurochemical responses occur to a variety of
insults, including neurogenic and psychogenic stressors, so that
the response to later challenges are increased. In addition to the
exaggerated responses elicited by stressors similar to those
initially encountered (or cues that act as reminders of these
stressors), cross-sensitization between different types of chal-
lenges may also occur. It is believed that the sensitization of
neurochemical responses might contribute to the development of
pathology, such as depression. Moreover, because these same
mechanisms also contribute to neurodegenerative processes, it is
suggested that synergies between stressors and cytokines, and the
sensitization of the neurochemical processes associated with
stressors, may contribute to comorbidity frequently seen between
psychological and neurodegenerative disorders.
4. Stressors induce biogenic amine changes akin to
those associated with depression
Given the prominent role of stressors in the provocation and
recurrence of MDD, analyses of stressor effects on brain
neurotransmission (using animal models) might provide
fundamental information concerning the specific changes
associated with this illness. As well, this line of research
may help in the identification of the specific sites at which these
alterations occur, the factors that favor the provocation of these
stressor-induced effects, and conversely, the conditions (and
treatments) that might limit their occurrence or impart
resiliency.
To a considerable extent, the sections that follow rely
heavily on data derived from animal studies that pertain to
stressor-provoked neurochemical changes. Of course, such
studies are fundamental in delineating the effects of stressors,
and at least some of the factors that moderate the impact of
adverse events on neurochemical processes and on behaviors
that might reflect a depressive-like state. Yet, as already
indicated, attempts to generalize animal-based findings to
human pathologies are exceptionally difficult given the
fundamental role of cognitive (e.g., stressor appraisal)
processes in accounting for the reaction to stressors. This is
made all the more difficult given that, in humans, certain types
of stressors (e.g., those dealing with social threats) may engage
different processes than those involving other forms of distress,
such as shame, loss and rumination (Anisman and Matheson,
2005; Dickerson and Kemeny, 2004). Indeed, these very potent
stressors that could have far reaching neurochemical and
psychological ramifications, cannot be mimicked in animal
models. Furthermore, in humans, stressors that involve
anticipation are generally associated with anxiety, whereas
those involving loss are frequently more closely aligned with
depression (Monroe and Depue, 1991). It appears, as well, that
gender differences may exist with respect to the impact of
certain types of stressors. For instance, there is reason to
suppose that depressive symptoms are more likely to be
induced by social stressors in females than in males, whereas in
males, factors such as job loss or demotion will be more likely
to induce depression. Thus, in evaluating the impact of
stressors, and the mediating role of neurochemical changes in
promoting depression, caveats concerning social determinants
of the stress response limit the utility of animal studies.
Although stressors have ubiquitous consequences, affecting
several neurotransmitter systems across a number of brain
regions, not all stressors have the same effects, and different
neural circuits may be engaged, depending on the nature of the
stressor encountered. ‘‘Processive’’ stressors (i.e., those that
involve higher-order processing, e.g., fear conditioning,
predator cues) are thought to induce hypothalamic–pituitary–
adrenal (HPA) activation through limbic processes, whereas
‘‘systemic’’ challenges (e.g., respiratory, cardiovascular,
immune and cytokine challenge) might do so through non-
limbic mechanisms (Herman and Cullinan, 1997). Interest-
ingly, despite the broad impact of stressors, some degree of
selectivity seems to occur. Of the processive types of stressors,
those with physically aversive properties (termed neurogenic
stressors) and those of psychological origin (psychogenic
stressors; learned threats and those that involve innate threats
such as predator odor) might also engage different neural
circuits. For example, although different stressors provoked the
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
in vivo release of amygdala CRH, antagonists of this peptide did
not attenuate the anxiety elicited by innate threats, but reduced
that associated with neurogenic and learned stressors (Merali
et al., 2004a,b, 2006a). To be sure, it is difficult to compare the
influence of different types of stressors given that they may be
appraised differently or they may not be equally aversive.
Nevertheless, it appears that psychogenic and neurogenic
insults differentially influence in vivo amygdala or prefrontal
cortical NE and CRH activity (Anisman and Matheson, 2005;
Hayley et al., 2001a; Lu et al., 1999; Merali et al., 2001, 2004a;
Morrow et al., 2000) and might thus have different behavioral
consequences.
4.1. Biogenic amines: acute stressor effects
Like the presumed neurochemical correlates of depression,
stressors may elicit NE, DA and 5-HT release in several brain
regions, varying as a function of experiential and organismic
factors (e.g., age, strain) (Ritter and Pelzer, 1978; Shanks et al.,
1994, 1991; Stanford, 1995). The NE and 5-HT variations are
notable in specific hypothalamic nuclei (e.g., paraventricular
nucleus; PVN) and various mesocorticolimbic sites, including
the hippocampus, amygdala and prefrontal cortex (PFC). The
DA changes are also exceedingly sensitive to stressors, being
notable within the arcuate nucleus, nucleus accumbens and
other mesocorticolimbic sites (Deutch et al., 1991; Kalivas and
Duffy, 1995; Puglisi-Allegra et al., 1991; Zacharko and
Anisman, 1991), and there have been reports that different
neurogenic insults may influence nigrostriatal DA activity
(Abercrombie et al., 1989; Nisenbaum et al., 1991). In vivo
studies indicated that mesocorticolimbic amine alterations
could be induced by relatively mild stimuli (tailpinch, novelty)
and by psychosocial stressors (Cenci et al., 1992; Doherty and
Gratton, 1992, 1996; Feenstra et al., 1995; Kalen et al., 1989;
Tidey and Miczek, 1996) and a hemispheric mesocorticolimbic
DA bias appears to exist in response to stressors (Sullivan and
Gratton, 1998). The latter findings may be important given the
finding that a key feature associated with MDD may be related
to dysregulation of hemispheric activation within the PFC
(Johnstone et al., 2007). Specifically, in nondepressed
individuals left-lateralized activation in the PFC occurred
when participants were down-regulating negative affect. In
contrast, bilateral PFC activation was evident among depressed
individuals when making such efforts. Furthermore, during an
effortful affective reappraisal task, an inverse relationship
between activation in left ventrolateral PFC and the amygdala,
likely mediated by the ventromedial PFC was apparent among
nondepressed individuals, whereas this relationship was
dysregulated among depressed individuals. In effect, these
data suggest that inappropriate engagement of right prefrontal
cortex, coupled with limited engagement of left lateral-
ventromedial prefrontal circuitry may serve an important role
in regulating affective (and perhaps cognitive) responses to
negative stimuli (Johnstone et al., 2007).
In addition to variations of monoamine reserves and
turnover, stressors influence the expression of various receptor
subtypes. By example, it was reported that 24 h following a
7
forced swim stressor, 5-HT1A receptor density was reduced in
the dorsal raphe nucleus (DRN) and in the hippocampus,
whereas 5-HT1A receptor density was elevated in the thalamus,
hypothalamus, and amygdala (Briones-Aranda et al., 2005).
Moreover, the development of behavioral impairments follow-
ing stressor exposure may be related to hypersensitivity of 5-
HT2 receptors and desensitization of 5-HT1B receptors
(Bolanos-Jimenez et al., 1995; Nankai et al., 1995). By
example, it was reported that a stressor regimen that
engendered behavioral impairments in a learned helplessness
paradigm, increased mRNA expression of 5-HT1B receptors
within the DRN, without affecting postsynaptic 5-HT1B
expression within the hippocampus or PFC (Neumaier et al.,
1997).
Like neurogenic challenges, psychogenic insults (e.g.,
predator odor, social defeat) influence NE release from
mesolimbic neurons (Anisman et al., 1993; Hayley et al.,
2001a; Merali et al., 2001, 2004a,b) and 5-HT release at the
hippocampus (Keeney et al., 2006). Likewise, social defeat was
found to increase hypothalamic 5-HT turnover, and the anxiety
that accompanied the 5-HT variations were attenuated by
chronic antidepressant treatment (Beitia et al., 2005). Despite
the obvious relevance of psychosocial stressors in determining
pathological outcomes, to this point analyses of the impact of
psychogenic stressors on monoamine functioning have not been
examined as extensively as those elicited by neurogenic insults
(but see Tamashiro et al., 2005). Nevertheless, it seems that
such challenges may instigate anxiety-like effects similar to
those elicited by neurogenic stressors. However, as alluded
to earlier, the response to some psychogenic stressors appears to
be ‘‘prewired’’ (e.g., predator-related stressors) and mono-
amine and neuroendocrine alterations may be distinguishable
from those elicited by learned stressors (Anisman et al., 2001;
Hayley et al., 2001a; Merali et al., 2004a; Morrow et al., 2000).
Thus, there is reason to believe that these different types of
insults will also elicit dissimilar behavioral disturbances.
In general, it is thought that given a sufficiently severe
challenge, particularly when termination of the stressor is not
controllable by the animal, amine release may exceed rate of
synthesis, and as a result depletion of NE and 5-HT stores will
ensue (Anisman and Zacharko, 1991; Heinsbroek et al., 1989;
Weiss et al., 1981). The diminished monoamine reserves would
render animals less able to contend with further insults, and as a
result behavioral impairments would be more likely to occur.
Consistent with this view, it has frequently been reported that
uncontrollable (inescapable) stressors engender reductions of
hypothalamic NE and hippocampal 5-HT relative to the effects
provoked by controllable (escapable) stressors (Anisman and
Zacharko, 1991), and are also more potent in provoking 5-HT
release at the basolateral amygdala (Amat et al., 1998a), medial
PFC (Bland et al., 2003a), ventral hippocampus and dorsal
periaqueductal gray (Amat et al., 1998b) as well as the nucleus
accumbens shell (Bland et al., 2003b). Moreover, just as
escapable and inescapable stressors differentially influence 5-
HT functioning, it was shown that if rats were first trained in an
escapable test (a treatment that immunizes animals against the
behavioral disturbances elicited by an uncontrollable stressor),
8 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
the increased 5-HT release at the DRN ordinarily elicited by an
inescapable stressor was prevented. As this effect was
dependent on activation of the ventral aspect of the medial
PFC, it was suggested that this site might be essential for
storage or plasticity as it relates to information concerning
stressor controllability (Amat et al., 2005, 2006).
4.2. Sensitized biogenic amine variations
Typically, stressor-provoked amine variations are short-lived,
lasting only minutes or hours, depending upon characteristics of
the animal (e.g., age, strain) and/or the stressor. However, stressor
experiences may proactively influence the response to subse-
quent challenges, so that monoamine responses occur more
readily and are more profound than in naive animals (i.e.,
sensitization). By example, upon re-exposure to a mild stressor,
the utilization of NE and mesocortical DA is enhanced, and this
occurs even if the later exposure involves a different type of
stressor (Abercrombie and Jacobs, 1988; Abercrombie et al.,
1989; Anisman and Sklar, 1979; Cassens et al., 1980; Fadda et al.,
1978; Jordan et al., 1994; Kalivas and Duffy, 1995; Pezzone et al.,
1992, 1993; Rabin et al., 1995; Roth et al., 1988; Smith et al.,
1992, 1997; Yoshioka et al., 1995). Likewise, 5-HT changes
within the ventral medial PFC associated with a stressor can be
readily re-engendered upon subsequent re-exposure to a stressor
(or upon subsequent morphine treatment), but this effect was
only apparent if the initial stressor was one that was
uncontrollable (Maier et al., 2006).
Among previously stressed animals augmented amine
responses are also observed in response to pharmacological
stimulants, such as amphetamine or cocaine (Anisman et al.,
2003; Antelman and Chiodo, 1984; Deroche et al., 1995;
Gresch et al., 1994; Herman et al., 1984; Kalivas and Stewart,
1991; Nisenbaum and Abercrombie, 1992; Nisenbaum et al.,
1991; Robinson, 1988; Robinson et al., 1987). Thus, stressor
experiences may not only influence behavioral responses to
later stressor challenges, but may also be important in
moderating the response to certain drugs (Kalivas and Stewart,
1991). It has been suggested that basic fibroblast growth factor
(bFGF), a neurotrophic factor produced by astrocytes, may be
essential for the neuronal plasticity leading to the protracted
responses elicited by stressor and/or catecholamine stimulants
(Flores and Stewart, 2000; Flores et al., 2002).
In addition to the altered amine levels and turnover, re-
exposure to stressors has been reported to enhance hippocampal
5HT1A receptor density, while decreasing the affinity of those
receptors. In contrast, whereas 5-HT2A receptor density was
unaffected, its affinity was increased (Harvey et al., 2003). It
seems that the sensitized neuronal changes that have been
reported may be tied to anxiety processes, as the amine changes
elicited by stressor re-exposure or stressor-related cues can be
attenuated by anxiolytics (Coco et al., 1992; Fadda et al., 1978;
Kaneyuki et al., 1991; Laveille et al., 1978; Wedzony et al., 1996)
and by 5-HT1A receptor manipulations (Wedzony et al., 1996).
The processes underlying sensitized neurochemical changes
have yet to be fully understood, however, it is likely that the
processes associated with sensitized 5-HT, DA and NE neuronal
activity, may be unique for each transmitter system. In the case of
stressor-induced sensitization of dorsal raphe 5-HT neuronal
activity, which has been implicated in depression and anxiety, it
was suggested that a ligand related to CRH2 receptors might be
essential in promoting this outcome (Maier and Watkins, 2005).
Moreover, it has been reported that the cross-sensitization
between stressors and amphetamine likely involves NMDA-
glutamatergic receptors, as the sensitization can be blocked by
the NMDA antagonist, MK-801, infused directly into the brain
(Pacchioni et al., 2002). Especially intriguing data have been
reported by Stewart and her associates (e.g., Flores and Stewart,
2000; Flores et al., 2002) suggesting that bFGF, a neurotrophic
factor produced by astrocytes, may be fundamental for the
neuronal plasticity associated with the protracted effects elicited
by stressors and by catecholamine stimulants. At this juncture it
is premature to dismiss any of these potential mechanisms in
mediating sensitization effects, and it is indeed possible that
multiple processes may subserve the diverse sensitized responses
that have been associated with stressors.
4.3. Impact of chronic stressor on biogenic amine activity
The variations of monoamine activity prompted by repeated
(chronic) insults are distinct from those engendered by acute
insults. Specifically, the reductions of amine levels provoked by
acute stressors may not be apparent following protracted or
repeated insults (Deutch and Roth, 1990; Deutch et al., 1991;
Irwin et al., 1986; Roth et al., 1988), probably owing to
compensatory enhancement of NE and 5-HT synthesis (Haleem
and Parveen, 1994; Irwin et al., 1986; Nankova et al., 1993) and
moderation of DA utilization (Gresch et al., 1994). However,
this outcome may be dependent upon the nature of the stressor,
as the effects of chronic social stressors appear to be relatively
persistent (Buwalda et al., 2005).
The ‘‘adaptation’’ frequently observed with chronic stres-
sors does not necessarily reflect a diminution of the high levels
of amine utilization. Indeed, in chronically stressed animals,
amine levels do not simply return to pre-stress levels, but may
actually come to exceed basal values, potentially because of the
compensatory increase of amine synthesis (Anisman and
Zacharko, 1991; Blanc et al., 1980). Interestingly, the elevated
monoamine synthesis may persist well after stressor termina-
tion, resulting in elevated monoamine levels, hence rendering
animals better prepared to deal with subsequent stressors
(Shanks et al., 1994).
Possibly as a consequence of the excessive monoamine
release, chronic stressors also promote down-regulation of b-
NE receptor activity and the NE sensitive cAMP response
(Stone, 1987) and reduce 5-HT1B receptor expression
(Bolanos-Jimenez et al., 1995). It was likewise reported that
acute and repeated stressors differentially influenced 5-HT2A
receptor mRNA and protein expression, and these effects were
brain region-specific. In particular, an acute stressor resulted in
a decline of 5HT2A receptor mRNA and protein expression in
hippocampus. However, this treatment resulted in elevated
frontal cortex 5-HT2A mRNA expression, coupled with a
decrease of receptor expression in the hippocampus and
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
hypothalamus of those rats that displayed behavioral impair-
ments in a learned helplessness paradigm (Dwivedi et al.,
2005). It was likewise reported that chronic unpredictable
stressor exposure was associated with an increase of 5-HT2A in
the cortex, coupled with an increase of D1 receptor density
(Ossowska et al., 2001).
Like acute insults, chronic stressors proactively influence
the response to later challenges; however, whereas acute
stressors provoke sensitization of mechanisms associated with
NE release, chronic stressors may also induce sensitization of
processes associated with synthesis (Anisman et al., 2003). It is
interesting, as well, that when rats were exposed to a chronic
stressor regimen, subsequent exposure to a different stressor
provoked a still greater increase of hippocampal NE release
(cross-sensitization), which was accompanied by elevated
transmitter synthesis (Finlay et al., 1995; Nisenbaum et al.,
1991). However, it seems that the specific pattern of stressor
exposure (and perhaps the nature of the stressor used) is
important in determining whether sensitization would be
established (Jedema et al., 1999).
Although anxiolytics attenuated the NE and DA release
elicited by acute stressors, in rats chronically stressed and then
exposed to a different stressor, the augmented amine release was
not attenuated by diazepam (Finlay et al., 1995). It seems that
following a chronic stressor experience, subsequent exposure to a
heterotypic stressor (i.e., ones different from the original
experience) provokes pronounced neurochemical alterations
that are relatively resistant to the effects of anxiolytics. In a like
fashion, chronic, unpredictable stressors might promote sus-
tained neurochemical alterations that could render animals more
vulnerable to pathological outcomes. Albeit speculative, these
findings may be relevant to psychological illnesses that appear to
be relatively treatment resistant.
Summarizing, the increased monoamine availability
(reserves) associated with chronic stressors may enable the
organism to deal with ongoing or impending challenges.
However, the elevated monoamine turnover can only go so far
in limiting adverse outcomes. As indicated earlier, if neuronal
activation is sufficiently sustained, then the wear and tear on
monoamine systems (and those secondary to the amine
activation) may become excessive, rendering animals vulnerable
to several pathologies, including depression (Fontenot et al.,
1995; McEwen, 2000; McEwen and Magarinos, 2001). In this
regard, vulnerability to pathology is not limited to psychological
disturbances, as it was reported that the immunoenhancement
provoked by acute stressors may turn to immunosuppression
after protracted insults (Dhabhar, 2000), potentially influencing
vulnerability to immunologically related disturbances.
5. Serotonin signaling and depression in stress-based
models of depression
5.1. 5-HT manipulations influence depressive-like
behavioral impairments in animal models
Consistent with the view that the 5-HT system plays a
pivotal role in depression, behavioral disturbances associated
9
with stressors can be attenuated by treatments that influence 5-
HT availability. For example, pharmacological treatments that
influence hippocampal 5-HT2C receptors may diminish anxiety
elicited by stressors (Merali et al., 2006a). Likewise, it was
repeatedly shown that when administered chronically, anti-
depressants that affect 5-HT reuptake effectively attenuated the
behavioral interference associated with prior uncontrollable
foot-shock in a learned helplessness paradigm (Anisman and
Zacharko, 1991), and that the effectiveness of these treatments
were related to frontal cortex 5-HT variations (Petty et al.,
1992, 1994). Likewise, the learned helplessness effect could be
attenuated by bilateral hippocampal infusion of a 5-HT
reuptake inhibitor, and this effect could be prevented by the
5HT1A antagonist 8-OH-DPAT, thus implicating this receptor
subtype in the stressor-induced interference (Joca et al., 2003).
As performance in shock escape tests may be confounded by
motoric factors (i.e., disturbances in the ability to initiate and
maintain active responses; Anisman et al., 1978), it is
interesting that the effects of antidepressants that influence
5-HT or both 5-HT and NE (escitalopram, desipramine) were
also apparent in cognitive tests, including disturbed cognitive
set-shifting and behavioral flexibility, both of which can be
features of depression (Bondi et al., 2007; Lapiz et al., 2007).
Paralleling the effects of pharmacological manipulations, in
mice with deletion of 5-HT1A receptors, anxiety responses were
elevated, as were autonomic indices of anxiety (Toth, 2003).
Yet, increased anxiety was not uniformly evident in either 5-
HT1A or 5-HT1B knockouts (Groenink et al., 2003), although
this may have been due to background strain (genetic context)
used in these studies. Further to this same point, a gender bias
was apparent in a forced swim test in that a reduction of
immobility was evident among females, but not males (or in
wild-type counterparts), with 5-HT1B receptor deletion (Jones
and Lucki, 2005). Based on analyses of 5-HT release in males
and females, coupled with the behavioral effects of the selective
serotonin reuptake inhibitor (SSRI), fluoxetine, these investi-
gators suggested that a sex-linked disinhibition of 5-HT release
was responsible for elevated baseline hippocampal 5-HT levels
as well as vulnerability to stressor-elicited 5-HT depletion and
the ensuing behavioral impairments.
In addition to the receptor changes, there have been several
reports implicating the 5-HT transporter (5-HTT) in depres-
sion. Specifically, siRNA-mediated knockdown of 5-HTT
within the raphe nucleus was associated with attenuated
immobility in a forced swim test, just as the antidepressant,
citalopram, provoked this outcome (Thakker et al., 2005). In
contrast to these findings, however, 5-HTT knockout mice
displayed increased immobility in a repeated forced swim test
(Wellman et al., 2007), and exhibited elevated anxiety and
depression in several behavioral paradigms (Lira et al., 2003).
The anxiety-like behaviors were particularly pronounced
among knockouts that had been exposed to early life stressor
experiences (Carroll et al., 2007), suggesting that the
influence of the 5-HTT knockout interacts with such
experiences (just as similar effects were documented in
human studies; see ensuing section). As well, it appeared that
the behavioral disturbances among 5-HTT knockouts could
10 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
be antagonized by repeated antidepressant (fluoxetine)
treatment (Holmes et al., 2002) as well as by the 5-HT1A
antagonist WAY 100635, once again implicating 5-HT1A
receptor involvement in such effects (Holmes et al., 2003a).
Interestingly, among 5-HTT knockouts the increased reac-
tivity to mild stressors and the elevated anxiety-related
behaviors were accompanied by diminished 5-HT1A receptor
expression. Thus, the effects of the 5-HTT knockout might be
secondary to the 5-HT1A receptor variations. Indeed,
adenoviral assisted elevation of 5-HT1A expression in these
5-HTT knockouts attenuated the exaggerated adrenocortico-
tropic hormone (ACTH) response elicited by a mild stressor.
However, other indices of anxiety (exploratory behaviors in
an open field and a plus maze) were unaltered. Furthermore,
although 5-HTT knockout mice displayed hypoactivity,
anhedonia was not apparent in a sucrose preference test
(Kalueff et al., 2006). It may be that the influence of 5-HT
neuronal functioning (like the effects of CRH manipulations)
is situation-specific. Alternatively, it may be that 5-HTT
influences one component of the depressive profile, whereas
5-HT1A variations affect a second feature (e.g., anxiety).
From this perspective, genetic deletion may have cascading
effects so that outcomes distal from the original genetic
manipulation might be responsible for the behavioral
changes. Of course, as in the case of many studies involving
the knockout strategy, it is important to consider that
neurodevelopmental changes (either of a compensatory or
maladaptive manner) may occur and hence the emergence of
later neurochemical alterations may stem from these
secondary factors, as opposed to the direct effects of the
gene manipulation. Furthermore, it seems that the back-
ground strain upon which a knockout is superimposed may
profoundly influence the behavioral outcomes observed
(Holmes et al., 2003b). Given that polygenic effects (and
background emotionality) might underlie a given phenotype,
any effects related to a given genetype, as in the case of the 5-
HTT knockout, can be expected to vary with background
conditions.
Commensurate with the proposition that depression is not
subserved by a single neurotransmitter dysfunction, it has been
reported that among 5-HTT knockouts chronic stressor
exposure provoked the desensitization of 5-HT1A receptors,
whereas among glucocortioid receptor knockouts the chronic
stressor did not impair 5-HT1A functioning (Lanfumey et al.,
2000). Moreover, it was observed that in contrast to wild-type
mice that exhibited reduced glucocorticoid receptor (GR)
mRNA expression and binding, among GR knockouts a chronic
mild stressor increased hippocampal, cortical and dorsal raphe
GR mRNA and GR binding sites. Moreover, the desensitization
of 5-HT1A DRN functioning evident in wild-type mice was not
apparent in the knockouts (Froger et al., 2004). Thus, it seems
that genes for 5-HTT and glucocorticoid receptors may act
together to influence processes that might be related to
depression.
Gene–gene interactions have also been examined in studies
where the 5-HTT knockout was combined with either MAO-A,
5-HT1B or BDNF knockouts (Hammack et al., 2003). Among
double knockout mice deficient of 5-HTT and BDNF, the
elevation of ACTH in response to a stressor was especially
marked, and the presence of dendrites on hypothalamic and
hippocampal neurons was diminished (Ren-Patterson et al.,
2006). In such double knockouts, the effects of 5-HT on
anxiety-related behaviors were more profound in males than in
females. As females also did not exhibit the marked reduction
in the expression of TrkB receptors or that of DA, it was
suggested that estrogen might afford protection against the
TrkB receptor changes (Ren-Patterson et al., 2006). Of course,
in relation to depression, such findings beg the question of why
human females are more likely to become depressed relative to
males. It appears likely that other biological factors underlie the
illness, or that females are more likely to encounter stressors,
appraise stressors differently, utilize different coping styles, or
are influenced by any of a number of other psychosocial factors.
5.2. Serotonin correlates of depression: human studies
Although considerable data have implicated both NE and
DA alterations in mediating MDD, particular attention has
focused on the involvement of 5-HT processes (Millan, 2006).
To a considerable extent this stems from the well-documented
influence of 5-HT acting agents in managing depressive illness
(Millan, 2006; Pineyro and Blier, 1999). The newer generations
of compounds have considerably reduced side effects
associated with older antidepressant drugs, increasing their
tolerability and compliance to their use. However, other things
being equal, the efficacy of the treatments has not improved
substantially (Millan, 2006). A characteristic feature of
antidepressant pharmacotherapy is that a substantial lag occurs
before treatment efficacy is seen. Moreover, still only 60–65%
of patients respond favorably to a given drug, remission is often
incomplete, and illness recurrence exceeds 50% (e.g., Fava
et al., 2007; Millan, 2006). Clearly, the overall picture
regarding the effectiveness of current antidepressant medica-
tion has not been impressive. Thus, continued attention has
been devoted to the development of more efficacious treatment
strategies, and identification of biomarkers that may be
informative in the diagnosis and development of tailored
treatments that might be most effective.
Several approaches have been taken to identify the neuronal
processes associated with depressive disorders in humans.
These have involved pharmacological studies that influence
various neurotransmitter systems, imaging studies to assess
blood flow or receptor binding capacity, and analysis of
components of neurotransmitter families in postmortem
(suicide vs. control) brain samples. As well, studies have been
conducted to identify gene polymorphisms in major depression.
5.3. Serotonin variations in depression and among
depressed suicides
Numerous advances have been made in the identification of
processes that might subserve MDD, but identification of the
specific serotonergic factors associated with depression has, in
several respects, yielded equivocal results. Postmortem
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
analyses and imaging studies revealed morphological and
functional disturbances within specific aspects of the PFC (e.g.,
dorsomedial and orbital cortex) as part of a wider system of
neuronal processes that may contribute to the emergence of
MDD (Anguelova et al., 2003a,b; Drevets, 2000a,b, 2001;
Rajkowska, 2000a,b). However, as will be described shortly,
studies assessing brain neurochemical processes have not
uniformly supported a relationship between suicide/depression
and 5-HT functioning (Anguelova et al., 2003a,b; Lowther
et al., 1997; Meyer et al., 1999; Purselle and Nemeroff, 2003;
Rosel et al., 1997; Stockmeier, 2003).
Consistent with the involvement of 5-HT in depression,
several investigators reported that 5-HT2A receptors were
increased in the PFC of suicides relative to controls (Arora and
Meltzer, 1989; Faludi et al., 2000; Hrdina et al., 1993; Lemonde
et al., 2003; Mann et al., 1986; Stanley and Mann, 1983;
Turecki et al., 1999). Likewise, mRNA expression of 5-HT2A
receptors, as well as the protein itself, was elevated in the PFC
of teenaged suicides (Pandey et al., 2002). In contrast, other
studies failed to detect alterations in the expression of 5-HT2A
receptors between suicides and controls in different portions of
the PFC (Arranz et al., 1994; Cheetham et al., 1988; Crow et al.,
1984; Lowther et al., 1994; Owen et al., 1983, 1986; Rosel
et al., 2000; Stockmeier et al., 1997). Further, among depressed
patients that had attempted suicide, PET analysis indicated that
5-HT2A receptor functioning was unaffected (Meyer et al.,
1999). Finally, DNA microarray analyses did not reveal
molecular genetic differences within the dorsolateral and
ventral PFC of suicides and controls (Sibille et al., 2004).
The data derived from imaging studies have, unfortunately,
been equally confusing. Several studies indicated reduced
ligand binding in aspects of the PFC of depressed individuals
(Attar-Levy et al., 1999; Biver et al., 1997; Yatham et al., 2000),
whereas others indicated no differences in this respect (Meltzer
et al., 1999; Meyer et al., 1999, 2001a,b). In this regard, PET
analysis also indicated that with symptom remission associated
with paroxetine treatment, the density of 5-HT2A receptors
increased in the frontal cortex, an effect not evident among
treatment non-responders (Zanardi et al., 2001). It is significant,
as well, that Meyer et al. (2003) were able to discern increased
5-HT2A binding in the dorsolateral PFC among those patients
who scored highly on the dysfunctional attitudes scale. It was
suggested that this might have reflected elevated feelings of
pessimism and hopelessness, which may be a precursor to
suicidal ideation or intent. Of importance, such findings suggest
that 5-HT receptor variations might not be a reflection of
depression/suicide per se, but rather may be tied to
endophenotypes comprising the depressive syndrome.
Suicide was also associated with fewer 5-HT2A binding sites
within the hippocampus, as well as lower binding affinity
(Cheetham et al., 1988; Mintun et al., 2004; Rosel et al., 1998,
2000; Sheline et al., 2004), but once again, there have been
reports indicating that 5-HT2A was not altered in this region
(Gross-Isseroff et al., 1998; Lowther et al., 1994; Stockmeier
et al., 1997). Interestingly, however, inositol triphosphate (IP3),
a second messenger of 5-HT, was elevated in the hippocampus
of depressed suicides, suggesting that depression (or suicide)
11
was related to hypersensitivity of 5-HT2A receptors (Rosel
et al., 2004).
As in the case of the animal models described earlier, there has
been considerable focus on the potential involvement of 5-HT1A
(auto)receptors in the DRN of depressed patients and depressed
suicides as these raphe changes potentially influence forebrain 5-
HT availability. It was reported that 5-HT1A receptors were
reduced in the DRN (Stockmeier et al., 1998); however, such an
outcome was not evident in a study reported by Arango et al.
(2001), although a reduced volume of the DRN was found. In
subsequent studies, however, it was observed that differences
were apparent in the rostral and caudal portions of the dorsal
raphe, being elevated rostrally and diminished caudally (Boldrini
et al., 2007). In our own studies we observed that 5-HT1A
receptor mRNA expression was unaltered in the raphe, although
variations of this receptor subtype were detected in other brain
regions (Anisman et al., in press, 2007a,b).
Although elevated 5-HT1A receptor binding (Arango et al.,
1995) and mRNA expression (Escriba et al., 2004) was reported
in some aspects of the PFC and in the CA1 of the hippocampus,
most studies indicated reduced 5-HT1A binding (Drevets et al.,
1999, 2000, 2007; Lopez et al., 1998; Lowther et al., 1997;
Parsey et al., 2006a,b; Sargent et al., 2000; Stockmeier et al.,
1997), particularly in primary recurrent familial depression
(Drevets et al., 1999, 2007). However, analyses of tissues
obtained from suicides and controls indicated that when factors
such as age of subject, postmortem interval (from the time of
suicide), and the time of tissue storage were controlled, the 5-
HT1A differences between depressed suicides and controls were
not evident (Stockmeier, 2003; Stockmeier et al., 1997). To
complicate matters further, Drevets et al. (1999) reported a
decrease of 5-HT1A binding in bipolar patients, but a similar
effect was not apparent in unipolar major depressive patients,
unless a familial history of bipolar disorder existed. Moreover,
it was reported that the presence of elevated 5-HT1A binding
potential, coupled with the presence of a 5-HT1A C-1019G
polymorphism, predicted poorer treatment response to anti-
depressants (Parsey et al., 2006a,b). It is interesting, however,
that receptor binding differed between those patients who had
previously received antidepressant treatment and those who had
not (Parsey et al., 2006b). Overall, it seems that MDD was
associated with diminished 5-HT1A binding in PFC and
hippocampus, but these effects were influenced by genetic
factors, history of depression and drug treatment (see Drevets
et al., 2007). It is noteworthy that many of these studies did not
account for the individuals stressor history, which has been
shown to interact with certain genetic polymorphisms (e.g.,
Caspi et al., 2003).
Recent studies have implicated 5-HT1B receptor functioning
in MDD. In an animal model of depression, chronic stressors
reduced 5-HT1B binding (Lopez et al., 1997; Svenningsson and
Greengard, 2006), and the expression of 5-HT1B protein was
diminished in the brains of depressed individuals (Svennings-
son et al., 2006), as was mRNA coding for p11 (also known as
calpactin I light chain and S100A10), a protein involved in the
functional expression of 5-HT1B receptors. Interestingly, in p11
knockout mice, the behavioral profile observed was reminiscent
12 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
of that seen in human depression, supporting the link between
p11 and 5-HT1B. Our research in depressed suicides likewise
indicated that the 5-HT1B and p11 mRNA expression was
diminished among depressed suicides and this outcome was
fairly widespread, being evident in the frontopolar cortex,
orbital frontal cortex, hippocampus and amygdala (Anisman
et al., in press, 2007a,b).
Beyond frank changes of 5-HT receptor mRNA expression,
elevations of RNA editing was reported at specific sites of the
5HT2C receptor in depressed suicides. The editing involved the
conversion of adenosine to inositol, resulting in alterations of
the amino acid sequence. It was proposed that this influenced
the efficiency of G-protein coupling, and hence second
messenger signaling disturbances among the depressed
suicides. In line with this, it has been shown that the SSRI,
fluoxetine, reduced the frequency of editing, suggesting that
RNA editing is regulated by 5-HT activity (Gurevich et al.,
2002; Schmauss, 2003). At the same time, however, it was
reported that the reduced signaling associated with increased 5-
HT2C receptor protein levels in suicides was not paralleled by
differences of mRNA expression (Pandey et al., 2006).
It is particularly interesting that in highly stressor reactive
BALB/cByJ mice (who also show an inclination toward anxiety
and depressive-like behaviors; Anisman et al., 2007a) stressor
exposure increased 5-HT2C editing, hence increasing the
mRNA pool that encodes diminished receptor functioning
(Alfonso et al., 2005). It was further reported that following
infant maternal separation, increased adult signs of depressive-
like behaviors were apparent, coupled with increased editing of
5-HT2C pre-mRNA expression. In contrast, fluoxetine admi-
nistered during adolescence (but not in adulthood) antagonized
both the behavioral disturbances and the 5-HT2C editing.
Unlike the effects of the SSRI, raising these mice in an enriched
environment (following weaning) did not affect 5-HT2C
editing, but the behavioral disturbances were attenuated
(Bhansali et al., 2007). Inasmuch as the enriched environment
influenced the G alpha q subunit of the G-protein that couples to
5-HT2A/2C receptors, whereas fluoxetine did not have such
effects, these investigators suggested that second messenger
systems adjusted to the effects associated with persistent 5-
HT2C pre-mRNA editing, thereby accounting for the differ-
ential effects of the drug and experiential treatments. When
these data are considered in the context of the 5-HT2C editing
associated with suicide, two important issues become apparent.
First, early-life events may have their depressogenic effects
through actions on the 5-HT2C receptor, particularly given a
genetic disposition toward depressive-like states (recall that
these studies were conducted in the highly stress-reactive
BALB/c mouse). Moreover, despite the profound effects that
early life experiences are known to have, these effects are
reversible by antidepressants (and to some extent by environ-
mental enrichment) applied during later development. Essen-
tially, despite a genetic predisposition and early life stressful
experiences, the disposition toward depression is not necessa-
rily fixed.
In addition to the receptor changes, considerable interest has
focused on variations of 5-HTT in mediating depressive illness.
Once again, unanimity has not been reached concerning 5-HTT
changes in suicide brain. Several studies indicated that 5-HTT
ligand binding was not altered among suicides (Arango et al.,
2001; Bligh-Glover et al., 2000; Stockmeier et al., 1998),
although a marked reduction was evident with respect to the
number of neurons that expressed 5-HTT mRNA (Arango et al.,
2001). Although earlier studies with relatively poor ligands for
5-HTT had revealed mixed results, several studies using better
ligands (e.g., 3H-paroxetine and 3H-citalopram) revealed that 5-
HTT binding was, in fact, reduced in the PFC of depressed
suicides (Arango et al., 1995; Leake et al., 1991; Mann et al.,
2000). Likewise, during a major depressive episode, 5-HTT
binding was diminished in the amygdala and midbrain (Parsey
et al., 2006c) and in the brainstem (Malison et al., 1998).
Paralleling their findings of 5-HT1A receptor presence, Meyer
et al. (2004) reported that 5-HTT binding potential during the
course of a major depressive episode was elevated in various
brain regions (PFC, anterior cingulate, thalamus, caudate, and
putamen) among patients that displayed extremely negative
dysfunctional attitudes (it will be recalled that these attitudes
may be aligned with later suicidality). At this juncture, it is
uncertain how the latter findings might map onto the data
reported by Malison et al. (1998) and Parsey et al. (2006c), but
they do suggest that individual difference factors might be an
important element in defining whether 5-HTT alterations
accompany depressive state.
5.4. Genetic links between serotonin functioning and
depression
Attempts to define the genotypic links to depression have
become a major focus of research in depression. As several
reviews of this literature have been provided in recent years (e.g.,
Arango et al., 2003; Serretti et al., 2005), only a capsulated
review of this work is covered here. Briefly, depression was
associated with 5HT2A receptor and tryptophan hydroxylase
gene polymorphisms (Faludi et al., 2000), increased frequency of
the long (L) allele of the 5-HT transporter gene (Du et al., 1999),
and a polymorphism was similarly reported with respect to the 5-
HTT promotor region (Serretti et al., 2005). It is interesting that
although postmortem analyses indicated that 5-HTT binding was
lower in the orbital frontal cortex of suicides (and throughout the
PFC among those individuals that had a history of major
depressive disorder), the 5-HTT gene promotor polymorphism
(5-HTTLPR) was related to depression, but not suicide, and was
not related to 5-HTT binding (Arango et al., 2003; Mann et al.,
2000). In addition to the potential contribution of the 5-HTT
promoter, other candidate genes have been reported to be related
to depression. These have included those for tryptophan
hydroxylase and G-protein beta 3 (see Serretti et al., 2005).
As well, it was demonstrated that a repressor of the 5-HT1A
receptor gene promoter in raphe cells (nuclear deformed
epidermal auto-regulatory factor (DEAF 1))/suppression)
was rendered inactive by a promoter polymorphism. In effect,
this loss of repression of the 5-HT1A autoreceptor expression
potentially reduces 5-HT neurotransmission, hence predisposing
to depression and suicide (Lemonde et al., 2003).
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
It is widely believed that genetic factors alone may not be
sufficient to promote depression. Instead genetic contributions
might dispose individuals to depression, and expression of the
illness would most likely occur in the face of certain
environmental or experiential factors. Consistent with this view,
Caspi et al. (2003) reported that depressive symptoms, and the
incidence of depression and suicidality, were more frequent
among individuals with one or two copies of the short allele of the
5-HTT promoter relative to individuals that were homozygous
for the long allele. However, the expression of these depressive
symptoms was contingent on individuals having experienced
major stressful life events. It was subsequently demonstrated
(Kendler et al., 2005) that individuals with two short alleles for 5-
HTT exhibited greater depressive vulnerability than those with
one or two large alleles. These individuals appeared more
sensitive to the impact of relatively mild life stressors, which
might thus have promoted their increased depressive symptoms.
Furthermore, among individuals with the two short alleles,
tryptophan depletion was likely to promote depressive symp-
toms, irrespective of family history of depression (Neumeister
et al., 2002). In accordance with these findings, multimodal
magnetic resonance imaging revealed that carriers of the short
allele had tonically activated amygdala and hippocampal
functioning, but diminished reactivity to negative stimuli (Canli
et al., 2006). These investigators suggested that this would
translate as a chronic state of distress, characterized by
hypervigilance, threat, or rumination, hence disposing indivi-
duals to stress-related disorders. Findings such as these suggest
that despite the mixed results accrued from postmortem and
imaging studies, 5-HTT likely may act as an important factor in
depression, but more detailed analyses of gene  environment
interactions are necessary to fully appreciate the contribution of
both these processes in the evolution and maintenance of the
depressive phenotype.
Overall, it seems that although imaging and postmortem
analyses have provided considerable data concerning the
neuronal circuitry that may be associated with depression, the
inconsistencies that exist preclude definitive conclusions. In an
extensive and insightful review, Stockmeier (2003) was able to
accommodate some of these inconsistencies, based on among
other things, presence of antidepressants (or time of washout
periods) before PET analyses, differences in outcomes as a
function of life-time depression, and particular aspects of the
brain examined (e.g., different portions of the prefrontal
cortex). Moreover, if one considers that multiple neurotrans-
mitters may be associated with depression (and these may differ
to a certain extent in depressed suicides), it is possible that some
of the between-study inconsistencies reflect the complex
interactions that may occur between transmitter systems. The
very fact that patients present with varied symptom profiles,
and are amenable to different drug treatments, would seem to
provide prima facie evidence consistent with this proposition.
For instance, reports indicating that 5-HT receptor subtypes,
such as 5-HT2A and 5-HT2C, may be relevant to anxiety (Merali
et al., 2006a; Millan, 2005; Weisstaub et al., 2006) raise the
possibility that the observed 5-HT receptor changes are actually
a reflection of anxiety that is often a comorbid feature of major
13
depressive disorder. Finally, the data indicative of interactions
between genetic factors (e.g., those related to 5-HTT variations,
for instance) and stressful experiences, and the data indicating
the 5-HT receptor changes associated with suicide may be most
apparent given particular behavioral features attest to the
importance of evaluating the neurochemical substrates of MDD
in a broad context.
6. Corticotropin releasing hormone (CRH)
Corticotropin releasing hormone, a primary regulator of the
HPA system, is released at hypothalamic and amygdaloid sites
in response to stressors (Herman and Cullinan, 1997; Owens
et al., 1990). The transcription of CRH genes within the
parvocellular portion of the hypothalamus may be regulated
through NE processes, whereas arginine vasopressin (AVP)
transcription, a second hypothalamic peptide, was seemingly
less affected by the same NE manipulations (Cole and
Sawchenko, 2002; Itoi et al., 1999). As well, it seems that
other peptides, such as bombesin, may stimulate CRH release
(Kent et al., 2001a,b) and GABAA has an inhibitory effect in
this regard (Cole and Sawchenko, 2002).
6.1. Stressor-induced CRH functioning: animal studies
Ordinarily, acute stressors promote the release of PVN
peptides (CRH and AVP), thus promoting ACTH and adrenal
glucocorticoid secretion (Lightman, 1994; Lightman et al.,
2000; Plotsky, 1991; Rivier and Vale, 1985; Windle et al.,
1998). These effects were associated with increased anxiety and
the initial HPA response was generally not influenced by
stressor controllability. Essentially, when an animal is first
confronted by a novel stressor, it is uncertain whether this
stressor will be brief or prolonged, controllable or uncontrol-
lable, and predictable or unpredictable. Thus, it would be
biologically advantageous to mount a strong defensive response
to maintain well-being. As information is acquired about the
stressor (e.g., its controllability), then it might be appropriate
for neuroendocrine responses to taper off. Thus, it is not
surprising that fast acting neuroendocrine factors would not be
markedly influenced by stressor controllability, although one
might imagine that with sustained stressor experiences,
differences between the HPA effects of controllable and
uncontrollable stressors would emerge.
In addition to the variations of hypothalamic CRH that
accompany acute stressors, such treatments increase CRH
mRNA expression and increase in vivo CRH release at the
central amygdala (CeA) (Davis, 1992; Lee and Davis, 1997;
Makino et al., 1999; Merali et al., 1998; Pich et al., 1995),
possibly through actions of 5-HT and NE processes (Pacak
et al., 1995a,b; Stutzmann et al., 1998). It is interesting that
unlike the suppression of hypothalamic CRH release elicited by
cortisol, in limbic regions, and specifically at the CeA and bed
nucleus of the stria terminalis, cortisol acts to increase CRH
expression, as well as GABAA neuronal functioning, that may
act to provoke anxiety (Duvarci and Pare, 2007; Schulkin,
2006; Schulkin et al., 1998; Shepard et al., 2005).
14 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Fear-eliciting stimuli markedly increase CRH expression
within the CeA and the basolateral amygdala (BSA) (LeDoux,
2000), which may be fundamental for the acquisition (rather
than the expression) of a fear response (Davis, 1992; Gray,
1990; LaBar et al., 1998; LeDoux, 2000). In contrast, diffuse
stimuli that promote general anxiety elicit greater CRH
variations at the bed nucleus of the stria terminalis (BNST)
(Davis, 1992). As well, it appeared that variations of in vivo
CRH release at the CeA, and the effectiveness of CRH
antagonists in attenuating anxiety, were dependent on the
nature of the stressor to which animals were exposed (Merali
et al., 1998, 2004a,b). As alluded to earlier, although a variety
of stressors provoked CRH release from amygdala neurons,
anxiety elicited by naturalistic stressors (e.g., predators), which
were proposed to involve pre-wired neural circuits, was not
altered by manipulations (CRH antagonists) that ordinarily
attenuate the response to neurogenic stressors or learned fear
cues. Further, although psychogenic and systemic stressors
have many similar effects, their actions on amygdala
functioning are not identical. Whereas systemic stressors
markedly impacted CeA activity, psychogenic stressors had
more potent effects on the medial amygdala, which may
influence HPA activity (Dayas et al., 1999, 2001a,b).
6.2. CRH and CRH receptors
Consistent with the assumption that specific CRH receptors
contribute to anxiety and depression, it was reported that in
chronically stressed animals, a condition that may be more
similar to the sustained distress of severe depression, a decrease
of CRH1 receptor expression was provoked within the PFC
(Iredale et al., 1996). Predictably, administration of the CRH
antagonist CP-154,526 attenuated the behavioral disturbance
associated with uncontrollable shock (in a learned helplessness
paradigm) (Mansbach et al., 1997). Moreover, studies of
genetically engineered mice with elevated or reduced CRH
receptors revealed, for the most part, predictable alterations of
anxiety and depressive-like behavior (Keck and Muller, 2005),
and have implicated glucocorticoid receptor (GR) signaling and
stressor responses in the emergence of depressive symptoms
(Keck and Muller, 2005). In general, mice that overproduced
CRH had higher levels of anxiety, which appeared to be
dependent on the specific behavioral test used (van Gaalen
et al., 2002a,b). Predictably, in CRH1 receptor knockout mice,
anxiety levels were diminished (Contarino et al., 1999; Smith
et al., 1998; Timpl et al., 1998) depending on the basal levels of
emotionality ordinarily apparent (Keck et al., 2001). Further-
more, among conditional knockout mice (Crhr1(loxP/loxP)-
Camk2a-cre), in which CRH1 receptors were inactivated
postnatally in the anterior forebrain and in limbic brain regions
(while leaving pituitary receptors unaffected), anxiety-like
behaviors were reduced. Conversely, among mice with elevated
CRH1 receptors, hypersensitivity to stressors was apparent
(Muller et al., 2003). Thus, it would seem that the gene
subserving this receptor subtype in limbic forebrain regions
may be pertinent to the development of anxiety states.
However, in relating such findings to human pathology, it is
necessary to consider state and trait anxiety, as well as subtypes
of anxiety disorders. Furthermore, anxiety may be tied to
significant stimuli or may be stimulus-independent. It is
certainly possible that mechanisms other than, or in addition to,
CRH functioning may contribute to these different phenotypes.
Less information is available concerning the involvement of
CRH2 receptor functioning in anxiety, although interest in this
receptor subtype has been increasing (Takahashi, 2002). Initial
studies had indicated that the contribution of CRH2 was limited,
as mice engineered for a deficiency of urocortin expression (a
peptide that acts as the endogenous ligand for CRH2 receptors)
did not display altered stressor-provoked anxiety (Wang and
Shuaib, 2002). In contrast, however, if the CRH2 receptor was
expressly knocked out, elevated anxiety-like behaviors were
apparent (Bale et al., 2000; Kishimoto et al., 2000), but this
effect was most notable among males (Bale and Vale, 2003;
Bale et al., 2002).
Given the independent effects of the CRH1 and CRH2
manipulations, Preil et al. (2001) assessed corticosterone and
ACTH under basal conditions and in response to social defeat
among double and single knockouts of the CRH1 and CRH2
genes. Overall, these studies indicated that in both the CRH1
knockouts and the double knockouts the corticosterone and
ACTH responses were abrogated, and having the presence of
the CRH2 did not compensate for the absence of the CRH1
gene, attesting to the primacy of the type 1 receptor. Yet, it was
observed that among the female CRH1 knockouts, a modest
corticosterone rise was apparent following stressor exposure,
which was not apparent in males. Further to this point, among
double mutants (combined CRH1 and CRH2 knockouts),
females displayed reduced anxiety, whereas males exhibited
higher levels of anxiety. Moreover, consistent with reports
suggesting a moderating role for experiential factors in
determining anxiety responses, the effects of the double
knockout varied as a function of maternal factors (Bale et al.,
2002). That is, elevated anxiety was apparent among CRH2
knockouts raised by a similar dam. However, if a pup was born
to a heterozygous or mutant dam, then greater anxiety was
evident regardless of the pup’s genotype (Bale et al., 2002).
Thus, it seems that both CRH1 and CRH2 receptors may
influence anxiety; however, early experiences, and particularly
maternal factors (related to either pre- or post-natal events)
appear to moderate the actions of the gene on anxiety behaviors.
6.3. CRH in depression/suicide
It has long been known that HPA functioning is altered
among major depressive patients, especially those with
melancholic features. Among other things, MDD has been
associated with elevated cortisol, early escape from dexa-
methasone-induced cortisol suppression, and a blunted ACTH
response to CRH or dexamethasone/CRH challenge (Heuser
et al., 1994; Nemeroff, 1996; Nemeroff and Vale, 2005). As
well, in suicides that had been diagnosed with recurrent
depressive episodes, MR mRNA expression was diminished in
the CA3 portion of the hippocampus, relative to controls
(Lopez et al., 1998). Although it had initially been thought that
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
cortisol changes might simply be a marker of distress or
depression, the view that it plays a provocative role in this
regard has received increasing attention. Indeed, several studies
indicated that GR antagonists diminished the symptoms of
depression (Belanoff et al., 2001; Gold et al., 2002; Murphy,
1997), as did treatments that inhibit cortisol production
(Murphy, 1997). Moreover, patients treated with glucocorti-
coids frequently experience pronounced mood disturbances
(Mitchell and O’Keane, 1998). It is significant, as well, that
among probands of patients with major depression, HPA
abnormalities were present prior to the presentation of clinical
symptoms (Holsboer, 2000).
The perspective that HPA dysfunctions are not simply a
consequence of depression/stress or bystanders of the illness,
but are aetiologically significant, has gained appreciable
support. At the same time, studies showing that corticoid
inhibitors diminish symptoms of depression are inconsistent
with the perspective that hypothalamic CRH elevations are
responsible for the depressive state (that is, corticoid inhibition,
through attenuation of the negative feedback ought to promote
elevated CRH and provoke greater symptoms). Nevertheless, it
has been suggested that the balance between GR and
mineralocorticoid (MR) receptors may be a pivotal factor in
determining stress reactions and depressive outcomes (de
Kloet, 2003; Hasler et al., 2004). Specifically, it is thought that
several rapid acting processes (catecholamines, CRH/AVP,
neurosteroids and corticosterone) are engaged in response to
stressors. The rapid initiation of corticosterone influences MRs,
which may affect defense-related behaviors, including vigi-
lance, alertness, arousal, and attention. This is followed by
slower changes involving GRs, which have the effect of
normalizing steroid levels (promoting homeostasis) and in
information storage (or sensitization of neuronal processes)
concerning potential stressors (de Kloet et al., 2005). Further,
there is reason to believe that MR activity influences the
functioning of CRH1 receptors (de Kloet, 2003) and may be an
essential component of 5-HT1A down-regulation associated
with chronic stressor exposure (Kuroda et al., 1994), whereas 5-
HT2A up-regulation induced by a stressor involves GR
functioning (Karten et al., 1999). Given the relationship
between CRH and monoamine functioning (Ruggiero et al.,
1991), these findings are consistent with the view that
depression involves the disruption of the interface between
CRH and 5-HT circuits (Claes, 2004; Price and Lucki, 2001). In
effect, through such cascading processes, CRH activity may
come to promote or exacerbate depressive symptoms.
It has been suggested that CRH may regulate a subpopula-
tion of raphe neurons, hence influencing PFC 5-HT release
(Kirby et al., 2000; Valentino et al., 2001). Just as CRH
administered to the DRN influenced forebrain 5-HT release
(Price and Lucki, 2001), chronic treatment with the CRH1
antagonist, NBI 30775 (also known as R121919), which has
antidepressant actions, influenced hippocampal 5-HT function-
ing (Oshima et al., 2003). Administration of a CRH2 antagonist
into the DRN also attenuated the effects of inescapable shock
(Hammack et al., 2002, 2003), hence implicating forebrain 5-
HT involvement in mediating the depressogenic actions of
15
CRH. However, it seemed that unlike the linkage between CRH
and 5-HT, mixed CRH1/CRH2 antagonists did not modify the
acute or chronic stressor effects on NE and DA activity within
the PFC (Murphy et al., 2003).
Consistent with the view that CRH may be related to
depression, CRH concentrations in cerebrospinal fluid (CSF)
were elevated among depressed patients (Arato et al., 1989;
Arborelius et al., 1999; Arranz et al., 1992; Heuser et al., 1998;
Nemeroff et al., 1984; Wong et al., 2000), which normalized
with pharmacotherapy or electroconvulsive therapy (De Bellis
et al., 1993; Heuser et al., 1998; Kling et al., 1994; Nemeroff
et al., 1991). Although there have also been reports indicating a
failure to detect elevated CRH within CSF (Kling et al., 1991;
Pitts et al., 1995; Roy et al., 1987), it seems that CRH CSF
levels were elevated in those patients who were dexamethasone
non-suppressors (Roy et al., 1987).
Increasing evidence has suggested that CRH hyper-
functioning within hypothalamic and extra-hypothalamic sites
(locus coeruleus, amygdala, hippocampus, nucleus accum-
bens, PFC) is associated with depression, at least that of a
relatively severe (melancholic) nature, or in which an
abnormal dexamethasone response was evident (Holsboer,
2003; Nemeroff, 1996; Reul and Holsboer, 2002). Although
CRH is widely distributed within the brain, the data concerning
concentration of this peptide or its receptors among depressed
patients is still limited. Nevertheless, it was reported that CRH
mRNA expression and/or CRH immunoreactivity was
increased in hypothalamic nuclei, locus coeruleus, PFC and
raphe nuclei of depressed suicides (Austin et al., 2003; Bissette
et al., 2003; Merali et al., 2004b; Raadsheer et al., 1994, 1995)
as was CRH mRNA expression in the PVN (Raadsheer et al.,
1995).
Despite the widespread assumption that disturbances of
frontal cortical processes may be involved in depressive
illnesses, data concerning CRH-related changes within this
region have been sparse and inconsistent. Whereas Nemeroff
et al. (1988) found reduced CRH-binding sites within the
frontal cortex of depressed suicides, neither Hucks et al. (1997)
nor Leake et al. (1990) observed such effects. Our own findings,
however, indicated that CRH levels and receptor mRNA
expression were altered in selective aspects of the frontal cortex
(Merali et al., 2004b). The CRH levels were elevated in the
right frontopolar (FPC) and dorsomedial prefrontal cortex (only
tissue from the right side was assessed) among suicides, and
mRNA expression of CRH1, but not CRH2, was reduced in the
FPC. Inasmuch as CRH1 desensitization develops upon
exposure to physiological concentrations of CRH (Aguilera
et al., 2001), and reduced CRH1 expression occurs after several
hours of exposing anterior pituitary cells to CRH (Pozzoli et al.,
1996), it is possible that the diminished receptor expression in
suicide brains reflected an outcome secondary to a sustained
increase of CRH activity. Thus, these data support the
involvement of CRH1 receptor in depression/suicide, although
it is certainly possible that that the CRH1 receptor variations
were related to the perceived stress that promoted depression
(or the stress associated with depression), rather than being
directly related to the affective state.
16 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
6.4. CRH has multiple actions
Clearly, multiple neurochemical changes are engendered by
stressors, which might ultimately promote depressive symptoms.
Although CRH might be an especially important factor, it is
likely that CRH activation represents only one component in a
sequence of changes that determine behavioral outcomes. It
appears that hippocampal 5-HT release induced by a stressor
involves a CRH receptor-dependent mechanism (Linthorst et al.,
2002). In fact, protracted intracerebroventricular CRH infusion
blunted hippocampal 5-HT release ordinarily elicited by LPS
(Linthorst et al., 1997). Likewise, paralleling the effects of
stressors, it was shown that CRH infusion increased locus
coeruleus NE neuronal activity, and conversely, CRH antagonists
attenuated such effects (Emoto et al., 1993a,b,c; Finlay et al.,
1997; Li et al., 1998; Shimizu et al., 1994; Valentino et al., 2001).
Moreover, as indicated earlier, in addition to attenuating stressor-
provoked ACTH and corticosterone increases (Ohata et al.,
2002), CRH antagonists also reduced in vivo hippocampal 5-HT
release (Linthorst et al., 2002). Further to this point, among mice
that overproduce CRH, pharmacological challenges provoked
the desensitization of post-synaptic, but not pre-synaptic, 5-
HT1A receptors (van Gaalen et al., 2002a,b), and it was similarly
reported that HPA functioning and forebrain 5-HT release were
altered in CRH1 knockouts (Penalva et al., 2002). There has been
limited work concerning the involvement of specific types of
CRH receptors in provoking 5-HT variations, but it has been
reported that DRN infusion of CRH or the CRH2 agonist
urocortin 2 increased 5-HT release at the basolateral amygdala,
and these effects were attenuated by selective CRH1 or CRH2
antagonists (Amat et al., 2004).
Several further issues ought to be introduced before ending
this section. First, the fact that clinical depression occurs more
frequently in females than in males begs the question as to
whether females are more vulnerable to glucocorticoid
disturbances. This issue is somewhat removed from the gist
of the present review, and a detailed examination of this
essential issue is provided by Swaab et al. (2005). Suffice it at
this juncture that cross-talk occurs between the HPA and the
hypothalamic–pituitary–gonadal (HPG) axis; alterations of
corticoid activity influences HPG functioning, and conversely
estrogen activity will affect HPA functioning, including effects
on the CRH mRNA expression (Bao et al., 2007; Vamvako-
poulos and Chrousos, 1993). Moreover, estrogen is coexpressed
in approximately 40% of CRH neurons among depressed
patients (Bao et al., 2007). In fact, the suggestion was offered
that sex steroids might operate to program CRH functioning
(just as early life stressors might be effective in this respect;
Meaney, 2001) so that vulnerability to HPA disturbances, and
hence depression, would occur upon subsequent stressor
experiences (Bao et al., 2007; Swaab et al., 2005).
The second point concerns the fact that subtypes of depression
exist that may involve different neurochemical processes, just as
they may comprise distinct symptom profiles. For instance, in
contrast to the poor mood, anhedonia and neurovegetative
features of typical MDD, atypical depression comprises mood
reactivity, coupled with reversed neurovegetative symptoms
(hyperphagia, significant weight gain, hypersomnia), extreme
fatigue and persistent rejection sensitivity that is not restricted to
episodes of depression (Asnis et al., 1995; Quitkin et al., 1991;
Stewart et al., 1993). In atypical, unlike typical MDD, HPA
activity may be diminished as reflected by reduced CRH in CSF
(Geracioti et al., 1997) and lower plasma ACTH (Gold and
Chrousos, 2002). Furthermore, it seems that elevated CRH may
be less prominent in atypical than in typical major depression
(Nemeroff, 1996), and desipramine-elicited plasma cortisol
secretion was greater in atypical patients, suggesting a less
dysfunctional noradrenergic system (Asnis et al., 1995; McGinn
et al., 1996). From the treatment perspective, it was reported that
atypical patients, and particularly females (Davidson and Pelton,
1986), responded preferentially to monoamine oxidase inhibitor
(MAOIs) relative to tricyclic agents (Quitkin et al., 1988;
McGrath et al., 1992; Thase et al., 1991). Such findings support
the importance of differentiating the features of depression
(endophenotyping) in evaluating the processes associated with
illness, and also have implications for the efficacy of treatment
strategies.
Finally, although CRH is usually considered in the context of
stressful encounters, it is clear that this peptide is also released
in response to spontaneous food ingestion (Merali et al., 1998,
2002b; Plamondon and Merali, 1994, 1998; Plamondon et al.,
1998). Indeed, both appetitive and rewarding stimuli can
activate the HPA axis, although it is uncertain whether such an
outcome reflects a response to arousal and/or anxiety or
whether food ingestion serves as a coping response to stressful
experiences (Dallman et al., 2003; Piazza and Le Moal, 1997).
Consistent with the dual effects of CRH in both anxiety and
appetitive processes, central CRH administration provokes both
anxiogenic behaviors and promotes suppression of food intake
(Heinrichs et al., 1992; Heinrichs and Richard, 1999; Hotta
et al., 1999; Momose et al., 1999). Conversely, pretreatment
with a CRH antagonist (e.g., a-helical CRH) attenuated the
anorexia induced by a stressor and also augmented
the hyperphagia induced by neuropeptide Y and reduced the
latency to initiate eating elicited by tail pinch (Heinrichs et al.,
1992). From an ethological perspective, the dual effects of CRH
(eliciting anxiety and inhibiting eating) are understandable, as
feeding is incompatible with defensive behaviors, and
suppression of appetitive behaviors would reflect a highly
adaptive response in the context of situations that represent
danger to the organism. In effect, it would be practically
important for systems subserving anxiety or stressor reactivity
to be linked, directly or indirectly, with those subserving
suppression of consummatory behavior. From this perspective,
it would be inappropriate to consider CRH to be exclusively an
anxiety/stress peptide. Instead, it may be that the function of
CRH, at least at certain brain sites, might be one of making
salient cues associated with motivational processes or increas-
ing the gain in response to aversive and/or rewarding stimuli.
7. Arginine vasopressin (AVP)
Parvocellular neurons of the PVN secrete AVP and CRH
from axon terminals located at the external zone of the median
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
eminence. Although AVP itself is a relatively weak secreta-
gogue of pituitary ACTH, it potentiates the effects of CRH in
promoting pituitary ACTH release (Antoni, 1993). As well,
magnocellular neurons in the PVN and supraoptic nucleus
project to the pituitary, releasing AVP into the blood in response
to osmotic stimuli (Swaab, 2004). Given the effect of AVP on
HPA functioning, the view was entertained that together with
other peptides, AVP might contribute to anxiety and depression,
and in modulation of the stress response (Landgraf, 2006).
7.1. Arginine vasopressin in relation to depression
Elevated plasma AVP concentrations have been noted in
melancholic patients (van Londen et al., 1997), as well as in
patients diagnosed with anxious-retarded depression (motiva-
tional inhibition) (Goekoop et al., 2006; de Winter et al., 2003).
Interestingly, anxiety and motivational inhibition were highly
correlated among patients with high plasma AVP levels, and
were elevated in suicidal depressed patients (Inder et al., 1997).
It has also been proposed that AVP may be important in
mediating the psychomotor retardation and in affecting
memory processes in depressed patients, possibly by altering
arousal and attention (van Londen et al., 1998a,b). Together,
these data support the contention that the inter-relationships
between subtypes of depression and HPA dysfunction may
involve an AVP component.
It is interesting that following a challenge with desmopressin
(an analog of vasopressin that stimulates the V3 receptor), the
ACTH and cortisol responses were appreciably greater in MDD
patients than in controls, suggesting that the V3 receptor was
more reactive in the depressed condition (Dinan et al., 2004).
Little information is available concerning molecular biological
aspects regarding AVP functioning in depression. Nevertheless,
it may be significant that the haplotype defined by A-T-C-A-G
for the AVP1b receptor was under-represented in depressed
relative to control patients, possibly indicating that this
haplotype ordinarily acts in a protective capacity insofar as
this pathology is concerned (van West et al., 2004).
In addition to peripheral AVP correlates of depression,
immunoreactive AVP and oxytocin (OXT) in the PVN of major
depressive and bipolar patients were elevated relative to
controls (although the investigators indicated that there was no
difference between uni- and bipolar individuals, the sample size
of each was likely insufficient to make adequate appraisals of
potential differences that might exist) (Purba et al., 1996). It
was similarly reported that AVP mRNA expression was
elevated in the supraoptic nucleus and PVN in a postmortem
analysis of depressed individuals relative to nondepressed
controls (Meynen et al., 2006). Importantly, the elevation was
only apparent in the six of nine suicides that had been classified
as being of the melancholic subtype. Paralleling these findings,
immunoreactive AVP was elevated in the PVN and locus
coeruleus of suicides. Moreover, although low levels of AVP
are generally found in frontal cortical areas, immunoreactive
AVP was elevated in the dorsomedial PFC (but not in the
frontopolar cortex), but was reduced in the dorsal vagal
complex (Merali et al., 2006b). It is interesting that within the
17
suprachiasmatic nucleus, a site of one the pacemakers for
circadian rhythms, the number of AVP immunoreactive
neurons was increased, but AVP mRNA expression was
reduced (Zhou et al., 2001). Thus, the circadian disturbances
frequently seen in depression may be related to AVP
dysfunction.
7.2. Arginine vasopressin and CRH synergy
The potential importance of AVP in subserving depression
comes from its synergistic actions with CRH, and the fact that
these peptides are highly co-localized within the hypothalamus.
Tilders and his associates (Bartanusz et al., 1993; Schmidt
et al., 1995, 1996; Tilders et al., 1993) indicated that
paraventricular neurosecretory neurons have the capacity for
phenotypic plasticity. In particular, the CRH containing
terminals in the external zone of the median eminence
(originating from the PVN) frequently exhibit AVP co-
expression. With the passage of time following a stressor
experience or in response to chronic stressor exposure,
increased co-storage of CRH and AVP occurs within CRH
terminals at this site (Bartanusz et al., 1993; Ma et al., 1999;
Tilders et al., 1993), and increased AVP mRNA expression in
the parvocellular portion of the PVN accompanied the elevated
co-expression (Bartanusz et al., 1993).
The shift in neuropeptide composition of CRH terminals in
the median eminence was not stressor-specific and similar
increases were reported after immobilization or social defeat
stressors (Bartanusz et al., 1993; de Goeij et al., 1991; Keeney
et al., 2006) and after adrenalectomy (Bertini and Kiss, 1991;
Sawchenko, 1987). This effect became progressively more
pronounced over time, peaking during the initial 2–4 weeks
after treatment (Schmidt et al., 1995). As CRH and AVP
synergistically stimulate ACTH secretion from the anterior
pituitary, it is significant that when these animals were later
exposed to a neurogenic stressor (footshock), plasma ACTH
and corticosterone release were augmented. It seems that
stressors increased the availability of secretagogues, such that
later challenges augmented glucocorticoid secretion. More-
over, the coexpression of these sectretagogues was long
lasting, thus favoring persistent sensitization to these
treatments.
It will be recalled that sensitization of neuronal processes
have been implicated as an important feature in promoting
depressive-like states. According to Post (1992), with each
stressor experience and with each successive episode of
depression, neuronal sensitization becomes more pronounced,
and hence the stressor severity necessary to elicit the
neurochemical changes (and hence the depressive episode)
becomes progressively smaller. From this perspective, it could
be argued that stressful events, by virtue of their effects on AVP
co-expression within CRH neurons, may increase vulnerability
to depressive episodes. Moreover, as even mild stressors may
ultimately come to provoke exaggerated ACTH and cortisol
release, the possibility exists that given a sufficiently sensitized
neurochemical system, even relatively innocuous stressor
experiences may promote depressive periods.
18 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Parenthetically, it has also been argued that chronic
depression (e.g., dysthymia) may be related to elevated levels
of AVP within CRH neurons, and likewise the high rates of
recurrence of depression may be related to the sensitization of
neuronal processes involving CRH/AVP co-expression (Grif-
fiths et al., 2000). It was suggested that in the case of dysthymia,
AVP was persistently increased within CRH neurons (essen-
tially reflecting a change of basal levels that occurs with a long-
standing illness), so that even minor day-to-day annoyances
would trigger excessive CRH/AVP release. This, in turn, would
favor the presentation of dysphoric symptoms, and might even
be a factor responsible for triggering double depression (i.e.,
where major depression is superimposed on a dysthymic state
and is typically more resistant to effective treatment) (Griffiths
et al., 2000).
8. Bombesin (neuromedin B and gastrin-releasing
peptide)
Bombesin (BB) is an amphibian peptide that is pharma-
cologically active in mammals (Battey and Wada, 1991), and
its mammalian analogues include the endogenous peptides,
neuromedin B (NMB) and gastrin-releasing peptide (GRP).
Whereas NMB binds preferentially to BB1 receptors, GRP
(GRP1–27) and neuromedin C (NMC (GRP18–27)) have a
greater affinity for BB2 receptors. Both GRP and NMB are
present in each of the major nodes of the HPA axis (Domin
et al., 1988; Houben et al., 1993; Minamino et al., 1984; Moody
and Merali, 2004) and have been identified within several
limbic regions (Merali et al., 2006b). These peptides and their
receptors are concentrated in brain regions associated with
stress and appetitive responses, including hypothalamic nuclei
(Battey and Wada, 1991; Ladenheim et al., 1992; Pinnock
et al., 1994; Wada et al., 1990), the nucleus of the solitary tract
(NTS), the BNST, several amygdaloid nuclei, and the
hippocampus (Chronwall et al., 1985; Moody et al., 1981;
Shumyatsky et al., 2002). In humans, NMB has also been
identified in several brain regions, being high in the dorsal
vagal complex, median eminence and locus coeruleus,
whereas the concentrations of GRP were most prominent in
the PVN, median eminence and frontopolar cortex (Merali
et al., 2006b).
A strong case has been made that bombesin-like peptides
contribute to the emergence of psychiatric and neurological
disorders (Roesler et al., 2006). These investigators indicated
that GRP and its receptor (GRPR) were altered in the CNS of
patients with schizophrenia and Parkinson’s disease, and
disturbed GRPR-induced cellular calcium signaling was
observed in fibroblasts from patients with Alzheimer’s disease.
Pharmacological and genetic studies in rodents have shown that
GRPRs are present in brain areas such as the dorsal
hippocampus and amygdala, which are likely involved in
anxiety, schizophrenia, depression, and dementia. Coupled
with animal studies supporting a role for GRP in modulating
behavioral changes and that stressors influence GRP function-
ing, these findings support the suggestion that the GRPR should
be considered a therapeutic target for a subset of CNS diseases.
8.1. Bombesin and CRH interactions
The bombesin (BB) family of peptides was initially
implicated in the mediation of peripheral satiety signals (Gibbs
et al., 1979; Kulkosky et al., 1982; Ladenheim et al., 1992;
Merali et al., 1999; Moody and Merali, 2004), but members of
this peptide family have since been shown to moderate the
stress response (Merali et al., 1998, 2002b), possibly through
their effects on CRH functioning. Importantly, just as BB-
related peptides are influenced by feeding behaviors, it has been
shown that stressors altered endogenous levels of hypothalamic
BB-related peptides and the density of BB binding sites at the
nucleus tractus solitarius, arcuate nucleus and PVN (Kent et al.,
1998). Moreover, in vivo analyses revealed that stressors
reliably elicited the release of BB-like peptides from the central
amygdala (Merali et al., 1998, 2004a). It is of significance that
administration of these peptides promote HPA activation
(Garrido et al., 1998; Kent et al., 2001a,b; Malendowicz et al.,
1995; Merali et al., 2002a, 2004a; Olsen et al., 1992), and the
variations of ACTH elicited by BB could be attenuated by the
CRH antagonist, a-helical CRH (Kent et al., 2001a,b). Thus, it
appears that BB-related peptides and CRH processes are
intertwined in the modulation of stress responses.
8.2. Bombesin and 5-HT interactions
It will be recalled that anxiety has been associated with
altered 5-HT functioning, and particularly 5-HT1A and/or 5-
HT2C receptor changes (Alves et al., 2004; Gordon and Hen,
2004; Lesch et al., 2003; Millan, 2005). It was argued that
bombesin-related peptides may, through their actions on 5-HT
and CRH, play a fundamental role in promoting anxiety (Merali
et al., 2006a). It was observed that in addition to the HPA
changes, NMB increased the firing rate of 5-HT cells in the
DRN (Pinnock and Woodruff, 1991), and, as expected, dorsal
raphe microinjection of NMB provoked the release of 5-HT at
the ventral hippocampus (terminal region). Conversely,
microinfusion of the BB1/BB2 antagonist caused a diminution
of extracellular 5-HT levels at this site (Merali et al., 2006a).
Thus, it seems that BB1 receptors (stimulated by NMB) are
located on the 5-HT cell bodies of neurons that project to the
ventral hippocampus. Localized infusion of the NMB
antagonist PD 176252 into the DRN attenuated anxiety in a
social interaction test, and provoked a marked reduction of 5-
HT release (60% of baseline release) from the ventral
hippocampus (Merali et al., 2006a). As the activity of forebrain
serotonergic neurons appear to be modulated by the BB1
receptor at the dorsal raphe, it is possible that anxiety/
depression may be associated with alterations in the functioning
of these receptors.
8.3. Bombesin and anxiety
It has been shown that BB-like peptides influenced anxiety
responses in several behavioral paradigms. By example, central
BB administration dose-dependently increased locomotor
activity in a familiar situation, but the same treatment provoked
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
a decline of exploration in a novel (presumably stressful)
context (Kent et al., 1998, 2001a,b; Itoh et al., 1994).
Conversely, antagonism of BB1 attenuated signs of anxiety
across a range of situations that included those that involved
conditioned fear (fear potentiated startle) as well as naturalistic
(unlearned) stressors, such as pup vocalization upon removal of
the dam, a social interaction test, and approach to a snack in a
novel environment (Merali et al., 2006a). Furthermore, bilateral
infusions of a GRP antagonist into the prelimbic cortex,
infralimbic cortex or CeA effectively reduced freezing in
response to both contextual or explicit cues that had been paired
with a neurogenic stressor (Mountney et al., 2006). Yet, it
seems that the effects of BB manipulations may be situation
specific, depending on the specific receptors activated or
blocked. It was reported that a NMB (BB1) receptor antagonist
elicited anxiolytic effects in the elevated plus maze, whereas
such an effect was not elicited by a GRP (BB2) antagonist.
However, in a fear potentiated startle paradigm, pretreatment
with either the BB1 receptor antagonist or a BB2 receptor
agonist attenuated the fear potentiated startle response, without
affecting basal startle amplitude. Thus, it seems that NMB
manipulations affected both anxiety and fear responses,
whereas GRP alterations selectively affected fear-related
responses (Bedard et al., 2007). In contrast to BB1 receptors,
it was reported that within the lateral amygdala, manipulation
of BB2 receptors influenced the acquisition and performance of
a conditioned fear response. Thus, there is reason to believe that
the BB2 receptor subtype might also contribute to anxiogenic
processes (Shumyatsky et al., 2002).
Consistent with the effects of pharmacological manipulations
of BB functioning, elevated 5-HT expression at the DRN was
reported in mice with targeted disruption of the BB1 receptor
gene. Moreover, the stressor-provoked 5-HT expression noted in
wild-type mice was not apparent in mice lacking the BB1
receptor (Yamano et al., 2002). These data suggest that these
receptors are important in fine-tuning subsets of 5-HT neurons. In
fact, 5-HT1A receptor gene expression was down-regulated in
BB1-deficient mice. Inasmuch as these mice also exhibited
increased indices of anxiety, particularly with respect to elevated
risk-assessment (reflected by higher frequencies of stretch attend
responses in anxiety provoking situations), these data implicate
bombesin in promoting anxiety (Yamada et al., 2002).
The use of BB manipulations within a clinical context has
received little attention, despite the fact that (a) pharmacolo-
gical treatments profoundly influence anxiety responses in
animal studies and (b) GRP-ir within the locus coeruleus of
suicides was higher than in controls, whereas NMB-ir was
reduced at the dorsal vagal complex (DVC) (Merali et al.,
2006b). It was suggested that BB receptors might turn out to be
a significant target for the treatment of anxiety disorders, and
perhaps for depression (Merali et al., 2006b). In this regard, as
GABAA subunits have been implicated in anxiety processes,
and inter-relations exist between GABA and 5-HT functioning
(Sibille et al., 2000), which might be moderated by CRH, it is
conceivable that BB manipulations might affect anxiety
through a cascade of actions that involve CRH, GABA and
5-HT functioning (see Section 10).
19
9. Leptin, feeding and stress
Leptin, a hormone primarily secreted from adipocytes, is
usually associated with appetite or energy regulation (Mal-
endowicz et al., 2007), likely involving the central actions of
this peptide (Banks, 2006). However, this hormone has also
been implicated in subserving symptoms of major depressive
disorder. Although many of the regulatory effects of leptin
involve hypothalamic nuclei, it seems that this hormone has
multiple effects beyond that of feeding and energy regulation.
Indeed leptin receptors are widely expressed within brain
regions, including the hippocampus, cortex and cerebellum,
which have not typically been linked to feeding or energy
regulation (Harvey, 2007).
9.1. Leptin and cytokines
There is impressive evidence suggesting that leptin
operates through IL-1b in modulating core body temperature
as well as feeding, although they may do so through different
processes (see Section 11 for a more detailed discussion of
cytokines and other inflammatory factors in relation to major
depressive disorder). In this regard, leptin may influence
appetite regulation through its neuronal actions, whereas the
effects on body temperature are subserved by COX-2 actions
involving endothelial cells (Harden et al., 2006; Inoue et al.,
2006; Luheshi et al., 1999). Specifically, administration of
leptin influenced hypothalamic IL-1b in rats, and concur-
rently diminished food intake and increased core body
temperature. Conversely, administration of the IL-1 antago-
nist (IL-1ra) attenuated the suppressed food intake ordinarily
associated with either peripheral or central leptin adminis-
tration (Luheshi et al., 1999). Further support for the IL-1b
involvement in the effects of leptin came from the
demonstration that mice lacking the Type 1 IL-1 receptor,
did not exhibit the reduction of food intake ordinarily
provoked by leptin (Luheshi et al., 1999). It seems, as well,
that microglia, a major source for brain cytokines, express
certain isoforms of leptin receptors, and that the release of
IL-1b likely occurs through a signal transducer and activator
of transcription 3 (STAT3)-dependent mechanism (Pinteaux
et al., 2007).
9.2. Leptin and reward processes
Leptin also interacts with processes other than cytokines in
moderating food intake. For instance, it has been shown that
prolactin treatment attenuated the effects of leptin on food
intake, possibly through STAT-3 changes (Naef and Woodside,
2007). Furthermore, intracerebroventricular infusion of leptin
diminished 5-HTT binding sites in the rat PFC (Charnay et al.,
2000), which coincides with changes thought to be associated
with MDD. Feeding processes have also been associated with
5-HT variations, and among obese ob/ob (leptin deficient) mice
that also exhibited a depressive-like behavioral profile, 5-HTT
mRNA expression was reduced within dorsal raphe neurons
(Collin et al., 2000).
20 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
It is of particular significance from the present perspective that
leptin administration may alter the rewarding value of otherwise
positive stimuli, as reflected by an increase in the reward
threshold (i.e., reduced value of the reward) among rats
responding for electrical stimulation from the lateral hypotha-
lamus (Fulton et al., 2004). Interestingly, this outcome was only
evident when the stimulating electrodes were present at sites
dorsal or dorsolateral to the fornix, but not in closely adjacent
regions (i.e., brain sites that did not support increased responding
for brain stimulation reward that ordinarily occurs from the
lateral hypothalamus among food deprived rats). It seems that
leptin may contribute to reward processes, and it is possible that
some of the appetitive behavioral changes exerted by leptin may
involve changes in motivation to perform (Fulton et al., 2000).
9.3. Relation to stress processes and depression
Like several other hormones, it seems that in addition to
being involved in regulation of feeding (and energy regulation),
leptin may also be influenced by stressors, and might thus be
involved in stress-related pathology. Specifically, stressors
increased serum and adipose leptin levels in rodents subjected
to the distress of water immersion (Konishi et al., 2006). It was
similarly observed that in female mice, a chronic (10 days)
restraint stressor regimen provoked an increase of hypotha-
lamic leptin levels. This same treatment, however, reduced
leptin levels in the thalamus of males and females (Manni et al.,
2007). The functional significance of these changes cannot be
deduced from this study; however, given that eating disorders
are more common in females than in males, the unique effects
of the treatment on hypothalamic leptin may turn out to be
functionally significant.
In light of the belief that stressors influence leptin
concentrations, and that leptin influences reward processes,
it has been suggested that leptin might also be associated with
major depressive illness, possibly subserving the neurovege-
tative features of depression (e.g., altered food intake and
weight change) (Lu et al., 2006). Studies in animals not only
demonstrated low leptin levels in association with stressor
exposure, but also that the depressive-like behavioral dis-
turbances introduced by a chronic stressor could be antagonized
by systemic or intrahippocampal (but not hypothalamic) leptin
administration (Lu et al., 2006). In fact, these investigators
suggested that leptin ought to be considered as a possible
therapeutic target for the treatment of depression.
Unfortunately, the data from human studies concerning
leptin variations in relation to depression have been incon-
sistent. Several investigators reported the expected low levels of
leptin in depressed patients (Jow et al., 2006; Kraus et al., 2001)
and in those who attempted suicide (Atmaca et al., 2002;
Westling et al., 2004), as well as potential changes of
glucocorticoid receptor sensitivity leading to leptin alterations
with successful treatment of depression (Himmerich et al.,
2007). As well, brain leptin mRNA levels were diminished in
suicides relative to controls (Eikelis et al., 2006). Furthermore,
in line with the view that leptin and cytokine variations may be
linked, it was reported that reduced leptin levels among
depressed patients were accompanied by elevated IL-6 and
TNF-a levels (Yang et al., 2007). In contrast to these findings,
however, other investigators reported either no differences of
leptin levels between controls and depressed patients (Deuschle
et al., 1996; Kauffman et al., 2005) or elevated levels of the
hormone (Antonijevic et al., 1998; Esel et al., 2005; Gecici
et al., 2005). Moreover, elevated perceived life stressors
(common in MDD patients) were associated with elevated
leptin levels (Otsuka et al., 2006). Still other reports indicated
that elevated serum leptin levels were associated with a lifetime
history of depression and that the levels predicted subsequent
development of a depressive disorder (Pasco et al., 2007).
9.4. Leptin involvement in atypical depression
Although these marked inconsistencies might, at first blush,
be disconcerting, they raise the question as to whether analyses
of a leptin–depression relationship would be better served by
assessing specific endophenotypes or at least to differentiate
between subtypes of depression. As already indicated, typical
and atypical depression are distinguishable from one another on
the basis of the vegetative symptoms that accompany illness.
Likewise, stressor experiences in some individuals are
accompanied by reduced eating, whereas in others these events
are accompanied by increased eating and especially carbohy-
drate craving. Dallman and her associates (Dallman et al., 2003;
Pecoraro et al., 2004) have provided an intriguing conceptua-
lization of how stressful events might come to produce these
effects, and as will be seen, although the focus of the model
deals with HPA functioning as well as glucocorticoid and CRH
variations at limbic sites, changes of cytokines and leptin might
also be relevant in this regard. According to Dallman,
chronically elevated levels of glucocorticoids (as described
earlier) have the effect of stimulating CRH release at the central
amygdala, thus instigating a stress-like cascade. As well, it was
suggested that glucocorticoids (or CRH variations) encourage
or make salient pleasure-related stimuli and compulsive
behaviors, including sucrose and fat consumption, thereby
motivating the consumption of ‘‘comfort foods.’’ The
consumption of these comfort foods, which promote abdominal
obesity, has the effect of inhibiting brainstem catecholamines
and hence limiting processes that lead to further CRH
variations, thereby diminishing anxiety. Given the relation
between leptin and CRH (and cytokine) and glucocorticoid
processes, it can be readily imagined that this peptide might
contribute to changes of ingestion associated with depressive
features in a subset of individuals.
In his insightful review, Black (2006) tied stress, various
hormones and neurotransmitters, cytokines, and free fatty acids
to several pathological conditions. This perspective, like that
advanced by Dallman, incorporates CRH changes into a model
that predicts variations of fat consumption and the development
of pathology. Essentially, it was suggested that stressors
stimulate NE release and hence NFkB activation in macro-
phages and visceral fat, ultimately resulting in the provocation
of an acute phase response. Visceral fat, from this perspective,
is a key player in this cascade, as cytokines (particularly IL-6
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
and TNF-a) as well as leptin, are released in response to
sympathetic signals. Significantly, stressors and inflammation
give rise to several hormone and enzyme changes (cortisol, IL-
6, angiotensin II, and 11b-hydroxysteroid dehydrogenase-1)
that might contribute to appetite stimulation and further fat
accumulation. In addition to these peripheral processes, leptin
released from fat cells come to stimulate hypothalamic CRH,
which then influences sympathetic and HPA functioning, and
may inhibit fat consumption. Moreover, by virtue of CRH
changes associated with this cascade, emotional changes can be
expected.
In view of the apparent linkage between leptin, food
consumption and depressive disorder, the proposition was
advanced that cytokines and leptin may be differentially
expressed in typical and atypical depression and may be
responsible for the symptom profiles expressed in these illness
subtypes (Andreasson et al., 2007). Commensurate with this
view, plasma leptin levels among patients with seasonal
affective disorder (characterized by hyperphagia with cravings
for carbohydrates and moderate weight gain) appeared to be
tied to seasonal changes (Cizza et al., 2005). Yet, it was also
observed that serum leptin levels were higher among patients
presenting with atypical depression than in those with typical
features (Gecici et al., 2005) contrary to the view advanced by
Andreasson. At this juncture there are simply too few published
studies to make definitive conclusions regarding the contribu-
tion of leptin to typical vs. atypical major depressive disorder.
Nevertheless, the views expressed by Dallman, Black and
Andreasson provide a framework that encourages further
analyses of the linkage between leptin and specific endophe-
notypes of these illnesses.
9.5. Ghrelin, food consumption and motivational processes
Unlike most peptides that have been implicated in feeding
through their actions on satiety processes, ghrelin, a relatively
recent addition to the group of peptides associated with food
ingestion, operates by stimulating food intake (Van der Lely
et al., 2004). Moreover, it was reported that the ghrelin receptor
growth hormone secretagogue 1 receptor (GHSR) is present
centrally, not only at hypothalamic sites involved in energy
metabolism but also within the ventral tegmentum, which it will
be recalled is fundamental in reward processes, and is sensitive
to stressor actions. Indeed, paralleling the increased food
consumption, ghrelin stimulated increased DA neuronal
activity at the ventral tegmentum and influenced DA turnover
at terminal sites within the nucleus accumbens (Abizaid et al.,
2006). Thus, it was suggested that beyond its other actions,
ghrelin might regulate feeding through its effects on
mesolimbic reward processes. Interestingly as well, it was
reported that intravenous ghrelin administration had the effect
of inhibiting cytokine production otherwise provoked by
endotoxin administration (Li et al., 2004a,b; Taub, 2007). In
addition, ghrelin also had anti-inflammatory effects through its
action on vagal afferents (Wu et al., 2007). In effect, the linkage
that exists between leptin and cytokines is also evident with
respect to ghrelin. Whether ghrelin and leptin variations are
21
coordinated, and whether these act together to influence
cytokine functioning, is uncertain. Nevertheless, as will be seen
in Section 11, cytokines have been implicated in depressive
illness, and as such the leptin–ghrelin connection to depression
warrants further consideration.
10. Gamma-aminobutyric acid (GABA)
Several lines of evidence have implicated GABAergic
processes in anxiety and depressive illness. These include the
demonstrations that (a) plasma and CSF GABA levels were
increased in stress and anxiety situations, (b) stressor exposure
influenced GABAA receptor functioning, (c) factors that
promote vulnerability to elevated anxiety and depressive-like
behaviors, such as early life stressors, also influence GABAA
g2 subunit expression, (d) GABAA acting agents influence
anxiety, (e) antidepressants influence interneuron functioning
(Akinci and Johnston, 1993; Brambilla et al., 2003; Caldji
et al., 2000, 2004; Krystal et al., 2002; Shiah and Yatham,
1998; Tunnicliff and Malatynska, 2003), and (f) marked
GABAA receptor subunit expression is disrupted in some brain
regions (e.g., frontopolar cortex) of suicide victims (Merali
et al., 2004a,b). The potential involvement of GABA in
mediating depression and anxiety was reinforced by findings
that reciprocal innervation might exist between GABAA and 5-
HT processes within brain regions that have been associated
with depression, such as the PFC and hippocampus (Brambilla
et al., 2003), and GABAA and DA activity appeared to
modulate amygdala functioning (Marowsky et al., 2005).
Likewise, estrogen and progesterone as well as the progester-
one metabolite, allopregnanolone, act on the GABAA receptor,
and may thus influence gender-based vulnerability to mood
states (Birzniece et al., 2006). Taken together, these findings
raise the possibility that treatments that target neuroactive
steroids and the GABAA receptor may be fruitful in the
treatment of depression.
10.1. GABAA variations associated with suicide/depression
Inconsistent results have been reported concerning GABA
variations in the brain of depressed suicides. It had been
reported that GABA levels within the PFC were inversely
related to severity of depression (Honig et al., 1988), but
subsequent studies indicated that neither GABA levels (Korpi
et al., 1988), GABA-related enzymes (Cheetham et al., 1988;
Sherif et al., 1991), the GABA transporter (Sundman-Eriksson
and Allard, 2002) nor GABAB binding in the frontal cortex
differed between drug-free depressed suicide victims and
controls (Arranz et al., 1992; Cross et al., 1988; Sundman et al.,
1997). Despite these negative findings, it is significant that
GABAA/BDZ (benzodiazepine) binding sites were elevated in
depressed suicides (Cheetham et al., 1988), indicating that
GABAA receptor subunit expression is likely changed. More-
over, whole genome analyses (using microarrays) have
indicated the presence of GABA-glutamate related genes in
depression and suicide (Sequeira and Turecki, 2006). In line
with this broad analysis, it was reported that the GABAA a1 and
22 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
a6 polymorphisms were associated with mood disorders in
female patients (Yamada et al., 2003a,b).
As the function/pharmacology of the GABAA receptor
complex is largely controlled by the expression of the a (a1, a2,
a3, a4, a5), d and g2 subunits, we assessed their expression and
inter-relations in control and suicide brains. In addition to CRH
receptor variations, mRNA expression of the a1, a3, a4, and d
receptor subunits were reduced in the frontopolar region of
suicide victims. It might be of significance that our partial
analysis of the GABAA receptor functional genome revealed
that within the frontopolar and dorsomedial prefrontal cortex
pronounced cross-correlations of GABAA subunit expression
was evident among nondepressed individuals, suggesting a high
degree of coordinated gene regulation. In contrast, the GABA
subunit intercorrelations were markedly diminished in suicide
brains (with the exception of the inter-relations between the a2,
a3 and a4 subunits). The frequency of significant relations, and
the specific profiles of these relations (in PFC regions) suggests
that the findings were not spurious (Merali et al., 2004b), and it
has, indeed, been reported that the expression of several
GABAA receptor subunits (a1, a2 a3, b2/b3, g2, d) within
dentate granule neurons also appeared to be coordinated (Benke
et al., 1997; Brooks-Kayal et al., 1999; Kern and Sieghart,
1994; Khan et al., 1996; Mertens et al., 1993). As the genes for
these subunits appear on different chromosomes, the subunit
coordination could not be attributed to factors related to shared
chromosomal localization (e.g., linkage effects; Brooks-Kayal
et al., 1999). These findings raise the possibility that the
GABAA receptor subunit changes, or the disturbed coordina-
tion between the GABAA receptor subunits, contribute to
depression/suicide or are secondary to the illness/distress
associated with it (Merali et al., 2004b).
10.2. GABA and CRH inter-relations
There is reason to believe that CRH and GABAA functioning
may be inter-related within hypothalamic processes as well as
in limbic neural circuits. Interestingly, in vitro application of the
GABAA antagonist bicuculline methiodide influenced AVP
mRNA, without affecting CRH expression (Bali and Kovacs,
2003), although in vivo, both CRH and AVP gene expression
were increased (Cole and Sawchenko, 2002). In line with the
supposition that GABAA may have functional influences on
CRH under stressor conditions, it was shown that the basal
expression of transcripts encoding several subunits of the
GABAA receptor were present within CRH neurons funda-
mental in the stress response (Cullinan, 2000; Cullinan and
Wolfe, 2000).
Beyond potential interactions between CRH and GABAA
within the hypothalamus, CRH is uniquely expressed in GAD
positive interneurons in rat cortex and chronic stressors can
affect GABAA receptor expression (Cullinan and Wolfe, 2000;
Yan et al., 1998). Likewise, GABAergic agents may affect CRH
mRNA expression within limbic sites (Cullinan and Wolfe,
2000; Gilmor et al., 2003; Skelton et al., 2000; Stout et al.,
2001). Given the important role for the PFC in subserving
various cognitive processes, including hedonia and behavioral
planning (Kalivas and Nakamura, 1999; Tanji and Hoshi,
2001), coupled with its influence on nucleus accumbens
functioning (a region that may be fundamental in the anhedonic
features of depression; Stevenson et al., 2003), the interactive
effects of GABAA and CRH neuronal activity may contribute to
aspects of depressive symptomatology.
10.3. GABA, CRH and 5-HT inter-relations
An interesting link between 5-HT and GABA receptors has
been reported, essentially indicating that 5HT1A receptors
regulate GABAA receptor expression (Sibille et al., 2000), and
indeed it appears that PFC 5-HT neuronal functioning plays a
prominent role in regulating GABAergic inhibitory transmis-
sion. Thus, it is significant that electrophysiological studies
indicated that 5-HT application induced a marked desensitiza-
tion of the amplitude and frequency of spontaneous inhibitory
postsynaptic currents (sIPSC) and also provoked a marked
reduction of electrically evoked IPSC (eIPSC). Further, chronic
(but not acute) SSRI treatment provoked the down-regulation of
the synaptic activity of forebrain 5-HT2 receptors (Zhong and
Yan, 2004). It is interesting, as well, that CRH treatment
prolonged the regulation of sIPSCs elicited by 5-HT in PFC
slices, and such an effect was also apparent in slices obtained
from previously stressed animals. Conversely, the effects of
CRH and of the stressor treatments were blocked by the CRH
antagonist a-helical CRH and by the CRH1 antagonist
astressin. Likewise, if phospholipase C or protein kinase C
(PKC) was inhibited, then the effects of CRH were also
antagonized (Tan et al., 2004). Taken together, it seems that
stressors and CRH (or CRH activation in response to stressors)
influence 5-HT regulation of GABA transmission, and PKC
may be fundamental in mediating this action. In view of the
fundamental role of GABAergic inhibitory transmission in PFC
functioning, it was suggested that chronic SSRI treatments may
ultimately have their therapeutic effects through actions on
GABA processes (Zhong and Yan, 2004). Yet, it has also been
reported that 5-HT1A knockout mice respond poorly to
benzodiazepine (BDZ) anxiolysis, an effect that was first
attributed to a loss of GABA binding sites, and specifically to a1
and a2 GABAA subunit reductions in the CA1 and dentate of
the hippocampus. This link between 5-HT receptor status and
GABAA receptor expression are consistent with the findings
that BDZ treatment when coupled with an antidepressant has
modest, albeit short-term, positive effects in treating depression
(Furukawa et al., 2002). However, given the limited actions of
such manipulations, it is unlikely that GABA functioning alone
accounts for depression, and other neurotransmitter processes
would have to be concomitantly altered for antidepressive
actions to become manifest.
In addition to 5-HT influences on GABAergic functioning
within limbic regions, the activity of 5-HT neurons within the
DRN appear to be regulated by GABAA and 5-HT1A inhibitory
receptors (Boothman et al., 2006; Cremers et al., 2007; Judge
et al., 2006). Given that raphe 5-HT1A autoreceptors influence
forebrain 5-HT release, it is likely that reciprocal influences
between GABA and 5-HT processes may affect mood states.
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
The inter-relations with GABAA functioning may also involve
other receptor subtypes, as 5-HT2C antagonists augmented the
acute effect of SSRIs on hippocampal 5-HT release, and this
effect was modifiable by GABA manipulations (Cremers et al.,
2007).
Just as CRH may influence both NE and 5-HT neuronal
activity, which could potentially impact upon depressive states
(Ruggiero et al., 1991), it is possible that CRH-GABA inter-
relations have such an effect. Indeed, based on studies using
dual immunoelectron microscopy to assess different types of
synaptic contacts, it was suggested that CRH has both direct
and indirect effects on DRN 5-HT neurons, and that GABA
might serve as an essential mediator by which CRH (and
possibly stressors) come to influence DRN 5-HT functioning
(Waselus et al., 2005). Alternatively, CRH variations may
instigate 5-HT receptor changes, which then influence frontal
cortical GABAA functioning (Tan et al., 2004). Of course,
further GABA-related interactions likely exist that could
influence depressive illnesses. For instance, it has been reported
that the progesterone metabolite allopregnanolone potentiated
the GABAA-mediated inhibition of DRN 5-HT neurons (Kaura
et al., 2007). Moreover, GABAA d subunit expression may be
influenced by progesterone, and the highly stressor-sensitive
neurosteroid 3 alpha,5 alpha-tetrahydrodeoxycorticosterone
(THDOC) (Reddy, 2003) might mediate this effect (Maguire
and Mody, 2007). As such, these data raise the possibility that
stressor effects on depressive symptoms, and the sex
differences that exist, may involve interactions between
GABAA subunits and THDOC and/or allopregnanolone.
11. Cytokines
The primary function of the inflammatory immune system is
that of protecting the individual from bacterial and viral insults.
Foreign particles ordinarily stimulate an orchestrated immune
response against specific antigens (foreign particles), and
immunological factors develop a memory for them. Thus, upon
subsequent encounters with these antigens, a rapid and robust
immune response is mounted. Immune cells (T and B
lymphocytes, macrophages as well as endothelial cells)
synthesize and secrete signaling molecules, referred to as
cytokines, which also elicit growth and differentiation of
lymphocytes. Thus, these cytokines are fundamental for the
organism to mount an effective immune response against
invading pathogens.
The list of polypeptides that comprise the rapidly increasing
family of immunotransmitters (cytokines) include the inter-
leukins (IL), tumor necrosis factors (TNF), interferons (IFN),
chemokines, and growth and cell stimulating factors (Rothwell,
1999; Elenkov et al., 2005). Classification of the cytokines has
been based upon their molecular structure, as well as common
physiological actions they possess, including the production of
fever (pyrogenicity) or inflammation (i.e. swelling and
irritation resulting from leukocyte (white blood cell) infiltra-
tion). IL-1b, TNF-a and IL-6 (all released from activated
macrophages) are potent proinflammatory cytokines, whereas
IL-4 and IL-10, which are released from T-cells, have anti-
23
inflammatory actions. As well, IL-1b and IFN-g are examples
of pyrogens, in that they provoke febrile responses, whereas IL-
2 is a non-pyrogenic cytokine. Interestingly, although TNF-a
and IL-6 are often referred to as pyrogens, under certain
conditions they may actually reduce the fever provoked by IL-
1b, thus acting in a cryogenic fashion (e.g., Long et al., 1992).
11.1. Cytokines as signaling molecules
Signaling involving IL-1b is dependent upon an interaction
between its type 1 receptor and the IL-1b receptor accessory
protein (Rothwell, 1999; Huang et al., 1997; Greenfeder et al.,
1995), both of which are found on the surface of numerous cell
types, including lymphocytes, macrophages/monocytes,
endothelium and even neurons and glial cells within the brain
(Mantovani et al., 1996; Vitkovic et al., 2000). A second IL-1
receptor, termed type II, acts as a ‘‘decoy receptor,’’ in that it
does not transduce a signal upon binding the cytokine (Colotta
et al., 1994). As well, there is an endogenous antagonistic
ligand, namely the IL-1b receptor antagonist (IL-1ra), which
competes with IL-1 for binding sites, in effect mopping up IL-
1b (Mantovani et al., 1996; Lucas et al., 2004). Essentially, the
actions of IL-1b are under tight regulation, involving a series of
different factors that comprise the IL-1 family. Ultimately,
activation of the IL-1b type 1 receptor initiates a cascade of
events culminating in the phosphorylation and consequent
degradation of the endogenous inhibitory factor kappa B (IkB),
resulting in the translocation of nuclear factor kappa B (NFkB)
to the nucleus where it promotes the expression of several genes
that play an important role in neuronal homeostasis and
inflammatory processes (Lucas et al., 2004).
Like IL-1b, IL-6 is typically secreted from a variety of
immune cells, particularly macrophages and T lymphocytes,
activated by antigenic challenge. Moreover, IL-6 and its
receptor are found on a variety of non-immune cells, including
fibroblasts, synoviocytes, adipocytes, osteoblasts, endothelial
cells, granulocytes, as well as microglia, astrocytes and even
neurons (Cichy et al., 1996; Helwig et al., 2007; Ringheim
et al., 1995; Rosell et al., 2003), indicating its importance in the
regulation of multiple physiological processes. The IL-6
receptor is an 80 kDa transmembrane glycoprotein, which
exists in a membrane bound form and may also be shed through
proteolysis to produce a 55 kDa soluble form (Mullberg et al.,
1994). Binding of IL-6 to its receptor results in a relatively low
affinity structure which requires subsequent recruitment of
glycoprotein-130 (gp130) to create a functional receptor
complex, thereby promoting a signaling cascade involving
the stimulation of various protein kinases (Taga, 1996).
Signaling through the IL-6 receptor-gp 130 complex primarily
involves activation of the Janus kinase (JAK)- signal and signal
transducer and transcription activator (STAT) pathway. Indeed,
activation of the IL-6 receptor complex triggers conformational
changes in the cytoplasmic domain of the receptor that results
in JAK aggregation and subsequent phosphorylation of various
STATs. Thereafter, nuclear translocation of STAT homo- or
heterodimers provokes the transcription of a number of immune
and CNS regulatory proteins (Murray, 2007).
24 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Interferons (IFNs) are broadly divided into either Type 1
IFNs, including the IFN-a and IFN-b isoforms, which
originated from a common ancestral gene, or the structurally
unrelated Type 2 form, IFN-g, which has many functional
actions in common with the aforementioned IFNs (De Maeyer
and De Meyer-Guignard, 1998). The a and b isoforms of IFN
bind to a 66 kDa receptor chain that is associated with several
accessory proteins (Maher et al., 2007). Likewise, a 90 kDa
receptor binds IFN-g; however, to be functionally active the
receptor requires the presence of an accessory protein (Farrar
et al., 1987). Like IL-6, the main signaling pathway utilized by
the IFNs is the JAK-STAT pathway, resulting in sequential
phosphorylation steps by intracellular protein kinases (Stark
et al., 1998; Maher et al., 2007). However, the Type 1
interferons can also stimulate phosphatidylinositol 3-kinase
(PI3K) and mitogen-activated protein kinase (MAPK) path-
ways, which may be responsible for their ability to interfere
with viral replication and promote the apoptotis of tumor and
other cells (Pokrovskaja et al., 2005).
Similar to the aforementioned cytokines, TNF-a is a
pleiotropic cytokine, having physiological actions upon mono-
nuclear and polymorphonuclear blood cells, fibroblasts, kera-
tinocytes, and insulin sensitive adipocytes, as well as brain
neurons and glial cells (Eigler et al., 1997). The major producers
of TNF-a are macrophages (and microglia in brain). TNF-a
receptors are often shed from the cell membrane and circulate
freely in a soluble form, binding any excess ligand (Rigby, 2007).
Endogenous antagonists for TNF-a, including a-melanocyte
stimulating hormone (a-MSH), which blocks the actions of
TNF-a after both central and peripheral administration, also
contribute to cytokine regulation (Rajora et al., 1997).
The actions of TNF-a are mediated by two distinct receptor
subtypes, which are termed p55 and p75, with molecular
weights of 55 and 75 kDa, respectively (Neta et al., 1992;
Dinarello, 1987). The p55 receptor is generally regarded as
playing an important role in apoptosis and cellular necrosis,
whereas the p75 receptor may be more important for nutritive
functions, such as the promotion of thymocyte proliferation
(Rigby, 2007). Although TNF-a shares several intracellular
signaling pathways with IL-1, it possesses a unique apoptotic
signaling mechanism involving a death domain region
intracellularly attached to its p55 receptor. Activation of this
death domain triggers the recruitment of caspases 1 and 8,
which may engender cytotoxic consequences (Ashkenazi and
Dixit, 1998). As well, activation of second messenger systems
may result in stimulation of phospholipase A2 and the
production of prostaglandins or leukotrines via an arachidonic
acid substrate (Woo et al., 2000). Many of the intracellular
actions of p55 may be counterbalanced by activation of the p75
receptor, which promotes stimulation of the transcription factor
NFkB and under certain circumstances may have inhibitory
effects on apoptosis (Rothe et al., 1994; Dopp et al., 2002).
11.2. Paracrine and autocrine actions of cytokines
Cytokines exert a range of effects on numerous cell types,
and thus may affect several physiological processes, such as
cellular proliferation, immune and inflammatory responses, and
behavioral states (e.g., those associated with sickness). Under
normal physiological conditions, systemic cytokines are
maintained at a low level, and they usually act in an autocrine
(local cellular actions in a feedback capacity) or paracrine (acts
upon cells in proximity of where they are produced) manner at
primary or secondary lymphoid organs, such as the spleen,
lymph nodes or liver (Alkharfy et al., 2000). Under homeostatic
conditions, cytokines rarely have actions on cells located some
distance away, and hence their endocrine actions are limited.
Typically, any cytokine spillover into the circulation is rapidly
diluted (Bocci, 1991). However, during severe immunological
challenge, such as septic shock, circulating levels of pro-
inflammatory cytokines are markedly increased (Damas et al.,
1997; Oberholzer et al., 2005). The elevated systemic cytokines
can provoke the liberation of acute phase proteins and
augmented utilization of steroidal hormones and central
monoamines (Raison et al., 2006). In effect, upon presentation
of a sufficient challenge, the role of cytokines may switch from
that of a locally acting paracrine or self-regulating autocrine to
that of an endocrine effector.
11.3. Cytokines influence CNS processes
Given that the blood brain barrier (BBB) is relatively
impermeable to cytokines, owing to their size and hydro-
philicity, the mechanism by which circulating cytokines
influence brain function is still a matter of debate. However,
cytokines may enter the brain through sites where the BBB is
somewhat compromised, namely at circumventricular organs
(median eminence, subfornical organ, area postrema, organum
vasculosum) (Goehler et al., 2006). As well, saturable transport
mechanisms capable of moving IL-1b and TNF-a may allow
for limited penetration of cytokines into the brain (Banks, 1999;
Banks et al., 1991; Gutierrez et al., 1993). In addition to routes
dependent upon the circulatory system, cytokines may also
influence brain processes by fibers projecting from the
periphery to the CNS. Indeed, IL-1b and TNF-a stimulate
visceral branches of the vagus nerve to modulate many
neuroendocrine and neurochemical states, and hence behavior
(Maier and Watkins, 1998; Wieczorek et al., 2005).
It is noteworthy that stressful events or certain immunologic
challenges may also compromise the integrity of the BBB,
thereby permitting greater cytokine action within the CNS. In
this regard, it has been proposed that CRH release promotes
brain mast cell activation, which in turn increases the release of
IL-6, IL-8 and vascular endothelial growth factor (Theoharides
and Konstantinidou, 2007; Esposito et al., 2001). Likewise,
pro-inflammatory cytokines themselves enhance permeability
of the BBB and hence up-regulate their own production at
vascular sites (de Vries et al., 1996; Saija et al., 1995).
Furthermore, it seems that chemokines (chemo-attractant
cytokines) may also disrupt BBB functioning, promoting the
formation of vasogenic brain edema that is associated with
various neuropathological conditions, including brain trauma,
ischemia, CNS infection, presence of brain tumors, and
recurrent MS flares (Stamatovic et al., 2006).
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Once cytokines gain entry to the brain, they interact with
receptors on cells lining the BBB, around the meninges as well
as vascular areas of the brain (Rivest et al., 2000). Through
volume diffusion, cytokines may ultimately reach nuclei deep
within the brain parenchyma, where they interact with
receptors located at hypothalamic, amygdaloid and brain
stem nuclei (Cunningham and De Souza, 1993; Kinouchi et al.,
1991; Konsman and Dantzer, 2001; Nadeau and Rivest, 1999;
Schobitz et al., 1994). In this respect, it seems that cytokines
may actually have several functions similar to those of
classical neurotransmitters by modulating neuronal Ca2+
channels, activation of intracellular second messenger
systems, and stimulation of the MAP kinase pathways
(Tancredi, 1992).
Induction of secondary mediators, such as prostaglandins,
may also be responsible for some of the central neurochemical
effects of cytokines. Evidence supporting this proposition
comes from studies showing that pretreatment with the
cyclooxygenase inhibitor indomethacin (inhibiting conversion
of arachidonic acid into prostaglandins) attenuated at least
some of the central actions of IL-1b, such as the altered NE
variations observed within the hypothalamus (Masana et al.,
1990).
Beyond their actions on CNS processes, cytokines and
their receptors are endogenously expressed in the brain
(Cunningham and De Souza, 1993; Buttini and Boddeke,
1995), likely reflecting de novo synthesis by glia and possibly
by neurons. Moreover, pro- and anti-inflammatory cytokine
levels are markedly increased by traumatic insults (Johnson
et al., 2006; Kamm et al., 2006; Zhu et al., 2006), endotoxin
treatments (Ledeboer et al., 2002; Rivest, 2001; Turrin et al.,
2001), and treatment with several inflammatory cytokines
(Churchill et al., 2006) as well as by neurogenic and
psychogenic stressors (Maier et al., 1999; Miyahara et al.,
2000; Nguyen et al., 1998; Zhu et al., 2006). In this regard,
endothelial cells that line the interior surface of blood vessels
and that of the ventricles produce IL-1b and IL-6, and their
concentrations are increased by infection or injury (Banks,
2001). Further, microglia, which serve as the brains
specialized immune cells, are primary cytokine producers,
and the synthesis of these cytokines were augmented by head
injury, stroke and by neurotoxins (Kamm et al., 2006; Sriram
et al., 2006; Zhu et al., 2006).
Cytokine–peptide interactions play an important role in
shaping both peripheral immunity, as well as neuroinflamma-
tory cascades within brain regions important for several
neurological and neuropsychiatric conditions. Indeed, most
centrally active peptides and cytokines also have co-existing
receptors present on peripheral immune cells, and may
influence immune functioning through activation of common
molecular signaling mechanisms. Moreover, immune cells
(e.g., T lymphocytes) produce and respond to DA and 5-HT
(Blalock, 1984, 1994; Cosentino et al., 2007). Thus, cytokines
and peptides may be viewed as messengers between the
immune system and the brain, and may either augment or
antagonize one another’s actions, depending upon the state of
their microenvironment.
25
11.4. Neurochemical effects of cytokines: implications for
depressive illness
Cytokine activation elicits several neurochemical and
behavioral responses reminiscent of those provoked by
stressors as well as those of depressive illness. As will be
discussed shortly, studies in animals revealed that pro-
inflammatory cytokines, like stressors, increased HPA func-
tioning, and influenced a range of monoaminergic and
peptidergic neurotransmitter changes at hypothalamic and
extra-hypothalamic sites (Anisman and Merali, 1999; Hayley
et al., 2004b; Kronfol and Remick, 2000). Paralleling these
effects, rodents treated with certain cytokines (or immune
activating agents) displayed a behavioral profile characteristic
of depressive-like states comparable to those elicited by
stressors (Anisman and Merali, 1999). Furthermore, humans
undergoing immunotherapy (e.g., using IFN-a) display
neurovegetative changes and pronounced depressive symp-
toms.
The mechanisms responsible for the cytokine-elicited
depressive features have yet to be identified, but several
possible candidate systems have been proposed. Pro-inflam-
matory cytokines influence central neurotransmitter and growth
factors that have been thought to be related to depression (e.g.,
CRH, 5-HT and BDNF), and also affect enzymatic pathways
involved in the production of oxidative species and other
neurodegenerative factors (Anisman and Merali, 1999;
Churchill et al., 2006; Ericsson et al., 1994; Hopkins and
Rothwell, 1995; Quan and Herkenham, 2002). However, in
considering the involvement of cytokines in depressive illness
there are several fundamentally important issues that need to be
emphasized from the start. Although about 50% of patients
treated with interferon-a (for certain cancers and hepatitis-C)
develop marked symptoms of depression (Capuron et al.,
2002a; Raison et al., 2006), rodents treated with this cytokine
(unlike IL-1b or TNF-a) exhibit few noticeable behavioral
changes, and certainly none that bring to mind depressive
features (Anisman et al., in press, 2007a,b). Reconciling the
disjunction between the effects seen in humans and those seen
in animals is possible by considering the broader context in
which IFN-a is administered. Specifically, patients receiving
immunotherapy are already under considerable strain given
their current disease state. As stressors and cytokines share
multiple similarities, it is not unreasonable to suppose that the
stressor background on which the treatment is applied would
moderate the effects of cytokines on neurochemical processes.
From this perspective, synergies between cytokines and
traditional stressors might increase the strain placed on
biologically adaptive processes, particularly when these occur
on a chronic basis, thus leading to allostatic overload, and hence
increased vulnerability to psychological disturbances.
11.5. Neurochemical consequences of IL-1b, IL-6 and
TNF-a
Given that systemic cytokine administration promotes a
cascade of neuroendocrine and brain neurochemical changes
26 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
reminiscent of those elicited by psychogenic and neurogenic
stressors, it has been suggested that the brain interprets
inflammatory immune activation, much as if these challenges
constituted stressors (Anisman and Merali, 1999; Dunn et al.,
1999; Herman and Cullinan, 1997; Herman et al., 2003). Of
course, the effects of cytokines and traditional stressors are not
identical (Buller et al., 2001). Moreover, when individuals are
exposed to neurogenic or psychogenic insults they engage in
the appraisal or processing of information related to the
stressor, leading to coping efforts to deal with the challenge
confronting them. Bacterial or viral infections certainly do not
promote comparable effects with respect to cognitive informa-
tion processing. Yet, this does not belie the possibility that
cytokine activation might result in appraisal or interpretive
processes being altered. Furthermore, as indicated earlier,
multiple neural pathways are excited in response to different
types of psychogenic stressors (Merali et al., 2004a; Morrow
et al., 2000), and it is likewise possible that cytokines and
stressors might induce their actions through different neural
circuits. It appears that in contrast to the HPA activation elicited
by psychogenic stressors that involve amygdala activation,
systemic stressors may do so through non-limbic circuits
(Buller and Day, 2002; Buller et al., 2001; Herman and
Cullinan, 1997).
It has been maintained that multidirectional communication
exists between the immune system and other systems within the
brain and periphery. There are, indeed, ample data indicating
that inflammatory immune activation (or administration of pro-
inflammatory cytokines), like processive stressors, increases
HPA activity as well as the utilization of 5-HT and NE within
the PVN, mPFC, and central amygdala (Anisman and Merali,
1999; Day et al., 1999; Hayley et al., 1999a, 2002b). In
addition, systemically or centrally administered IL-1b stimu-
lated in vivo hypothalamic and hippocampal NE, DA and 5-HT
release (Linthorst et al., 1995; Mohankumar and Quadri, 1993;
Zhang et al., 2001), as well as that of 5-HT at several limbic
sites (Linthorst et al., 1995; Merali et al., 1997; Shintani et al.,
1993, 1995; Song et al., 1999). Moreover, inhibition of IL-1b
attenuated the neurochemical consequences of an immobiliza-
tion stressor, suggesting a role for this cytokine in mediating the
central effects of the stressor (Shintani et al., 1995). More
recently, it was reported that the behavioral and neuroendocrine
effects of a chronic mild stressor was prevented among IL-1b
type 1 receptor knockout mice (Goshen et al., 2007). As well,
mice lacking the IL-1b receptor also failed to display the usual
reduction of neuroplasticity (hippocampal neurogenesis) that
was evident in wild-type mice that received this stressor
treatment (Goshen et al., 2007). In contrast, genetic ablation of
the TNF-a p55 receptor did not influence the HPA response
provoked by restraint or LPS, although, as predicted, the
corticoid elevation elicited by TNF-a was greatly attenuated
(Hayley et al., 2004b). Hence, there is reason to suppose that
selective IL-1b changes that foster the emergence depressive-
like consequences might occur following exposure to ceratin
stressors.
Most studies that assessed the influence of cytokines on
neurochemical and behavioral processes focused on the impact
of acute bolus treatments, and the data concerning the effects of
repeated or sustained cytokine administration are sparse. This is
somewhat puzzling, as inflammation, viral insults and cytokine
immunotherapy all involve persistent cytokine elevations.
Moreover, there is reason to believe that chronically increased
cytokine levels may engender more profound effects than acute
treatment, possibly owing to the potential for compromised
BBB functioning. As well, chronic cytokine elevations may
exert excessive strain on physiological systems, just as chronic
stressor exposure might have such an effect (McEwen, 2000).
In fact, sustained systemic or intracerebroventricular IL-1b
administration promoted persistent HPA activation, including
protracted variations of CRH, CRH receptor and proopiome-
lanocortin gene expression, as well as elevated secretion of
ACTH, beta-endorphin and corticosterone (Parsadaniantz et al.,
2000; van der Meer et al., 1996). Further, chronic central or
intravenous IL-1b treatment increased immediate early gene
expression in the PVN, CeA and supraoptic nucleus (Niimi
et al., 1997).
Beyond their independent effects on neurochemical pro-
cesses, certain cytokine combinations (e.g., IL-1b plus IL-6, or
IL-1b plus TNF-a) may synergistically increase the behavioral
and neuroendocrine alterations (Bluthe et al., 1994; Brebner
et al., 2000; van der Meer et al., 1995; Zhou et al., 1996).
Likewise, the combination of IL-1b and a stressor synergis-
tically increased the in vivo release of hippocampal 5-HT
(Lacosta et al., 1998; Merali et al., 1997; Song et al., 1999).
More recently, it was observed that the synergistic effects on
cortisol and central monoamine turnover were pronounced
when a cytokine (IFN-a), viral analogue (poly I:C) or bacterial
endotoxin treatment (lipopolysaccharide: LPS) was super-
imposed on a backdrop of psychosocial distress (Anisman et al.,
2007a; Gandhi et al., 2007; Gibb et al., 2005; Quan et al., 2003).
These findings are consistent with the perspective described
earlier, namely that in considering the potential neurochemical
or behavioral consequences of cytokine treatments in humans,
it is essential to consider the backdrop upon which these
treatments are superimposed.
In contrast to IL-1b and TNF-a, the central neurochemical
and behavioral effects of IFN-a (and IFN-g) have received
limited attention, despite the fact that this cytokine has been
used in clinical conditions, and as already indicated, it is known
to engender depression in treated patients. In vitro studies
demonstrated that IFN-a stimulated CRH release within the
amygdala and hypothalamus (Raber et al., 1997), and
administration of this cytokine provoked several in vivo brain
neurochemical and hormonal changes (Schaefer et al., 2003),
although the magnitude of the effects were considerably less
than those elicited by IL-1b. As the non-steroidal anti-
inflammatory (NSAID) diclofenac attenuated the HPA hormo-
nal effects, it is likely that the inflammatory cyclo-oxygenase
pathway (or other inflammatory factors) plays a pivotal role in
the elicitation of the HPA response to IFN-a.
In humans, acute IFN-a treatment in healthy volunteers and
in hepatitis patients increased ACTH, cortisol and circulating
IL-6, but did not appreciably influence other cytokines (Cassidy
et al., 2002; Shimizu et al., 1995). With repeated treatment,
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
however, the elevated HPA activity elicited by IFN-a (when
administered acutely) was no longer apparent (Gisslinger et al.,
1993). In rodents, however, a similar profile was not apparent. It
will be recalled that in contrast to the potent effects of IFN-a in
humans, the effects of this cytokine on circulating ACTH and
corticosterone is modest in rats and mice (Anisman et al., in
press, 2007a,b; Menzies et al., 1996). It was even reported that
neither 1 nor 5 days of treatment increased corticosterone levels
(De La Garza and Asnis, 2003). In contrast, Anisman et al. (in
press, 2007a,b) observed that IFN-a increased corticosterone
levels (although not to the extent that IL-1b had such effects),
and although the sickness associated with the cytokine
diminished over five successive days of treatment, the
corticosterone elevations were not reduced and, in fact, were
moderately increased relative to a single day of treatment
(Anisman et al., in press, 2007a,b).
The dose-related effects of IFN-a have not been thoroughly
examined with respect to most biological processes, including
brain functioning. However, it was reported that at low doses
IFN-a reduced corticosterone, but when administered directly
into brain it increased circulating corticosterone levels
(Saphier, 1995). Interestingly, in the latter studies IFN-a
inhibited the activity of PVN neurons that are fundamental for
HPA activation (Saphier, 1995).
Systemic IFN-a administration influences central neuro-
chemical functioning, but, once again, these effects were
modest compared to those evident following IL-1b adminis-
tration. By example, IFN-a treatment stimulated activity of the
amino acid transmitters GABA and glutamate within limbic
and hypothalamic regions (Yokoyama et al., 2005), modestly
increased hypothalamic and hippocampal NE utilization
(Anisman et al., in press, 2007a,b) and reduced DA
concentrations within the amygdala (Kitagami et al., 2003).
With repeated treatment, IFN-a diminished DA utilization
(Shuto et al., 1997) and 5-HT levels in PFC, increased 5-HT
turnover within the amygdala (De La Garza et al., 2005), and
also increased low-affinity 5-HT1A receptor sites (Abe et al.,
1999). In line with inflammatory involvement in depression,
IFN-a reduced 5-HT turnover in PFC, and the depressive
effects of the treatment were attenuated by pretreatment with an
NSAID (Asnis et al., 2003; De La Garza et al., 2005).
When IFN-a was administered directly into brain, fever,
anorexia and analgesia were elicited, as were changes of
hypothalamic neuronal firing (Hori et al., 1998). This treatment
also reduced 5-HT concentrations in the PFC (De La Garza and
Asnis, 2003), increased hippocampal DA activity (De La Garza
and Asnis, 2003; Morikawa et al., 1998), and increased 5-HTT
mRNA expression, which ought to promote reduced 5-HT
availability (Morikawa et al., 1998). It is noteworthy that IFN-a
administration promoted 5-HT2C receptor mRNA editing,
resulting in receptor down-regulation (Yang et al., 2004). This
outcome may be particularly relevant, as it will be recalled that
5-HT2C receptor functioning has been associated with anxiety
and depressive symptoms (Merali et al., 2006a), and altered 5-
HT2C editing was associated with depression/suicide.
There are several processes by which pro-inflammatory
cytokines may come to affect 5-HT functioning, including
27
effects secondary to CRH release (Hayley et al., 2005). An
alternative view that is not exclusive of other processes is that
cytokines, such as IFN-a, may stimulate indoleamine-2,3-
dioxygenase (IDO) and GTP-cyclohydrolase activity, which
foster degradation of the 5-HT precursor tryptophan (Menkes
and MacDonald, 2000) thereby reducing 5-HT functioning and
leading to depressive illness (Capuron et al., 2002a,b,c).
Relatedly, IDO may have neuroprotective functions by limiting
inflammatory processes associated with infectious or traumatic
insults (Kwidzinski and Bechmann, 2007). However, IFN-a
also promotes metabolism of tryptophan into kynurenine and
subsequently into the oxidative metabolites 3-hydroxy-kynur-
enine and quinolinic acid (which themselves are increased in
depression) that may have neurotoxic actions (Wichers and
Maes, 2004; Wichers et al., 2005). These kynurenine
metabolites synergistically induce free radical generation and
have been implicated in neurodegenerative diseases, including
Huntington’s, Parkinson’s and AIDS dementia (Hartai et al.,
2005).
11.6. Cytokine-induced behavioral changes
Although the immunological, neurochemical and behavioral
alterations elicited by pathogens may represent adaptive
changes to meet environmental demands (Dantzer et al.,
1999a, 2000; Dantzer, 2001a,b; Hart, 1988; Konsman et al.,
2002; Maier and Watkins, 1998), they may also elicit adverse
psychological consequences (Hopkins and Rothwell, 1995;
Quan and Herkenham, 2002; Rothwell and Hopkins, 1995).
Immune activation as well as administration of IL-1b or TNF-a
typically engenders an array of behavioral symptoms (soporific
effects, ptosis, anorexia, fever, fatigue, reduced motor activity,
curled body posture) referred to as ‘‘sickness behaviors’’ (Kent
et al., 1992). These symptoms appear to be mediated, in part, by
central mechanisms, as low doses of IL-1b or TNF-a
administered directly into the brain elicited these behaviors
(Dantzer, 2001a,b; Konsman et al., 2002; Maier and Watkins,
1998). The behavioral expression of sickness is contextually
dependent in the sense that the signs of malaise are suppressed
under conditions where sickness would be a disadvantage (e.g.,
in a novel or threatening environment; Kusnecov et al., 1999).
It was suggested that the sickness behaviors reflect
depressive symptoms as the behaviors (Yirmiya et al., 1999,
2001) and elevated Fos expression (Castanon et al., 2002, 2003)
elicited by endotoxins were attenuated by antidepressant
treatments. Furthermore, cytokines disrupt operant responding
for food reward (Bret-Dibat et al., 1995; Kent et al., 1996) as
well as exploration and social interaction (Bluthe et al., 1997),
which would also be expected if cytokines elicit a depressive-
like state. Some of these behaviors are, indeed, reminiscent of
neurovegetative features associated with major depressive
illness (e.g., reduced libido, diminished food intake, motor
retardation), but it can be argued that they are simply a sign of
general malaise, rather than a reflection of depression per se.
Of particular relevance to depression are reports that
cytokines and bacterial endotoxins may elicit anhedonia, a key
symptom of depressive illness, independent of any effects of
28 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
anorexia (Anisman and Merali, 1999; Anisman et al., 1998,
2002; Merali et al., 2002a). By example, endotoxin treatment
(lipopolysaccharide: LPS) disrupted responding for rewarding
brain stimulation during the ascending portion of a current
titration schedule (Borowski et al., 1998). Likewise, we have
shown that the anorexic and motivational (anhedonic) effects of
cytokines (such as IL-1b) are distinguishable from one another,
and only the latter is attenuated by chronic antidepressant
treatment (Merali et al., 2002a; see also Larson and Dunn,
2001; Larson et al., 2002; as well as Sammut et al., 2001, 2002
for effects of interferon-a). Using a progressive ratio (PR)
schedule for a tasty treat, namely sucrose reinforcement (i.e.,
progressively increasing the number of operant responses that
are required for a fixed amount of sucrose, thereby providing an
index of the motivation to work for reward), we found that IL-
1b reduced both PR performance and free-chow consumption.
However, whereas chronic antidepressant (fluoxetine) treat-
ment attenuated the PR performance deficit, it did not affect the
diminished free chow consumption provoked by the cytokine,
thus indicating that the cytokine may promote anhedonia, quite
apart from its anorexic effects. These varied findings using
animal models of depression, coupled with the effects of
antidepressants on sickness behaviors and other behavioral
disturbances associated with cytokine challenges, are consis-
tent with a role for inflammatory factors in the provocation of a
depressive-like state.
Although cytokines may elicit effects pertinent to mood/
anxiety disorders (Anisman and Merali, 1999; Dantzer, 2001a;
Dantzer et al., 2000; Hayley et al., 2005, 2002a; Kent et al.,
1992; Lyte et al., 1998; Maier and Watkins, 1998; Musselman
et al., 2001; Reichenberg et al., 2001), and appear to involve
CNS mechanisms (Bluthe et al., 1997; Dantzer, 2001a; De
Sarro et al., 1997; Kent et al., 1996), the pleiotropic effects of
these cytokines (such as sickness) often complicate analysis of
these effects. It is questionable, however, whether analyses of
sickness itself could be considered as an analogue of depressive
illness. Assessment of the effects of cytokines on behavioral
outputs, with the intent of simulating depressive illness, would
be better positioned if they focused on specific features that, in
fact, bore greater face validity than sickness behaviors.
11.7. Proactive effects of cytokines and stressors
Paralleling the effects of stressors described earlier, cytokine
administration increased the response to later challenge with
either a stressor or the cytokine treatment (Anisman et al., 2003;
Hayley et al., 1999b, 2001c, 2002b; Schmidt et al., 1995), and,
conversely, stressor exposure augmented the neuroendocrine
response elicited by later LPS administration (Johnson et al.,
2002, 2003). For instance, stressors increased central IL-1b
levels and also enhanced the effects of later central LPS
administration. However, if rats were pretreated with the IL-1
antagonist, IL-1ra, then the effects of the subsequent stressor
treatment were attenuated (Johnson et al., 2004).
As described earlier, variations of CRH and AVP may be
fundamental to the sensitization associated with cytokine
treatment. Specifically, it was demonstrated that like stressors,
IL-1b and TNF-a provoked a time-dependent and persistent
increase in the co-expression of CRH and AVP within the
external zone of the median eminence. That is, although the co-
expression was not evident at short intervals following the
cytokine challenge, it developed over several weeks following
the cytokine treatment, and once evident the co-expression
persisted for an extended period of time. It will be recalled that
the co-release of these peptides synergistically stimulate ACTH
secretion from the anterior pituitary, and thus it was suggested
that the development of the CRH-AVP co-expression might
contribute to the depressive symptoms elicited in response to
later stressor or cytokine challenges (Hayley et al., 2001b,
2002; Schmidt et al., 1995; Tilders and Schmidt, 1999). This
proposition is in line with the view described earlier (Post,
1992), wherein it was suggested that the sensitization of
neuronal processes, including those governing neuropeptide
release, may increase over time and/or with repeated illness
episodes, and may play a fundamental role in the emergence of
depression (Post, 1992). In this instance, however, rather than
being instigated by a traditional stressor, the stimulus eliciting
the co-expression comprises an inflammatory challenge.
The studies that have assessed the sensitizing effects of
cytokines have typically done so in adult animals. Yet, given
that early life stressors, including impoverished dam–pup
interactions, increase the stress response measured during
subsequent adulthood (Meaney, 2001), the possibility was
considered that early life endotoxin treatment might similarly
influence the adult stress response. Indeed, rat pups that had
been exposed to a bacterial endotoxin, when subsequently
tested as adults, exhibited increased stressor-elicited corti-
costerone reactivity, elevated lymphocyte sensitivity to
suppression by stressors, and protection against adjuvant-
induced arthritis (Shanks et al., 2000). Whether the effects of
early life stressors and early life cytokine treatments involve
similar neural circuits is uncertain. Nevertheless, these
findings raise the possibility that early life immunological
insults, like other stressors, might by virtue of greater stressor
sensitivity or reactivity, increase vulnerability to pathological
states.
11.8. Cytokines in relation to depression in humans
Human studies have provided considerable evidence in favor
of the view that cytokines contribute to the evolution of major
depression. Correlational studies have indicated that depressive
symptoms occurred fairly frequently in physical illnesses
associated with inflammation and with elevated IL-1 levels
(Dantzer et al., 1999b). As well, there have been reports that
depression was accompanied by aspects of an acute phase
response, such as elevated complement protein levels (C3 and
C4) as well as positive acute phase proteins, haptoglobin, a1-
antitrypsin, a1 and a2 macroglobulin and C-reactive protein
(CRP), whereas negative acute phase proteins were reduced
(Danner et al., 2003; Miller et al., 2002). Furthermore,
depression was associated with an increase of activated T cells
(CD25+ and HLA-DR+), and secretion of neopterin, prosta-
glandin E2 and thromboxane (Maes, 1995, 1999).
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
In addition to these indices of inflammation, it has been
reported that circulating and mitogen-provoked cytokine
concentrations were elevated in major depressive disorder,
especially in relatively severe (melancholic) illness (Maes,
1999). The cytokine elevations included IL-2 and its soluble
receptors (sIL-2R), IL-1b, IL-1 receptor antagonist (IL-1Ra),
IL-6, sIL-6R, and IFN-g. As well, it was reported that the
normal IL-6 circadian rhythm was disturbed in individuals
diagnosed with major depressive disorder (Alesci et al., 2005).
Moreover, there have been indications that the elevated levels
of IL-1b, IL-6, TNF-a, and IFN-g normalized with anti-
depressant medication (Basterzi et al., 2005; Sluzewska et al.,
1995; Tuglu et al., 2003). In contrast to these reports, however,
it was also found that the elevated production of sIL-2R, IL-6,
IL-10 and sIL-6R in severe depression (Maes, 1999; Sluzewska
et al., 1995) and the elevated IL-1b associated with chronic low
grade depression (dysthymia) (Anisman et al., 1999a,b) were
not attenuated with antidepressant treatments. The fact that
most cytokines did not normalize with attenuation of clinical
symptoms suggests that these cytokines are not causally linked
to depression, but might serve as trait markers of the illness. Of
course, the possibility should not be dismissed that cytokine
normalization might only be evident with sustained treatment,
or that cytokines normalize in only a subset of individuals, with
elevated levels being a harbinger for illness recurrence.
Few studies have considered that subtypes of the illness,
particularly typical vs. atypical depression, may be associated
with different cytokine profiles, despite the possibility that
these illness subtypes may involve different underlying
processes. It was reported, however, that T cell proliferation
was diminished in typical relative to atypical depression
(Zaharia et al., 2000), but no such effects were apparent in IL-
1b production (Anisman et al., 1999a). Nevertheless, it has
been suggested that cytokine activation might contribute
selectively to some of the symptoms that comprise the
depressive profile (e.g., IL-1b contributes to impaired appetite
associated with depression; Andreasson et al., 2007).
The finding that elevated cytokine levels accompany
depressive illness has been taken as support for some form of
relation (although not necessarily causal) between these factors.
Yet, as described by Irwin (1999), processes not directly related
to the mood alterations associated with major depression may
have promoted the altered cytokine levels. Among other things, it
was suggested that depression may be associated with several
antecedent conditions, including recent stressful experiences,
stressors encountered early in life, and altered appraisal and
coping with respect to ongoing stressors, any one of which could
have influenced cytokine levels. Further, institutionalization (and
the accompanying social and environmental change) of
depressed patients may itself have contributed to cytokine
variations, as would an increase of drug use (including nicotine,
alcohol, as well as illicit drugs). Indeed, Haack et al. (1999)
reported that when they statistically controlled for age, body
mass index, gender, smoking habits, recent infection or prior
medication, differences of circulating cytokine levels between
controls and depressed patients were absent. Further to this issue,
it is not unreasonable to hypothesize that neurovegetative
29
features (reduced eating and weight loss, reduced sleep) evident
in typical major depression could promote altered cytokine
functioning. In fact, it has been known for some time that sleep
disturbances are associated with cytokine variations (Moldofsky,
1995), and disturbances of circadian cycles that may be evident
among depressed individuals may similarly influence cytokine
production (Cover and Irwin, 1994). Finally, any of the many
comorbid features of depression, such as anxiety, heart disease,
diabetes and Parkinson’s disease (McDonald et al., 2003), could
potentially influence circulating cytokine levels.
11.9. Immune activation provokes depressive mood state
The studies showing that depressive illness is accompanied
by variations of inflammatory processes comprise correlational
data and do not speak to the causal role of cytokines or acute
phase reactants to the provocation or exacerbation of
depression. However, two lines of research have suggested
that cytokines (or other inflammatory factors) are causally
related to this illness: (1) immune activating agents (e.g.,
vaccines or endotoxin treatment) administered to healthy adults
may elicit depressive-like behaviors in direct relation to TNF-a
and IL-6 secretion associated with the treatment (Reichenberg
et al., 2001; Wright et al., 2005) and (2) immunotherapy (using
IFN-a in the treatment of some forms of cancer and hepatitis C)
may be associated with the induction of depressive-like states.
There have now been an appreciable number of studies
showing that individuals treated with IFN-a (and IL-2 in earlier
studies; Denicoff et al., 1987) displayed cognitive disturbances,
retarded cognitive processing and impaired executive function-
ing, impaired concentration and memory, irritability, and anxiety,
as well as manic periods (Constant et al., 2005; Dieperink et al.,
2003; Hilsabeck et al., 2005; Lieb et al., 2006; Meyers, 1999;
Meyers and Valentine, 1995; Pavol et al., 1995; Sceibel et al.,
2004; Valentine et al., 1995; Valentine and Meyers, 2005). There
have also been studies that failed to detect such outcomes
(Caraceni et al., 1998; Mapou et al., 1996), possibly reflecting
between study differences in the dosage and treatment regimens
employed. The latter studies notwithstanding, it has been
reported that IFN-a reduced frontal lobe electrophysiological
activity (Rohatiner et al., 1983; Smedley et al., 1983), and the
increase of depressive symptoms elicited by the cytokine were
accompanied by reduced frontal cortical functioning measured
by PET analysis (Juengling et al., 2000).
Particularly troublesome from a clinical perspective was that
IFN-a engendered pronounced depressive symptoms (Capuron
and Ravaud, 1999; Capuron et al., 2000, 2001, 2002a,b,c,
2003a,b, 2005; Caraceni et al., 1992; Maes and Bonaccorso,
2004; Maes et al., 2001; Miyaoka et al., 1999; Musselman et al.,
2001; Scalori et al., 2005; Wichers and Maes, 2002, 2004). An
appreciable portion of patients reported suicidal ideation
(Dieperink et al., 2000) and, in some, the symptom severity
necessitated discontinuation of therapy (Valentine and Meyers,
2005). Although, depressive symptoms ordinarily resolved with
treatment cessation (Loftis and Hauser, 2004), patients were
sensitized to the treatment, becoming highly reactive to further
cytokine administration.
30 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Just as MDD may comprise both neurovegetative (e.g.,
lethargy, somnolence, psychomotor retardation) and cognitive/
mood symptoms, IFN-a elicits each of these symptom
dimensions, and high doses may provoke a confusional state
characterized by disorientation, as well as psychotic-like
features (Asnis and De La Garza, 2006; Raison et al., 2005a,b).
Over the course of treatment, depressive symptoms and
cognitive impairments (e.g., disturbances of immediate recall)
may become increasingly pronounced (Capuron et al., 2005;
Lieb et al., 2006; Raison et al., 2005b). In addition, IFN-a
immunotherapy may initially engender disturbed vigilance,
alertness and some memory problems, which diminish with
treatment cessation (Kraus et al., 2005a,b,c,d). Despite the link
with depression and immunotherapy, given the non-specificity
of symptoms (reflected by the wide array of disturbances
associated with IFN-a immunotherapy), the obvious question
arises as to whether the effects observed are a genuine
manifestation of neurochemical changes that underlie depres-
sion, or whether the constellation of symptoms is more a
reflection of general malaise or toxicity.
Contrary to the latter view, however, it seems that the
development of depression following IFN-a therapy is linked to
some of the same characteristics that predict MDD. Specifi-
cally, the presence of subsyndromal levels of depression prior to
immunotherapy predicted major depressive symptoms in
response to the IFN-a (Beratis et al., 2005; Capuron et al.,
2001, 2004) as did the early signs, such as sadness, pessimistic
thoughts and sleep disturbances (Capuron and Ravaud, 1999).
As well, poor social support at baseline was also related to the
emergence of depressive symptoms following IFN-a treatment
(Capuron et al., 2004). Interestingly, like the mood changes
associated with depletion of the 5-HT precursor tryptophan
(Neumeister et al., 2004; Young and Leyton, 2002), suscept-
ibility to the depressive symptoms elicited by IFN-a were
greater among women and among those with a history of
depression (Capuron et al., 2003a). It also appeared that low
levels of tryptophan were predictive of depressive illness
(Capuron et al., 2003a) as were the initial elevations of ACTH
and cortisol in response to IFN-a (Capuron et al., 2003b).
Along these same lines, individuals with the highest baseline
levels of sIL-2r, IL-6, and IL-10 were most prone to depressed
mood following immunotherapy (Wichers et al., 2006).
Together, these findings suggest that the depression that
emerges following immunotherapy is, in fact, tied to 5-HT and
cytokine related processes.
Consistent with this perspective, several investigators
reported that SSRIs, such as sertraline, paroxetine and
citalopram, attenuated the depressive symptoms provoked by
IFN-a (Kraus et al., 2005c; Musselman et al., 2001; Maddock
et al., 2004; Schramm et al., 2000). Moreover, SSRI treatment
could be used prophylactically to limit the emergence of
depressive symptoms (Kraus et al., 2005b; Schaefer et al., 2005).
It seems that the neurovegetative and mood-related features
introduced by IFN-a therapy are independent of one another, as
paroxetine primarily affected the mood-related symptoms, with
only minor effects on fatigue and anorexia (Musselman et al.,
2001; Raison et al., 2005a,b). Given that antidepressants may
improve tolerability to the immunotherapeutic side effects, these
findings are of practical as well as theoretical importance.
In addition to altered 5-HT functioning, other processes,
including actions on neuropeptide and growth factor as well as
on inflammatory processes, are also likely involved in
determining the effects of SSRIs. It was reported, for instance,
that fluoxetine reduced expression of IL-1b, IL-6, IFN-g and
TNF-a, and increased the circulating levels of the inhibitory
cytokine IL-10 (Chiou et al., 2006). It was similarly observed
that amitriptyline, clomiprimine, imiprimine, and bupropion,
all diminished IL-1b and TNF-a release provoked by LPS
(Brustolim et al., 2006; Obuchowicz et al., 2006) and had potent
anti-inflammatory effects, including suppression of macro-
phage migration (Bianchi et al., 1994). These actions were not
restricted to SSRIs, as another class of compounds with
antidepressant effects, namely the phosphodiesterase IV
inhibitors (e.g., rolipram), also diminished cytokine production
in response to LPS (Griswold et al., 1998; Zhu et al., 2001).
Centrally, hippocampal and brainstem levels of TNF-a were
reduced by desimipramine (Reynolds et al., 2004, 2005), and
the clinical efficacy of this compound was linked to its ability to
alter the sensitivity of NE neurons to TNF-a (Reynolds et al.,
2005). Paralleling the effects of antidepressants upon cytokines,
administration of 5-HT itself reduced TNF-a and IFN-g
expression, and it is significant that this outcome could be
reversed by CRH treatment (Maes et al., 2002). As such, these
findings suggest that cytokines and 5-HT neuronal activity, as
well as CRH, might reciprocally influence one another, and
might thus come to influence depressive mood.
If inflammatory factors contribute to depressive sympto-
matology, it would be expected that anti-inflammatory
compounds might themselves possess antidepressant proper-
ties, or at least enhance the effects of conventional
antidepressants. In this regard, cyclooxygenase-2 (COX-2)
antagonists (non-steroidal anti-inflammatory drugs) were found
to attenuate the depressive-like behavioral and neurochemical
alterations associated with both LPS and IFN-a treatment in
animal models of depression (Asnis et al., 2003; De La Garza
et al., 2004), and such treatments also diminished glucocorti-
coid responses to social stressors (Bugajski et al., 2003). As
well, pre-treatment with the COX-2 antagonist indomethacin
prevented the inhibitory effects of LPS upon ambulatory
locomotion, rearing and grooming, and also diminished the
endotoxin’s effect on Fos immunoreactivity within 5-HT
neurons (Hollis et al., 2006). As expected, a COX-2 inhibitor
enhanced the effectiveness of antidepressant medication in
treating depression (Muller et al., 2006), but the usefulness of
combining NSAIDs with antidepressant medication are limited
by the increased risk of gastrointestinal disturbances that may
come about (de Jong et al., 2003).
11.10. Mechanisms linking cytokine activation and
depressive illness
The processes by which anti-inflammatory agents modulate
affective processes is a matter of ongoing research. Simply
because SSRIs attenuate the adverse effects of cytokines cannot
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
be taken as definitive evidence of direct 5-HT involvement,
particularly given the multiple downstream effects of these
treatments. Nevertheless, in view of the factors associated with
depression proneness in IFN-a treated patients (e.g., tryptophan
levels), it is likely that 5-HT contributes directly or indirectly to
the outcomes observed. It was suggested (as depicted in Fig. 1)
that these immunotransmitters, like stressors, provoke the
release of hypothalamic CRH, which then stimulates ACTH
and corticosterone secretion. Concurrently, release of amygdala
CRH triggered by pro-inflammatory cytokines, alone or in
combination with GABA activation, leads to forebrain and
hippocampal 5-HT release, and either the CRH or the 5-HT
alterations may elicit anxiogenic and/or depressive effects.
As alluded to earlier, cytokines may promote depressive
states through any of several different neuronal processes (and
these are not mutually exclusive). Among its other effects, it
will be recalled that IFN-a increases IDO, which is responsible
for the catabolism of tryptophan to kynurenine (Menkes and
MacDonald, 2000). Thus, the IFN-a elicited increase of IDO
may diminish tryptophan availability, thereby reducing 5-HT
synthesis. In line with this view, it was reported that depression
induced by IFN-a was accompanied by reduced tryptophan
coupled with elevated levels of kynurenine (Bonaccorso et al.,
2001, 2002). It is tempting to conclude that depression elicited
by IFN-a was, indeed, related to diminished levels of
tryptophan. However, as indicated by Wichers and Maes
(2004), kynurenine metabolites, such as 3-hydroxy-kynurenine
and quinolinic acid, through their effects on reactive oxygen
species or stimulation of hippocampal NMDA receptors, may
engender neuronal cell loss that could favor the development of
depression. Finally, other neurotransmitters, including NE, may
play a fundamental role in subserving the mood regulatory
actions of cytokines. In fact, it was posited that increased
central TNF-a levels might provoke depressive illness by
activation of adrenergic autoreceptors leading to a subsequent
reduction of NE neurotransmission (Reynolds et al., 2005).
In addition to changes of monoamine activity, cytokines may
influence the development of depressive pathology by affecting
processes aligned with neuroplasticity, such as neurogenesis
(Hayley et al., 2005). Indeed, among transgenics with elevated
IL-6 levels, neurogenesis was markedly reduced (Vallieres
et al., 2002). As well, when IFN-a was chronically
administered to rodents (in a schedule mimicking an
immunotherapeutic protocol), hippocampal neurogenesis was
diminished, and this outcome was attenuated by the IL-1
antagonist IL-1ra (Kaneko et al., 2006). To be sure, this does
not necessarily imply a causal relation between cytokine
immunotherapy, neurogenesis and depression. Nevertheless,
animal studies have shown that psychogenic stressors may
promote death of cortical neurons through apoptotic mechan-
isms, and that IL-1b as well as the TNF-a family member Fas
were involved in this regard (Lee et al., 2006a,b). In line with
this perspective, as will be discussed shortly, antidepressants
elevated neurogenesis and prevented the effects otherwise
engendered by chronic stressor exposure (Chiou et al., 2006).
Furthermore, attenuating the inflammatory response through
indomethacin administration had the effect of restoring
31
neurogenesis otherwise reduced by endotoxin treatment or
by irradiation (Monje et al., 2003). Likewise, over-expression
of IL-6 or administration of LPS inhibited hippocampal
neurogenesis, and several anti-inflammatory treatments,
including minocycline and indomethacin, prevented this
outcome (Monje et al., 2003; Vallieres et al., 2002). Together,
these findings raise the possibility that cytokine actions on
depressive states stem from effects on neuroplasticity.
An alternative process by which cytokines may influence
depressive disorder is through NFkB. This transcription factor
is fundamental in the mobilization of inflammatory chemokines
and lymphocyte proliferative responses to both infection and
traumatic injury (Lucas et al., 2004; Poynter et al., 2004).
Ordinarily, NFkB, which is composed of five subunits, is held
in an inactive state by an endogenous inhibitory factor, IkB.
Inflammatory stimuli trigger the phosphorylation and degrada-
tion of IkB, and then the translocation of NFkB to the nucleus
where it promotes gene expression (Lucas et al., 2004). There is
reason to believe that NFkB contributes to CNS processes that
are fundamental for neuronal survival and plasticity, and may
be involved in memory processes (Mattson et al., 2004). In
particular, within the hippocampus, NFkB expression is
increased during activation of neuroplastic processes, such
as the induction of long-term potentiation, and it has been
suggested that this transcription factor may be involved in
promoting neuronal survival following hippocampal injury
(Kassed and Herkenham, 2004; Freudenthal et al., 2004).
The neuroprotective action of NFkB may stem from the
induction of anti-apoptotic proteins, such as bcl-2, as well as the
antioxidant enzyme manganese-superoxide dismutase (Matt-
son et al., 2004). At the same time, it is possible that NFkB
signaling may also result in the synthesis of inflammatory
cytokines, reactive oxygen species, and excitotoxins that
contribute to neurodegeneration (Mattson et al., 2004; Pahan
et al., 2001), and as such NFkB may be an important down-
stream signaling factor for cytokines that contribute to
pathologies, such as Parkinson’s disease (PD), MS and MDD
(Barger et al., 2005). For instance, IL-1b infusion into the
lateral ventricles induced the translocation of NFkB to the
nucleus at several brain regions distal to the site of infusion,
including the choroid plexus, ependymal cells, cerebral
vasculature and meninges as well as at the basolateral
amygdala (Konsman et al., 2000). It is thought that some of
these changes, including the variations of NFkB, may be
instrumental in promoting or sustaining depressive-like
symptoms (Miller and Raison, 2006; Raison et al., 2006). As
well, there is reason to believe that NFkB might contribute to
anxiety, as mice deficient for the p50 subunit of NFkB
(resulting in impaired NFkB activity) displayed reduced
anxiety (Kassed and Herkenham, 2004). In effect, immuno-
logical insults and the ensuing IL-1b and TNF-a activation may
initiate the NFkB cascade (Lucas et al., 2004), ultimately
affecting CNS processes.
Summarizing, although the primary role of the inflammatory
immune system is that of protecting the individual from
bacterial and viral insults, there is considerable evidence
supporting the view that cytokines may also be involved in the
32 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
provocation of depressed mood and anxiety. Like stressors,
cytokines influence HPA functioning, as well as monoaminer-
gic and peptidergic processes at hypothalamic and extra-
hypothalamic sites, and may influence neurogenesis. The
notion that cytokines are directly or indirectly involved in MDD
is reinforced by the findings that certain cytokines, notably
IFN-a, promote the appearance of MDD, and these effects are
attenuated by antidepressant medication. As will be seen in
ensuing sections, MDD has also been linked to changes of
growth factors and neurogenesis, and the case will be made that
inflammatory factors may influence depressive illness by
modifying these processes.
12. Morphological correlates of major depressive illness
Major depressive disorder has been associated with both
structural and functional changes within discrete brain
regions, including limbic regions such as the hippocampus
and the amygdala (Drevets et al., 2007; Videbech and
Ravnkilde, 2004). It was reported that hippocampal volume
was reduced in patients diagnosed with major depression, and
postmortem analyses indicated that the extent of the
hippocampal reduction was related to illness duration
(Bremner et al., 2000; Campbell et al., 2004; Kempermann
et al., 2003; Sheline et al., 2003; Videbech and Ravnkilde,
2004). Consistent with the view that pre-existing morpho-
logical changes might contribute to MDD, it was reported
that the reduction of hippocampal volume was evident at the
time of the first depressive episode in relatively young
individuals (Frodl et al., 2002). Yet, it has also been reported
that hippocampal reductions were most apparent after
repeated depressive episodes and that the magnitude of the
reduction was positively associated with illness duration
(MacQueen et al., 2003). Despite this strong evidence for
morphological changes being associated with MDD, reduced
hippocampal volume was also associated with other
pathologies, such as schizophrenia (Boos et al., 2007), and
alterations of the right caudate nucleus were not only
associated with depression, but were evident in association
with anxiety, obsessive compulsive disorder (OCD) and
paranoia (Starkman et al., 2007). Thus, it is possible that
these morphological alterations may be a predisposing
influence for pathological states in general, as opposed to
being uniquely linked to depressive illness.
This caveat not withstanding, paralleling studies that
implicated 5-HTT in depression, it was reported that reduced
hippocampal volume was most pronounced in MDD patients
carrying the long variant of the 5-HTT allele (Frodl et al., 2004).
Furthermore, the hippocampal volume was lower in non-
remitted patients than among those in remission (Frodl et al.,
2004), and this was especially notable within the left
hemisphere (Mervaala et al., 2000; MacMaster and Kusumakar,
2004; Vakili et al., 2000). Still, it is possible that the reduced
hippocampal volume is not a consequence of MDD, but instead
represents a risk factor for the illness, just as small hippocampal
volume may function in this capacity in relation to PTSD
(Gilbertson et al., 2002; Pitman et al., 1999).
The morphological changes associated with MDD could
come about owing to genetic factors (Gass et al., 2000),
distressing early life events, or chronic strain (McEwen, 1999;
Brunson et al., 2001; MacQueen et al., 2003; McEwen, 2005;
Vythilingam et al., 2002, 2004), but it is equally possible that
structural changes may be secondary to illness. In this regard,
caution should be exercised in the interpretation of imaging
studies given the observation that (a) large variations of
hippocampal volume exist within the general population and
(b) the difference in volume between individuals in the lowest
quartile compared to the mean of a sample of young healthy
adults exceeded the difference observed between healthy adults
and depressed subjects (Lupien et al., 2007).
12.1. Stressor and corticoid actions in relation to
morphological changes associated with MDD
Clinical depression may be related to the direct actions of
glucocorticoids, which are frequently elevated in relatively
severe cases of depression or in response to chronic stressors
(Sapolsky et al., 1985), and the proposition was advanced
that glucocorticoids might contribute to the reduced
hippocampal volume associated with MDD. Consistent with
this view was the finding that impaired hippocampal
neurogenesis occurred in rodents exposed to a chronic
corticosterone or stressor regimen (Coyle and Duman, 2003).
As well, in monkeys, hippocampal implantation of cortisol
pellets for an extended period (1 year) engendered
morphological changes in the hippocampal CA3/CA2
subfields, including irregular cell layers, soma shrinkage
and dendritic atrophy (Sapolsky et al., 1990). Furthermore, in
rats, intermittent stressor (restraint) exposure promoted
hippocampal neuronal loss, coupled with increased expres-
sion of the degenerative marker tau protein (Stein-Behrens
et al., 1994). The hippocampal cell loss was not only
apparent in response to physical stressors but was also
elicited by psychosocial disturbances. That is, reduced apical
dendrite length of hippocampal pyramidal neurons and fewer
dendritic branching points were evident among subordinate
male tree shrews chronically exposed to a dominant animal
(Magarinos et al., 1996). Such effects were not confined to
the hippocampus, as a chronic restraint stressor regimen also
reduced apical dendritic branching and length in pyramidal
PFC neurons (Cook and Wellman, 2004).
There are several processes by which glucocorticoids could
affect cell survival. For instance, corticoids could impair
glucose transport into hippocampal pyramidal neurons, hence
promoting an energetic compromise of these cells (McEwen,
2000, 2005). It is similarly possible that glucocorticoids might
potentiate elevations of free cytosolic calcium, and hence may
either directly impair neuronal survival or render cells
vulnerable to other insults. As well, excessive corticoid levels
may contribute to free radical accumulation, largely by
reducing the capacity of antioxidant enzymes (Sapolsky,
2000). Furthermore, neuronal survival could be influenced
through excitotoxic processes involving elevations of NMDA
and/or AMPA glutamate receptors (McEwen, 2000, 2005).
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
13. Growth factors in relation to stressors and
depression
As already indicated, depression is likely mediated by
several concomitant neurochemical disturbances, and effective
treatment strategies ought to consider the interconnected
central pathways involved. There have been reports indicating
that in addition to monoamine and neuropeptide variations,
stressors may influence neurotrophic growth factors (Duman
and Monteggia, 2006; Duman et al., 1999; Manji and Duman,
2001). Moreover, their functions may be related to one another
as well as to 5-HT activity (Hayley et al., 2005; Manji et al.,
2003). As 5-HT and BDNF reciprocally innervate one another
(Mattson et al., 2004), the possibility exists that this process
might influence depression.
13.1. BDNF involvement in depression
Consistent with a role for BDNF in depressive illness,
stressors were shown to reduce the expression of BDNF in
limbic regions that mediate mood states (Duman and
Monteggia, 2006; Manji et al., 2001) and that BDNF variations
may be responsible for the hippocampal atrophy associated
with depression (MacQueen et al., 2003). Conversely, treatment
with antidepressant agents had the effect of increasing BDNF
expression and attenuating the effects of stressors (Jacobs,
2002; Manji et al., 2003). The present review focuses on the
potential contribution of BDNF in depression, but this should
not be taken to exclude a role for other growth factors, including
FGF1 and FGF2, that are influenced by stressors and have also
been implicated in the evolution of depressive states (Evans
et al., 2004; Newton and Duman, 2004; Turner et al., 2006).
Analyses of signaling processes involved in depression have
increasingly focused upon alterations of trophic factors that
might lead to deficiencies of neuroplasticity and the subsequent
provocation of depressive pathology (Manji et al., 2001). In line
with a role for BDNF in depression, it was reported that BDNF
expression and protein levels and that of its receptors (tyrosine
kinase B, TrkB) were lower within the PFC and hippocampus of
suicides than in age- and sex-matched controls (Dwivedi et al.,
2003). Moreover, antidepressant treatment was found to elevate
cortical BDNF levels and enhance TrkB signaling and these
effects were required for the induction of the behavioral effects
of the antidepressant (Saarelainen et al., 2003). As well, BDNF
levels were reduced in the serum of depressed patients and the
reduction correlated negatively with the degree of clinical
impairment, as well as reductions of hippocampal volume
(Shimizu et al., 2003). As would be predicted, chronic
antidepressant treatment normalized BDNF serum levels in
parallel with clinical improvement (Piccinni et al., 2007).
However, it was also reported that reduced serum BDNF levels
occurred in depressed females, but not males, and that chronic
antidepressant treatment selectively elevated the growth factor
in females (Huang et al., 2007), suggesting that the role of
BDNF in depression may be gender specific.
Consistent with the contention that BDNF is involved in
depression and anxiety, it has been reported that elevated
33
anxiety was associated with reduced hippocampal BDNF
expression (Yee et al., 2007), and transgenic mice over-
expressing this neurotrophin displayed elevated anxiety
(depression and anxiety are frequently co-morbid) (Govindar-
ajan et al., 2006). Moreover, BDNF infusion into the DRN
provoked an antidepressant-like effect while concomitantly
promoting sprouting of central 5-HT neurons (Altar, 1999).
Likewise, hippocampal infusion of BDNF or NT-3 produced
antidepressant-like effects in the learned helplessness and
forced swim models of depression (Shirayama et al., 2002).
Interestingly, antidepressant treatment was associated with
increased hippocampal BDNF, whereas variations of neuro-
trophic factors in the amygdala appeared to be more closely
aligned with anxiety (Govindarajan et al., 2006). In effect,
depression may be uniquely related to hippocampal BDNF
variations, whereas other features of the illness may involve
other brain regions or other processes. It will be noted that in
addition to being implicated in depression, it has been reported
that BDNF present in DA neurons contributes to the normal
expression of D3 receptors in the nucleus accumbens, and may
be responsible for behavioral sensitization by triggering
overexpression of D3 receptors in striatum of hemiparkinsonian
rats (Guillin et al., 2001). As such, BDNF may contribute to
pathology involving altered DA functioning.
Studies concerning the impact of acute and chronic stressors
(including chronic mild stressors) indicated that aversive events
reduced hippocampal BDNF levels (Smith et al., 1995; Song
et al., 2006), and that such effects could be induced in response
to a psychological stressor (explicit or contextual cues
previously paired with footshock) (Rasmusson et al., 2002).
In addition to the variations evident within the hippocampus, a
neurogenic stressor (tailshock) increased BDNF mRNA
expression within the anterior cingulate gyrus (Bland et al.,
2007), a region important for the processing of emotionally
salient events. However, following exposure to a predator
stressor, BDNF mRNA was reduced within the CA1 region of
the hippocampus and simultaneously up-regulated expression
of its TrkB receptor (Kozlovsky et al., 2007). It is interesting
that with chronic exposure to a uniform (homotypic) stressor
(restraint) the magnitude of the BDNF reduction in hippo-
campus was less pronounced than after acute treatment
(Murakami et al., 2005), suggesting some degree of adaptation.
Yet, exposure to a chronic unpredictable stressor over several
weeks reduced BDNF protein within the dentate gyrus but
surprisingly did not affect levels of the growth factor within the
hippocampus proper (Grønli et al., 2006). It is uncertain
whether the between-laboratory differences were due to the
chronicity of the stressors, the stressor schedule employed, or
effects that were unique to some types of stressful events.
As would be expected, several clinically beneficial
treatments, including SSRIs, tricyclics, and electroconvulsive
therapy, increased hippocampal BDNF expression (Shirayama
et al., 2002; Castrén et al., 2007; Rogóz et al., 2007). Likewise,
the reduced BDNF associated with restraint was prevented by
antidepressant treatment (Duman et al., 1999), and up-
regulation of BDNF expression was also associated with
improved performance among rats in the forced swim test (i.e.,
34 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
reduced immobility), a paradigm that has been used to screen
antidepressant agents (Shirayama et al., 2002). More recently,
the atypical antidepressant tianeptine was also shown to elevate
BDNF expression within the amygdala, but curiously had no
such effect within the hippocampus (Reagan et al., 2007).
There is evidence that the efficacy of antidepressant
treatments is related to their ability to promote central BDNF
signaling. For instance, inhibition of BDNF functioning, using
a conditional knockout manipulation, attenuated the antide-
pressant actions of desipramine in the forced swim test
(Monteggia et al., 2007). However, it seems that the impact of
antidepressants upon growth factor expression may be
dependent upon the physical or metabolic state of the animal.
Although fluoxetine elevated central BDNF expression in
physically active rats, the antidepressant actually reduced
mRNA for the growth factor in sedentary animals (Greenwood
et al., 2007). It also appeared that BDNF expression was
dependent on estrus cycle, being reduced when estradiol levels
were high, and could also be diminished by exogenous estradiol
treatment. Of particular interest, however, was the finding that
estradiol could attenuate the up-regulation of BDNF elicited by
a 5-HT2A agonist treatment (Cavus and Dman, 2003). Together,
these findings suggest complex interactions between sex
hormones, 5-HT receptors and BDNF, and could potentially
help explain the sex differences that have often been noted in
illnesses, such as depression.
13.2. Neurogenesis, growth factors and depression
An increasing number of neurotrophic peptides, including
BDNF, glial derived neurotrophic factor (GDNF), FGF, and
leukemia inhibitory factor (LIF), have been shown to promote
or influence neurogenesis (Bauer et al., 2007). For instance,
intracerebroventricular infusion of GDNF enhanced neurogen-
esis within the hippocampus, and administration into the
striatum promoted neurogenesis within the sub-ventricular
zone (Kobayashi et al., 2006). As well, administration of novel
agonists of the BDNF receptor TrkB enhanced neurogenesis
and promoted neuronal survival and neurite growth (Qian et al.,
2006). Likewise, the neurotrophic cytokine granulocyte
colony-stimulating factor (G-CSF) influenced both hippocam-
pal and sub-ventricular neurogenesis (Schneider et al., 2005).
In contrast to these hippocampal effects, over-expression of LIF
caused self-renewal of neural stem cells, coupled with a
reduction of neurogenesis within the olfactory bulb and
subventricular zone (Bauer and Patterson, 2006).
Disturbances of hippocampal neurogenesis may contribute
to the primary or secondary symptoms associated with
depression. As already indicated, several different types of
stressors may inhibit neurogenesis, and it seems that the
controllability of the stressor may be important in this respect.
In fact, although uncontrollable tailshock reduced FGF levels
and impaired hippocampal neurogenesis, when rodents had
some degree of control over termination of the shock, FGF
levels actually increased and neurogenesis was unaltered
(Bland et al., 2006). It may be that stressors influence specific
stages of the cell cycle, as exposure to a series of mild stressors
did not influence the initial proliferation or differentiation of
new-born cells, but diminished their survival (Lee et al.,
2006a,b).
In keeping with the view that neurogenesis is associated with
depression, the antidepressant effects of electroconvulsive
shock were accompanied by increased generation of new
hippocampal neurons in adult non-human primates (Perera
et al., 2007). Similarly, several antidepressants enhanced
neurogenesis in rodents and it was suggested that these newly
born neurons might contribute to affective and cognitive
processes (Warner-Schmidt and Duman, 2006). Indeed,
inhibition of neurogenesis by selective irradiation of the
hippocampus also blocked the antidepressant effects of
fluoxetine and imiprimine (Santarelli et al., 2003), suggesting
that neurogenesis may be fundamental in determining the
functional consequences of antidepressant treatment. In effect,
antidepressant treatments may elevate mood, at least in part,
through their pro-mitotic neuronal effects. It may be that the
enhanced neurogenesis stems from activation of growth factor
signaling (e.g. BDNF) following antidepressant exposure, but it
has been suggested that enhanced 5-HT neurotransmission may
also support such processes (Djavadian, 2004; Ueda et al.,
2005).
The role of 5-HT in supporting neurogenesis appears to be
controversial as recent reports indicated that 5-HT depletion
alone did not alter neurogenesis, whereas co-depletion of both
5-HT and NE effectively reduced neurogenesis (Jha et al.,
2006). Moreover, hippocampal neurogenesis did not differ
between 5-HTT deficient mice, which display chronically
elevated synaptic 5-HT levels, relative to non-transgenic mice
(Schmitt et al., 2007). Interestingly, neurotoxin induced
depletion of 5-HT was found to reduce the immediate elevation
of neurogenesis associated with environmental enrichment, but
did not influence the number of new neurons measured weeks
later (Ueda et al., 2005). Hence, 5-HT may be important for
birth of new neurons stimulated by enrichment, but this amine
might not directly contribute to the survival and maturation of
these cells.
Although stressor-induced glucocorticoid elevations can
potently inhibit neurogenesis (Manji et al., 2003), factors other
than these hormones may also contribute to the observed effects
in depression. In this regard, chronic electroconvulsive shock
treatment was associated with increased neurogenesis, even in
the presence of elevated corticoid levels (Hellsten et al., 2002).
Moreover, the SSRI fluoxetine normalized hippocampal
neurogenesis in animals exposed to inescapable electric
footshock, independent of any actions upon corticosterone
(Malberg and Duman, 2003). It may be that neuropeptides,
rather than glucocorticoids, contribute to the modulation of
neurogenesis in stressor associated pathologies. Indeed,
normalization of reduced neurogenesis associated with a
chronic mild stressor was elicited by CRH1 or AVP1b receptor
antagonists (Alonso et al., 2004). Other peptides, such as
pituitary adenylate cyclase-activating polypeptide (PACAP)
and vasoactive intestinal peptide (VIP), might also contribute to
processes similar to neurogenesis, including astrogenesis and
dendritic branching (Nishimoto et al., 2007; Henle et al., 2006).
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
The appearance of growth factors following ischemic injury
influenced hippocampal neurogenesis within the subventricular
zone (Wang et al., 2004; Lee et al., 2007). By example, the
infusion of GDNF following ischemia stimulated the prolif-
eration and maturation of subventricular progenitor cells, which
eventually migrate into the striatum and become mature
neurons (Kobayashi et al., 2006). Similarly, in addition to
attenuating neuronal degeneration following cerebral ischemia,
G-CSF markedly increased hippocampal double labeling of the
proliferative marker BrdU, together with the mature neuronal
marker NeuN (Sehara et al., 2007; Solaroglu et al., 2007). It is
likely that enhanced hippocampal or subventricular neurogen-
esis serve as an adaptive response to compensate for damaged
neurons or function in a protective capacity to limit future
injury.
Just as antidepressants influence growth factor expression,
such treatments may limit the reduction of neurogenesis
ordinarily associated with stressor exposure or neural injury. In
parallel with the attenuation of the deficit of escape
performance provoked by the stressful treatment, fluoxetine
blocked the down-regulation of hippocampal cell proliferation
ordinarily induced by inescapable (uncontrollable) shock
(Malberg and Duman, 2003). Similarly, hippocampal progeni-
tor cell proliferation and BDNF levels were decreased in
chronically stressed mice, and repeated administration of the
antidepressant moclobemide normalized cellular proliferation
and BDNF concentration (Li et al., 2004a,b). As well,
decreased hippocampal cell proliferation elicited by chronic
restraint was prevented by administration of the SNRI
venlafaxine (Xu et al., 2006).
In contrast to the effects of stressors, enriched environmental
conditions promoted neurogenesis and such an outcome was
mediated by the provocation of several growth factors.
Specifically, environmental enrichment enhanced the produc-
tion of immature neurons and increased residual neurogenesis
following irradiation. Concomitantly, enriched conditions also
improved spatial and motor learning in a water-maze and
rotorod test, indicating that the positive impact on neurogenesis
was associated with functional improvements (Fan et al., 2007).
However, heterozygous BDNF knockout mice, which have low
levels of the neurotrophin, failed to show the normal elevation
of neurogenesis after exposure to enriched housing conditions
(Rossi et al., 2006), attesting to the fundamental role of this
growth factor in neurogenesis.
13.3. Neurodegeneration and depression
There is evidence that indirectly links activation of pro-death
pathways with depression as several studies hinted at the
possibility that apoptotic, excitotoxic or oxidative stress factors
may be altered over the course of depressive illness or
following exposure to chronic stressors. For instance,
postmortem analysis revealed modest DNA fragmentation in
11 of 15 depressed cases (Lucassen et al., 2001). Furthermore,
in vitro, antidepressants such as imiprimine and fluoxetine
prevented apoptotic cell death (Peng et al., 2007; Nahon et al.,
2005). However, data are unavailable concerning the expres-
35
sion of the prototypical apoptotic initiators Fas, p53, Bax and
downstream caspases in clinical depression. Yet, animal studies
indicated that stressor exposure reduced expression of the anti-
apoptotic factor bcl-2 (Manji and Chen, 2002; Manji et al.,
2003), and exposure to a severe stressor exacerbated infarct size
in response to ischemia through the suppression of bcl-2 (Manji
et al., 2003). The suggestion has even been made that
experimental treatments modulating bcl-2 expression may be
effective for the treatment of depressive disorder (Duman,
2004). Although frank neurodegeneration is probably not the
primary factor subserving clinical depression, as will be
discussed shortly, it might contribute to several comorbid
features of this illness.
As alluded to earlier, depression is highly co-morbid with
several neurological conditions, including PD, AD, stroke and
MS (McDonald et al., 2003; Ramasubbu, 2000). In this context,
depressive illness may interact or co-occur with neurodegen-
erative pathology because they share underlying mechanisms
(e.g., inflammatory cytokines). Alternatively, the aetiological
processes leading to depression (e.g., stressor experiences)
might influence neurodegenerative disorders, but these effects
could potentially occur through processes unrelated to
depression.
13.4. Downstream growth factor signaling pathways in
depression
Reductions of BDNF and bcl-2 expression elicited by
stressors and neurodegenerative insults have been linked to
altered levels of neurotrophic factors and induction of mitogen-
activated protein (MAP) kinase pathways (Manji and Chen,
2002). These signaling pathways may be important for BDNF
and associated growth factor functioning (Ying et al., 2002;
Eom et al., 2004; Wang et al., 2006; Duman et al., 2007).
Growth factors have, indeed, been shown to stimulate
extracellular signal-regulated kinase (ERK), c-Jun N-terminal
kinase (JNK) and p38 pathways. These three MAP kinase
pathways are believed to be fundamental in cellular responses
to environmental events through the transmission of synaptic
signals to the nucleus, thereby promoting synthesis of proteins
important for cellular survival/death as well as inflammatory
processes (Curtis and Finkbeiner, 1999).
Recent in vitro work revealed that imiprimine induced
BDNF and bcl-2 expression and had anti-apoptotic conse-
quences that were prevented by the MAP kinase inhibitor
U0126 (Peng et al., 2007). As such, these data raise the
possibility that MAP kinase signaling may be fundamental for
neuroprotective as well as affective regulatory consequences
of antidepressants. Indeed, studies using animal models of
depression, as well as those that assessed the impact of
antidepressants, supported the view that MAP kinase signaling
cascades may contribute to the modulation of depressive
pathology (Duman et al., 2007; Qi et al., 2006). For instance,
systemic administration of the MAP kinase inhibitor PD184161
blocked the antidepressant-like effects of desipramine and
sertraline in a forced swim test (Duman et al., 2007). However,
when administered directly into the amygdala, PD098059,
36 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
another MAP kinase antagonist, attenuated immobility in a
forced swim test (Huang and Lin, 2006). Whether these effects
reflect the route of administration or the unique properties of
these inhibitors remains to be established.
Olfactory bulbectomy (which elicits depressive-like beha-
viors in rodents) also influenced MAP kinase signaling, as this
treatment elicited enhanced amygdaloid expression of the
immediate early gene c-Jun (Wrynn et al., 2000), which is a
fundamental messenger of the JNK pathway. Following JNK
activation, c-Jun dimerizes with c-Fos to control expression of
several genes that promote either adaptive neuroplastic changes
or apoptotic responses to toxic insults, such as trophic factor
withdrawal, traumatic brain injury or neurotoxin exposure
(Cowan and Storey, 2003; Crocker et al., 2001; Hayley et al.,
2004a; Saporito et al., 2002). Augmented JNK expression
within the amygdala and hippocampus was also provoked by
administration of electroconvulsive shock that involved a
protocol similar to that used in the clinical treatment of
depression (Brecht et al., 1999). Although this treatment
initially enhanced c-Jun activation, diminished expression of
the active immediate early gene was apparent with progressive
treatment (Brecht et al., 1999), suggesting neuroplastic changes
corresponding to the clinical efficacy of the treatment.
In addition to JNK signaling, the ERK pathway appears to be
particularly sensitive to stressful manipulations. For instance,
chronic restraint enhanced ERK phosphorylation within
serotonergic raphe neurons (Imbe et al., 2004). However,
ERK-2 expression and activational state (through phosphoryla-
tion) was diminished in the hippocampus and prefrontal cortex
of rats exposed to 14 days of forced swim, a treatment that also
led to anhedonic-like behavioral consequences (Qi et al., 2006).
Paralleling the effects seen in animals, protein and mRNA
expression of ERK was reduced in the hippocampus and PFC of
depressed suicides (Dwivedi et al., 2001, 2006).
Antidepressant treatments influenced the ERK pathway,
with chronic (but not acute) fluoxetine treatment promoting a
long-lasting reduction of phosphorylated ERK-1 and -2 within
the cytosol and nuclear compartments within the frontal cortex,
but were differentially regulated within the hippocampus.
Interestingly, however, imipramine increased ERK-1 in the
cytosol of frontal cortex neurons (Fumagalli et al., 2005). As
such, these data raise the possibility that the differential 5-HT
and NE functioning elicited by these two antidepressants (or the
combined actions of imipramine) may be responsible for the
divergent ERK-1 changes reported. It might be noted, as well,
that treatment with fluoxetine enhanced central GDNF
expression through the ERK and p38 kinase signaling pathways
(Mercier et al., 2004). Essentially, these data raise the
possibility that MAP kinases serve as an interface, bridging
neuronal plasticity with the emotional state elicited by various
challenges.
In addition to their modulation by stressful stimuli and
antidepressant treatments, MAP kinases are also influenced by
cytokines, and conversely the downstream effects of cytokines
may involve activation of certain elements of MAP kinase
pathways. The p38 MAP kinase pathway appears to be
necessary for microglial activation and release of oxidative
factors and cytokines (e.g., TNF-a and IL-1b) that occur
following traumatic ischemic injury (Piao et al., 2003). In
peripheral tissues, it was likewise observed that in response to
infection (Mycobacterium), p38 signaling mediates macro-
phage responses involving the synthesis of TNF-a and other
cytokines (Roach et al., 2005). However, IL-1b administration
stimulated central expression of elements of all three MAP
kinase pathways (Maher et al., 2004; Minogue et al., 2003; Wu
et al., 2004). In this respect, IL-1b administration stimulated
ERK activity, as indicated by the enhanced phosphorylation of
ERK-1 and -2 at the meninges, circumventricular organs, PVN,
arcuate nucleus and central amygdala (Nadjar et al., 2005). The
possibility exists that through MAP kinase pathways (e.g.,
ERK), IL-1b may inhibit neuroplastic processes. In fact,
selectively blocking these pathways also influenced the
establishment of long-term potentiation and the degree of
neuronal injury sustained following central insults (Minogue
et al., 2003; Wang et al., 2004).
In addition to MAP kinases, the cAMP response element-
binding protein (CREB) may be important for controlling
affective and neuroplastic processes through its transcriptional
regulation of stressor sensitive genes (D’Sa and Duman, 2002;
Duman et al., 2007). In fact, CREB deficient mice displayed an
antidepressant phenotype in the forced swim and tail suspension
tests, which was accompanied by augmented hippocampal cell
proliferation (Gur et al., 2007). As well, mice lacking the CREB
gene had a more rapid positive behavioral response following
antidepressant treatment (Gur et al., 2007). Beyond these effects,
CREB signaling within the hippocampus appeared to be involved
in the regulation of long-term potentiation (Nguyen and Woo,
2003) and stressors may impair these processes by affecting
CREB expression (Song et al., 2006).
Consistent with a role for CREB in depression, the
behavioral impairment elicited by repeated exposure to
inescapable footshock was associated with diminished
[3H]cAMP binding, accompanied by alterations of several
intracellular kinases, including PKA, that are important for
CREB signaling (Dwivedi et al., 2004). Further, amygdala
CREB over-expression, which may be important for anxiety
associated with depression, was apparent with attenuation of
behavioral impairments in the learned helplessness model of
depression (Wallace et al., 2004). The reduced CREB
expression reported in rodents exposed to a chronic stressor
was reversed by 5-HT acting antidepressant treatments (Shen
et al., 2004), and antidepressants that influenced 5-HT and NE
uptake also provoked increased hippocampal and cortical
expression of phosphorylated CREB (Sairanen et al., 2007).
As in animals, reduced expression of CREB was observed
within the prefrontal and orbitofrontal cortices of depressed
suicides (Dwivedi et al., 2003, 2004; Yamada et al., 2003a,b).
However, increased cortical CREB levels were also found in a
mixed group of major depressive and bipolar disorder suicide
victims (Odagaki et al., 2001). Moreover, Sibille et al. (2004)
failed to observe any CREB or BDNF changes in the
dorsomedial and orbital prefrontal cortices of depressed
suicides. Overall, it would appear that the role of CREB
signaling in depression is controversial and the discrepancies in
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
findings may reflect procedural differences, including varia-
tions in subject populations examined. As indicated repeatedly,
depression is a heterogeneous illness, in which the sub-types
may be characterized by different signaling mechanisms as well
as co-morbid conditions that could potentially influence
neurotrophic factors.
14. Neuropeptide and cytokine influences on
neurodegeneration: Contribution of the inflammatory
immune system
As indicated earlier, there is a high degree of comorbidity
between depression and several neurodegenerative illnesses,
including Alzheimer’s disease (AD) and Parkinson’s disease
(PD) as well as the aftermath of stroke. In addition to their
potential effects on depressive illness, neuropeptide and
cytokine factors have been implicated in neurodegenerative
disorders, and inflammatory processes might be a common
denominator among these pathologies, and may contribute to
the comorbidity that appears among them.
Accumulating evidence has pointed to an important role for
neuroinflammation in the progression, and in some cases the
onset, of acute and chronic neurological conditions, such as AD,
PD, stroke and MS (Mogi et al., 1996; Griffin et al., 2006; Owens,
2002; Sawada et al., 2006). Several peptides influenced the
expression and activity of inflammatory factors that have been
implicated in neuronal injury. In this regard, centrally acting
peptides, including CRH, insulin-like growth factor I (IGF-I),
alpha-melanocyte-stimulating hormone (a-MSH), VIP, and
PACAP, have potent anti-inflammatory actions under most
conditions, whereas others, including calcitonin gene-related
peptide (CGRP) and substance P (SP) have pro-inflammatory
actions (Gonzalez-Rey and Delgado, 2007; Gravanis and
Margioris, 2005; Calcagni and Elenkov, 2006). Some of these
neuropeptides (e.g., CRH and angiotensin II (AGII)), may
simultaneously influence both pro- and anti-inflammatory
factors, resulting in shifts between these states, depending upon
the timing of exposure and concentration of these peptides.
The majority of neuropeptide-induced changes of immune
cell activity and inflammatory cascades are mediated, at some
level, by pro- and anti-inflammatory cytokines (Blalock, 1999;
Ho et al., 1996; Ransjo et al., 1998). In fact, it seems that
reciprocal neuropeptide and cytokine interactions may be
fundamental in the regulation of virtually all neuroinflamma-
tory processes. In the ensuing section we describe the role of
cytokines in orchestrating inflammatory immune responses,
and the contribution of peptides in promoting these responses.
Finally, the involvement of inflammatory cytokines in acute
(stroke and head injury) and chronic (AD and PD) neurode-
generation is presented, together with potential processes by
which cytokines might interact with peptides to influence such
pathology.
14.1. Anti-inflammatory properties of CRH
The anti-inflammatory actions of neuropeptide factors often
stem from their ability to regulate HPA functioning. Indeed,
37
CRH-induced release of glucocorticoids has well-established
inhibitory effects on the production of numerous pro-
inflammatory cytokines and peripheral lymphocytes (Glazer
and Rivest, 2004). Systemic administration of CRH or the
CRH2 agonist urocortin increased corticoid production,
resulting in the attenuation of the normal rise of IL-1b and
TNF-a associated with LPS treatment (Agnello et al., 1998).
Central CRH infusion likewise inhibited the inflammatory
effects of LPS, including the induction of the intracellular
adhesion molecule ICAM-1 on cerebral vessels, and this
treatment also impaired leukocyte infiltration into the brain
parenchyma (Casadevall et al., 1999). Furthermore, along with
a marked reduction of plasma corticosterone, the levels of IL-4,
IL-5, IL-13, IFN-g and the chemokine RANTES were all
increased in CRH knockout mice (Silverman et al., 2004),
suggesting that the balance of anti- and pro-inflammatory
cytokines was altered in the absence of normal HPA drive.
Consistent with the animal studies, in a subset of depressed
patients, hyperactive basal HPA functioning was coupled with
reduced TNF-a levels (Himmerich et al., 2006), again
suggesting that CRH-dependent corticoid activity was linked
to inflammatory cytokine functioning.
It seems that CRH may have anti-inflammatory effects
independent of glucocorticoids, as the peptide directly inhibited
TNF-a production in primary macrophages by modulating
COX-2 dependent prostaglandin production (Tsatsanis et al.,
2007). Similarly, the corticosterone antagonist cyanoketone
prevented the inhibitory effects of urocortin on TNF-a
production, but did not influence IL-1b expression, raising
the possibility that the peptide modulated IL-1b expression
through processes independent of corticosterone (Agnello
et al., 1998).
14.2. Anti-inflammatory properties of a-MSH, VIP, PACAP
and IGF-1
Like CRH, the centrally active peptide a-MSH has marked
anti-inflammatory properties, and does so through melanocor-
tin receptors that are found throughout the periphery and at
several hypothalamic and extra-hypothalamic brain regions
(Vulliémoz et al., 2006). In particular, a-MSH down-regulated
leukocyte activation and simultaneously blocked the elevation
of corticosterone, as well as inducible nitric oxidase synthase
(iNOS) and COX-2 expression in response to several
immunogenic insults (Caruso et al., 2004). Overall, many of
the anti-inflammatory effects of a-MSH may be mediated by its
ability to inhibit the transcription factor NFkB (Catania et al.,
1999). Indeed, the ability of a-MSH to inhibit TNF-a, IL-1b,
IL-6 and IFN-g secretion from olfactory and Schwann cells was
dependent upon the down-regulation of NFkB signaling (Teare
et al., 2003, 2004).
Both VIP and PACAP belong to the secretin/glucagon
family of peptides and are produced by several immune cells,
such as T lymphocytes, and share many common functions with
one another, including their anti-inflammatory effects (Gonza-
lez-Rey and Delgado, 2007). VIP and PACAP inhibit pro-
inflammatory cytokine production and reduce the action of
38 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
dendritic and T cells, as well as microglia (Gonzalez-Rey and
Delgado, 2007; Hill et al., 2007). Administration of VIP alone
elevated levels of the anti-inflammatory cytokine IL-10, and
when the peptide was co-administered with LPS, it limited the
elevation of IL-6 and plasma corticosterone ordinarily
provoked by the endotoxin (Bik et al., 2004). Similarly,
PACAP markedly reduced the ability of LPS to promote
corticosterone and TNF-a elevations and concomitantly
increased levels of T4 thyroid hormone (Baranowska-Bik
et al., 2006). In addition to these peripheral actions, systemic
VIP administration had central anti-inflammatory conse-
quences, as indicated by its ability to reduce microglial
activation following exposure to the DA neurotoxin MPTP
(Gonzalez-Rey and Delgado, 2005).
Like several other peptides, IGF-I plays a fundamental
role in the regulation of metabolism, proliferation and
differentiation of most cell types. This growth factor is also
essential for normal neuronal development and is critically
involved in the maturation of immunocompetent microglia
within the CNS (Kaur et al., 2006). Like the previously
mentioned peptides, IGF-I stimulates several anti-inflamma-
tory cytokines, including both IL-4 and IL-10 (Kooijman and
Coppens, 2004). In response to acute tissue injury, such as
third degree burns or hematoma, IGF-I functions to
equilibrate pro- to anti-inflammatory cytokine ratios,
inhibiting IL-1b, IL-6 and TNF-a, while enhancing IL-4
and IL-10 production, thereby protecting against inflamma-
tion-induced organ failure (Jeschke et al., 2002). Reciprocal
interactions exist between IGF-I and cytokines, as reflected
by the finding that TNF-a administration reduced IGF-I
expression and the apoptotic effects of TNF-a were related to
its ability to down-regulate IGF-I (Anwar et al., 2002;
Venters et al., 1999).
Taken together, it seems that certain neuropeptides act on
cytokines to promote anti-inflammatory actions or to limit the
pro-inflammatory effects that would otherwise occur. As will
become evident shortly, these anti-inflammatory effects may be
fundamental in limiting pathology related to several neurolo-
gical conditions.
14.3. Proinflammatory effects of peptides
In addition to their anti-inflammatory actions, several
neuropeptides possess pro-inflammatory effects that may come
about by virtue of their influence on COX-2, oxidative
metabolism, induction of adhesion molecules, and production
of pro-inflammatory cytokines (Agelaki et al., 2002; McEvoy
et al., 2004). However, the nature of inflammatory reactions
may change over the course of peptidergic activation, as well as
the microenvironment in which these peptides act. For instance,
although acute exposure to CRH ordinarily has anti-inflam-
matory consequences, prolonged exposure to the peptide
actually enhanced TNF-a expression within macrophages,
suggesting that the peptide had a time-dependent biphasic
effect in this regard (Tsatsanis et al., 2007). Moreover,
administration of the CRH1 receptor antagonist antalarmin
suppressed LPS induced production of IL-1b, IL-6 and TNF-a
in macrophages (Agelaki et al., 2002), indicating the
importance of this receptor in the pro-inflammatory effects
of the peptide. Conversely, IL-1b administration elevated CRH
expression within the periphery, as well as within hypothalamic
and amygdaloid brain nuclei (Nguyen et al., 1998; Day et al.,
1999).
Following injury or immune challenges, peptides such as
CGRP, SP and AG II provoke potent pro-inflammatory actions
on some cell types (Dunzendorfer et al., 1998). For instance,
central infusion of CGRP antagonists reduced IL-6 release from
injured neurons (Ma and Quirion, 2006) and CGRP itself
enhanced the production of IL-1b and TNF-a from herpes
simplex virus type-1 infected macrophages (Yaraee et al.,
2003). Similarly, SP provoked IL-1b, IL-6 and TNF-a release
from blood monocytes, and perpetuated activation of lympho-
cytes and mast cells (Lotz et al., 1988; Kimball et al., 1988;
Delgado, 2003). Following neurogenic inflammation provoked
by afferent nerve stimulation, application of SP sensitized
central pain fibers, provoked alterations of cerebral blood vessel
constriction and recruited circulating lymphocytes and macro-
phages (Gendek-Kubiak, 2002). As well, SP may influence
BBB permeability through mast cell activation elicited
following exposure to inflammatory and stressful insults
(Annunziata et al., 2002; Singh et al., 1999).
In the case of AG II, the osmoregulatory peptide may have
some anti-inflammatory actions in addition to its potent pro-
inflammatory effects upon the cardiovascular and renal systems
(Schmieder et al., 2007; Ferder et al., 2006). Indeed, AG II
inhibited the inflammatory effects of a cold stressor, causing a
reduction of stress-induced expression of TNF-a, prostaglandin
(PGE2) and adhesion protein ICAM-1, and prevented
neutrophil infiltration into the gastric mucosa (Bregonzio
et al., 2004). However, in the absence of a stressor, the peptide
induced vascular expression of adhesion molecules, and
promoted cytokine and chemokine expression (Dandona
et al., 2007; Ferder et al., 2006). Correspondingly, AG II
receptor blockers inhibited inflammatory mediators, including
oxidative species and C-reactive protein (Dandona et al., 2007).
Certainly, in the case of cardiovascular insults, AG II acts in a
pro-inflammatory capacity since the peptide was found to
contribute to cytokine and chemokine regulated inflammatory
damage following myocardial infarction (Schmieder et al.,
2007).
Summarizing briefly, depending upon the peptide in
question and the specific physiological context, neuropeptides
may have anti-inflammatory or pro-inflammatory effects.
Clearly, in considering the influence of these peptides in the
development of pathology, these divergent peptidergic actions
ought to be considered. Although the present review focuses
only on a subset of such peptidergic factors (largely owing to a
paucity of information), the possibility should not be ruled out
that a wide range of peptides could potentially influence
neuronal survival and functioning. Moreover, as indicated
earlier, it ultimately may be important to consider the
interactive effects of different peptides or peptide-cytokine
combinations in mediating or moderating the effects of various
challenges.
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
15. Neuropeptide and cytokine interactions in the
modulation of neurodegeneration
Neuroinflammatory factors, including both pro- and anti-
inflammatory cytokines, are elevated in response to acute
trauma as well as chronic disease states, including stroke, acute
head injury, AD, PD and MS (Hillhouse et al., 1998; Hopkins
and Rothwell, 1995; Mogi et al., 1994, 1995, 1996; Mrak et al.,
1995; Rothwell, 1999; Griffin et al., 1995). Certain disease
states, such as cardiovascular conditions, are accompanied by a
rapid and persistent increase of TNF-a within the hypothala-
mus (Francis et al., 2004). As will be seen shortly, if one accepts
that cytokines contribute to depressive illness, then the long-
term central cytokine changes might contribute to the
comorbidities that have been reported (e.g., the comorbidity
between cardiovascular illness and depression; Frasure-Smith
and Lesperance, 2005). Yet, it ought to be underscored that
cytokines may have both neuroprotective and neurodestructive
factors, depending on the specific cytokine considered, the
concentration of the cytokine, and the specific constellation of
cytokines that might be present (Stoll et al., 2000).
As already indicated, peptides may influence neurodegen-
erative processes through their impact on cytokines and
neuroinflammatory mechanisms (Allan et al., 2005; Hayley
et al., 2005; Niissalo et al., 2002), and peptide-cytokine
interactions likely play a role in disturbed neuroimmune
communication that typically characterizes these pathological
conditions. Yet, it is uncertain whether the peptide-cytokine
mediated inflammation primarily acts to promote neurotoxic
outcomes, or whether they actually serve in a neuroprotective
capacity. For instance, it may be that relatively low endogenous
cytokine levels act protectively to buffer against damage related
to death processes, whereas chronically elevated levels (or very
high levels) of these factors might contribute to neuronal
damage (Bruce et al., 1996). Indeed, low levels of cytokines can
provoke the release of beneficial trophic factors and free radical
scavengers, such as GDNF and manganese superoxide
dismutase (MnSOD), whereas elevated levels of cytokines,
including IL-1b and TNF-a, can provoke damaging oxidative
radicals and caspase-dependent apoptotic cascades (Rogers
et al., 2001; von Boyen et al., 2006; Saud et al., 2005).
Ultimately, the concentration and timing of release of these
cytokines and the activation state of neighboring immune cells,
such as microglia, likely determine the nature of cytokine
consequences within specific microenvironments. As such, it is
likely that the ‘‘ebb and flow’’ of cytokine and peptide changes
that occur over the course of neurodegeneration might
differentially influence neuronal survival and functioning. It
is possible that factors that may be beneficial at early stages of a
disease may assume a deleterious role later in disease
progression.
The conjoint and temporal patterns of action of multiple
cytokines (i.e., shifts of pro- and anti-inflammatory factors)
likely determine the course of neurological diseases. At the
same time, however, the neuropeptide factors associated with
one form of illness may be distinct from those associated with a
second disease state. In the case of acute neurodegeneration
39
associated with stroke and head injury, CRH is thought to play a
prominent role, and hence will be discussed in detail. In relation
to chronic conditions, specifically AD and PD, important roles
for VIP and IGF-I have been suggested, and are thus discussed
accordingly.
15.1. Role of cytokines and CRH in stroke
Several lines of evidence favor a role for IL-1b in stroke,
including those demonstrating that IL-1b and its receptor
antagonist, IL-1ra, were elevated by middle cerebral carotid
artery occlusion (MCAO) and that central infusion of IL-1b
exacerbated the neuronal damage provoked by ischemic insult,
as well as that induced by administration of excitotoxins such as
kainic acid or glutamate analogues (Rothwell, 1999; Yamasaki
et al., 1995). Conversely, inhibition of IL-1b reduced ischemic
infarct size, whereas immuno-neutralization of IL-1ra (i.e.,
attenuating the effects of the endogenous IL-1 receptor
antagonist) markedly exacerbated neuronal damage (Loddick
et al., 1997; Lucas et al., 2006). The effects of IL-1b upon
ischemic neural damage may be mediated, at least in part, by
the well-established stimulatory actions of the cytokine on
CRH expression within the hypothalamus or cortical regions
(Allan et al., 2000). That said, a reciprocal relationship appears
to exist between IL-1b and CRH, as knockout mice lacking
CRH displayed attenuated mRNA for the cytokine following
LPS administration (Pournajafi Nazarloo et al., 2003),
suggesting that endogenous CRH levels were necessary for
production of the cytokine. Furthermore, as indicated earlier,
IL-1b augments monoamine turnover and depolarization of
hypothalamic parvocellular soma in the PVN, resulting in
enhanced CRH release from terminals in the median eminence
(Ferri et al., 2005; Mohankumar and MohanKumar, 2005). As
well, cytokine-induced elevation of CRH expression within the
hypothalamus, coupled with enhanced sensitivity of these
neurons to subsequent stressful challenges (Schmidt et al.,
1995; Tilders and Schmidt, 1998), may influence the response
to later insults, such as cerebral ischemia and myocardial
infarction.
It is likely that the deleterious effects of CRH in stroke
depend upon its modulation of one or more intermediate
messengers, including IL-1b or other vascular factors, as direct
in vitro application of CRH on primary cortical neurons did not
cause cell death nor did it modify the neurotoxic actions of
NMDA (Craighead et al., 2000). Although CRH alone did not
influence neuronal survival of cultured hippocampal neurons,
in the presence of oxygen and glucose deprivation, CRH
augmented hippocampal degeneration, and conversely, a CRH
antagonist prevented such an outcome (Wang et al., 2004).
As in the case of in vitro models, analyses of CRH and
cytokine variations within in vivo models of stroke have
supported a link between these factors in the modulation of
neural injury. Moreover, ischemia stemming from MCAO
resulted in a time-dependent increase of CRH mRNA
expression together with elevation of several cytokines,
including IL-1b and TNF-a (Block et al., 2005; Loddick
et al., 1997; Minami et al., 1992), and it appears likely that like
40 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
IL-1b, TNF-a may play an important role in mediating some of
the effects associated with stroke (Heldmann et al., 2005;
Martin-Villalba et al., 2001; Zaremba and Losy, 2001). In this
regard, TNF-a was rapidly induced following MCAO (Intiso
et al., 2004; Sairanen et al., 2001; Vila et al., 2000) and may act
upon microglia to promote glial-dependent neural injury.
Indeed, inhibition of TNF-a, using either genetic or pharma-
cological manipulations, attenuated infarct volume following
ischemia (Dawson et al., 1996; Esposito et al., 2007; Martin-
Villalba et al., 2001). Parenthetically, a genetic link between
TNF-a and stroke was suggested by the significant association
found between a polymorphism of the TNF-a type 1 and 2
receptors and increased susceptibility to stroke within a Korean
population (Lee et al., 2004).
Interestingly, under some conditions, TNF-a may also have a
neuroprotective action with respect to particular aspects of
stroke. For instance, the cytokine was found to be fundamental
for the establishment of ischemic tolerance, wherein a mild non-
degenerative ischemic or inflammatory insult protected neurons
from the damaging effects of a subsequent more severe ischemic
challenge (Castillo et al., 2003; Pradillo et al., 2005). In effect,
after an ischemic preconditioning challenge the cytokine that is
released may function in a neuroprotective capacity, but in the
absence of this precondition it may contribute to neural injury
(Rosenzweig et al., 2004). Finally, it is also important to consider
that other cytokines might, either independently or in conjunc-
tion with IL-1b and TNF-a, influence the neurodegenerative
course of cerebral ischemia. In this regard, the elevated central
expression of IL-6 provoked by stroke may act in a
neuroprotective fashion. Indeed, the cytokine was reported to
protect neurons from the NMDA mediated neuronal excitotoxi-
city associated with an ischemic event (Ali et al., 2000).
15.2. Role of cytokines and CRH in sequelae of acute head
injury
In addition to playing a role in moderating the response to
stroke, it seems that other forms of brain injury are also
associated with marked cytokine and CRH changes. Once again,
it is not entirely certain whether the elevated cytokine levels
reflect an effort to act in a protective capacity or whether the
cytokines, in fact, contribute to pathology. Acute traumatic head
injury induced CRH expression within the amygdala and
hypothalamus, but surprisingly not in the cortical area that
sustained direct damage (Roe et al., 1998). Although elevated
hypothalamic CRH mRNA was provoked by traumatic head
injury, levels of hypothalamic AVP and circulating corticoster-
one were not affected by the insult (Grundy et al., 2001).
Likewise, fluid percussion injury increased hypothalamic CRH
mRNA, even in the absence of increased circulating corticoster-
one, suggesting that the peptide might moderate the con-
sequences of traumatic injury, independent of glucocorticoid
activation (Grundy et al., 2001). It is possible that CRH
contributes to neural injury through its effects upon cytokines and
inflammatory microglia. In support of this contention, in vitro
application of CRH alone had no effect on hippocampal neurons,
but when they were co-cultured with microglia, CRH promoted
neuronal degeneration through up-regulation of the pro-
apoptotic TNF-a family member Fas (Wang et al., 2004).
Moreover, it seems that the impact of CRH on TNF-a release
from microglia may have stemmed from activation of MAP
kinase signaling (Wang et al., 2003). Thus, it appears that MAP
kinase signaling may be fundamental in the promotion of
neurodegenerative processes, just as they appeared to play a role
in subserving depression. In both instances, CRH and cytokines
might contribute to stressor- or trauma-induced pathology by
virtue of their effects on MAP kinase signaling.
Although the BBB ordinarily protects the brain from large
molecules that might disturb neural integrity, it seems that with
traumatic head injury there is a breakdown of the BBB (at least
temporarily), coupled with activation of resident glial cells, and
the consequent induction of pro-inflammatory cytokines
(Feuerstein et al., 1997; Jensen et al., 1997; Sullivan et al.,
1999). Electron microscopy studies indicated that TNF-a was
elevated in lysosomes of glial cells at the site of injury 30 min
after a percussive insult, and levels of this cytokine were
elevated within the hippocampus and parasagittal cortex 1 h
following the injury (Kita et al., 1997). The severity of
traumatic brain injury influences the nature of cytokine changes
observed, with moderate injury provoking IL-6 and TNF-a,
whereas a relatively severe insult was required to elevate IL-1b
expression (Ahn et al., 2004).
It is thought that up-regulated cytokine expression might be
fundamental in the provocation of the brain damage observed
after traumatic head injury as well as in association with the
edema seen after percussion injury (Knoblach et al., 1999;
Morganti-Kossmann et al., 1992). Such an outcome may occur
through alterations of growth factors, metabolic turnover or brain
temperature, especially as hypothermic treatments not only
reduced severity of injury, but also diminished TNF-a expression
within the injured hippocampus (Vitarbo et al., 2004).
Several studies have begun to focus on lesser known
cytokines, such as IL-23 and IL-18 (which have also been
implicated in multiple sclerosis; Wheeler and Owens, 2005), in
the modulation of neural injury following traumatic insults. For
instance, inhibition of IL-18, a member of the IL-1 family,
significantly improved functional recovery following a closed
head injury (Yatsiv et al., 2002). Similarly, greatly attenuated
infarct volume following cerebral ischemia was apparent in IL-
18 deficient mice (Hedtjärn et al., 2002). It has been suggested
that IL-18 and it’s family member IL-1b might contribute to
different phases of degeneration following cerebral ischemia,
as IL-1b was elevated in microglia within hours following the
insult, whereas IL-18 expression only became apparent after
several days (Jander et al., 2002). It may be that IL-18
contributes to later occurring neuronal loss following cerebral
damage, possibly by influencing TNF-a, Fas or IFN-g signaling
(Prinz and Hanisch, 1999; Zhang et al., 2007).
15.3. Role of cytokines, VIP, and PACAP in Parkinson’s
disease
Epidemiological studies have implicated several environ-
mental toxins in the development of PD, with the incidence of
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
the disease being high in areas with heavy usage of certain
pesticides, such as rotenone and paraquat (Betarbet et al., 2000;
Jenner, 2001; Liu et al., 2003; Thiruchelvam et al., 2000; Tsui
et al., 1999). These pesticides also promote a loss of substantia
nigra pars compacta (SNc) DA neurons in rodents and induce
the activation of microglia and production of neuroinflamma-
tory factors (Gao et al., 2003a; Liu et al., 2003; Peng et al.,
2004). Additionally, repeated exposure to certain viral or
bacterial infections was associated with increased risk of
developing PD. In fact, a viral hypothesis for PD suggests that
prenatal or early in life infection with latent virus(es) (having a
long incubation period) may instigate this disease state
(Ringheim and Conant, 2004; Takahashi and Yamada, 1999).
For instance, cases of PD associated with von Economo
encephalitis, influenza epidemics and HIV have been reported
years after infection (Dickman, 2001; Koutsilieri et al.,
2002a,b). Exposure to a bacterial pathogen may also play a
role in PD, as prenatal LPS exposure provoked SNc DA neuron
loss coupled with elevated nigrostriatal TNF-a in adulthood
(Carvey et al., 2003). Similarly, early endotoxin treatment
elicited protracted effects upon emotional and ischemic
responses in adulthood (Perry et al., 2003; Spencer et al.,
2005, 2006). Thus, early immunogenic exposure may provoke
mild neuroinflammation that, over time, causes neurodegen-
eration or renders DA neurons vulnerable to the effects of
normally low-grade insults (Thiruchelvam et al., 2000).
In addition to their independent consequences, immune
infection may interact with environmental insults (pesticides)
that were related to exaggerated neuroinflammatory, neurode-
generative and behavioral changes in neurological patients
(Perry et al., 2003). For instance, co-administration of LPS with
the pesticide rotenone synergistically augmented DA loss in
midbrain-microglial co-cultures (Gao et al., 2003a,b). In vivo
studies also indicated that although the pesticide maneb had no
effect on DA neurons, when co-administered with paraquat it
synergistically enhanced nigrostriatal damage primarily
through microglial-dependent reactivity (Thiruchelvam et al.,
2000). Evidently, different classes of environmental insults may
synergistically activate neurodestructive mechanisms that
involve inflammatory processes.
Inflammatory insults may also sensitize DA neurons to the
neurodegenerative effects of subsequent paraquat treatment.
Specifically, infusion of LPS into the SNc sensitized DA
neurons, such that the neurodegenerative effects of the pesticide
were greatly increased when administered 2 days following the
endotoxin (Mangano and Hayley, in press). It is possible that
activation of neuroinflammatory cascades within the SNc
enhanced DA neuronal vulnerability by promoting microglial-
dependent damaging processes, while concomitantly down-
regulating astrocyte protective responses. This perspective is
consistent with previous reports that the anti-inflammatory drug
3-hydroxymorphinan protected DA neurons from the effects of
LPS by stimulating astrocytes and inhibiting the actions of
microglia (Zhang et al., 2005).
Consistent with a role for pro-inflammatory cytokines in PD,
postmortem analyses of brain tissue revealed numerous signs of
inflammation, including microglial activation and increased
41
levels of several pro-inflammatory cytokines (IL-1, IL-2, IL-6
and TNF-a), as well as expression of elements of the
complement cascade important in mediating antibody depen-
dent cytotoxicity (Czlonkowska et al., 2002, 2005; Sawada
et al., 2006; McGeer et al., 2002, 2003). However, unlike the
data regarding multiple sclerosis and stroke, definitive evidence
of T lymphocytes within the PD brain is lacking. Yet, reduced
circulating levels of T cells and impaired mitogen induced
proliferative responses in PD patients indicate some degree of
altered peripheral immunity (Czlonkowska et al., 2002).
Further support for an immune abnormality in PD stems from
the finding that circulating natural killer cell (NK) levels were
elevated in patients and positively correlated with disease
severity (Bokor et al., 1993). Moreover, auto-antibodies
reactive against basal ganglia neurons were present in a subset
of PD patients (30%) (Abramsky and Litvin, 1978),
suggesting a humoral immune response that was directed
against the CNS. Likewise, examination of cases of parkinson-
ism related to encephalitis revealed that 95% of patients had
auto-antibodies reactive against basal ganglia antigens (Dale
et al., 2004).
Ordinarily IFN-g and TNF-a participate in immune
surveillance mechanisms responsible for protecting the
organism from tumor and viral invasion. Yet, these factors
may be inappropriately activated in neurological disease states,
and might actually damage neurons by promoting inflammatory
and oxidative factors. Several studies involving TNF-a receptor
knockout mice reported that neutralization of TNF-a signaling
attenuated the degeneration of SNc neurons and the accom-
panying striatal DA alterations associated with MPTP treatment
(Ferger et al., 2004; Sriram et al., 2002). As well, among IFN-g
knockout mice attenuated DA neuronal loss occurred following
in vivo MPTP treatment, and in vitro neutralization of IFN-g
attenuated the impact of rotenone upon mesencephalic DA and
microglial co-cultures (Mount et al., 2007).
Like IFN-g the administration of IFN-a was found to
influence processes that might be related to PD. By example, in
rodents IFN-a depressed motor activity, coupled with reduced
DA levels (Shuto et al., 1997) Likewise, in rhesus monkeys
IFN-a altered DA functioning in association with elevated
huddling (Felger et al., 2007), and in normal human volunteers,
IFN-a disrupted psychomotor responding (Smith et al., 1988).
Moreover, in patients undergoing immunotherapy, the cytokine
elicited symptoms reminiscent of PD that could be attenuated
by l-DOPA (Sunami et al., 2000). Together these data are
consistent with the perspective that IFN-a may influence brain
regions relevant to Parkinson’s disease, namely the basal
ganglia and substantia nigra.
In contrast to the deleterious consequences of IFN-g and
TNF-a, certain interleukins, including IL-6 and the potent anti-
inflammatory cytokine IL-10 may have neuroprotective actions
in PD. Indeed, IL-6 knockout mice exhibited enhanced
degeneration of SNc DA neurons and striatal terminals
following MPTP, suggesting augmented sensitivity in the
absence of endogenous levels of the cytokine (Bolin et al.,
2002). The IL-6 deficient mice also displayed attenuated
microglial and inducible nitric oxide responses, but normal
42 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
astrocyte levels after MPTP (Cardenas and Bolin, 2003).
Support for a potential role for IL-10 in PD also comes from the
finding that a polymorphism of the IL-10 gene promoter was
associated with an earlier age of disease onset (Hakansson
et al., 2005). Moreover, IL-10 administration protected SNc
DA neurons from the damaging consequences of the
inflammatory endotoxin LPS (Arimoto et al., 2006; Qian
et al., 2006).
Although IL-6 can have pro-inflammatory actions, including
the provocation of an acute phase response, this cytokine also
shares many anti-inflammatory immune functions with IL-10,
including the inhibition of macrophage activation and release of
TNF-a (Niemand et al., 2003; Petersen and Pedersen, 2005;
Riley et al., 1999). Many of the overlapping effects of IL-6 and
IL-10 may stem from similar signaling mechanisms primarily
involving activation of JAK and STAT proteins. Essentially,
STATs are phosphorylated by JAK kinases, resulting in their
dimerization and subsequent translocation to the nucleus to
initiate the transcription of several target genes that regulate
inflammatory and neurodegenerative processes. Particular
attention has focused upon STAT3 in modulating many actions
of IL-6 and IL-10 (Niemand et al., 2003; Riley et al., 1999).
Moreover, several other cytokines with neurotrophic properties,
including G-CSF, ciliary neurotrophic factor and erythropoie-
tin, had neuroprotective effects through STAT3 activation in
models of stroke and retinal degeneration (Ji et al., 2004; Kretz
et al., 2005; Schabitz et al., 2003).
It has been our contention that through JNK signaling,
cytokines might promote neurodegerative processes, whereas
activation of JAK-STAT pathways might actually act in a
neuroprotective capacity. In this respect, IFN-g and TNF-a are
proposed as having primarily neurodestructive actions, whereas
IL-6 and IL-10 serve in a protective fashion. Fig. 2 depicts
proposed neurodestructive pathways involving microglial
activation by IFN-g and TNF-a, and the view is offered that
IL-6 and IL-10 may act through astrocytes to attenuate
neurodegenerative processes that may be fundamental in
promoting toxin-induced PD-like pathology.
Although limited evidence is available concerning neuro-
peptide alterations in PD, several reports suggested that certain
peptide factors, through their anti-inflammatory properties,
may be neuroprotective in animal models of this disorder. Of
these, VIP has recently emerged as having potent neuropro-
tective consequences in several models of PD, including
exposure to DA toxins, such as MPTP (Delgado and Ganea,
2003). As well, it has been shown that leptin administration,
through activation of the ERK pathway, attenuated the
neurodegerative effects of 6-OHDA (Weng et al., 2007).
Both VIP and PACAP (which share 60% homology), but not
other members of this peptide family, including secretin and
glucagons, greatly attenuated the loss of DA neurons associated
with MPTP treatment (Delgado and Ganea, 2003). As well, VIP
prevented the neurotoxic effects of 6-OHDA upon cultured
neurons, possibly by buffering the resistance of these cells to
oxidative stress (Offen et al., 2000). It appeared that the
neuroprotective effects of VIP and PACAP were dependent
upon their inhibition of microglial activation and release of IL-
Fig. 2. Schematic representation of the route by which cytokines might
influence degeneration of DA neurons as occurs in Parkinson’s disease.
Following toxin exposure (e.g. paraquat), IFN-g together with TNF-a (both
of which may stem from peripheral immune cells or from local glial production)
may promote microglial reactivity and drive production of inflammatory
prostaglandins (PGEs), reactive oxidative species (O2 , NO), and neuronal
apoptotic factors (JNK, caspases). These, in turn, induce behavioural variations
and may contribute to neurodegeneration. In addition, the lower portion of the
figure depicts the proposition that IL-6 and IL-10 might act upon astrocytes to
promote activation of JAK kinases resulting in STAT3 phosphorylation and the
production of neuroprotective factors, such as the anti-oxidant, MnSOD or other
growth and anti-apoptotic factors (e.g. oncostatin M, Bcl-2). Essentially,
astrocyte activation by these cytokines may have neuroprotective consequences
by inhibiting microglial activity or directly blocking pro-death cascades at
nigrostriatal DA neurons (dashed lines). Of course, IL-6 and IL-10 may also
have anti-inflammatory or neuroprotective actions independent of astrocytes,
but these are not considered in detail in the figure.
1b, TNF-a and reactive oxygen species (Delgado and Ganea,
2003). These neuroprotective effects likely stemmed from their
inhibitory actions on the transcription factor, NFkB (Hulley
et al., 1995). It will be recalled that NFkB is a well-established
transcriptional regulator of pro-inflammatory cytokine produc-
tion, and inhibition of its expression prevented LPS-induced
cytokine release from microglia (Laflamme and Rivest, 1999;
Lee et al., 2005; Takatsuna et al., 2005). Moreover, NFkB was
shown to modulate microglial expression of other transcription
factors (e.g., STAT1) that are associated with IFN-g and IL-6
signaling (Lee et al., 2005). Hence, VIP and PACAP may have
their positive actions on neurodegenerative processes by acting
on neuroinflammatory NFkB signaling pathways (as described
in Fig. 2).
Besides microglial NFkB signaling, the neuroprotective
consequences VIP may have involved modulation of brain mast
cell activity (Tunçel et al., 2005). In fact, VIP prevented the
behavioral disturbances normally associated with the DA
neurotoxin 6-OHDA, and this effect was related to changes in
brain mast cell expression without affecting the inflammatory
exocytosis associated with these cells (Tunçel et al., 2005). It
seems, as well, that VIP may influence DA neuronal survival by
promoting the activity of protective growth factors. Specifi-
cally, the peptide imparted neuroprotective actions by
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
stimulating astrocytes to secrete activity-dependent neuro-
trophic factor (Dejda et al., 2005). Similarly, the orphan nuclear
receptor Nurr1, which is essential for proper development of
DA neurons, may influence neuronal survival through its
impact upon VIP (Luo et al., 2007).
15.4. Role of IGF-I and cytokines in Alzheimer’s disease
(AD)
Cytokines have been implicated in the formation of senile
plaques, which represent a defining histological feature of AD.
For instance, IL-1b and IL-6 have been associated with the
deposition of b-amyloid in neuritic plaques and with the
development of neurofibrillary tangles (Cotter et al., 1999;
Eikelenboom et al., 2006; Heneka and O’Banion, 2007).
Activated microglia, together with IL-1b, IL-6 and TNF-a,
have frequently been found in conjunction with neuritic plaques
(Cotter et al., 1999; Eikelenboom et al., 2006; Kim and Joh,
2006; Haga et al., 1989). These cytokines may interact with one
another or with endogenous b-amyloid to influence neurode-
generation. In this regard, TNF-a, IL-1b and IFN-g synergis-
tically enhanced the release of the free radical nitric oxide from
astrocytes, an effect that was further amplified by addition of
soluble b-amyloid fragments (Chiarini et al., 2006). As well,
neuritic plaque-associated microglia expressing IL-1a were
more likely to be in an activated phagocytic state than those not
associated with plaques (Sheng et al., 1997).
Indirect evidence concerning inflammatory processes in AD
comes from studies of arthritic patients, in which anti-
inflammatory drugs that antagonized these cytokines were
associated with reduced risk of AD (Heneka and O’Banion,
2007; McGeer and McGeer, 1999; McGeer et al., 2002). The
mechanism by which anti-inflammatory treatments attenuate
AD plaque formation is uncertain. Nevertheless, it was reported
(Simard et al., 2006) that in contrast to resident microglia, those
derived from bone marrow might actually play a role in limiting
senile plaque formation.
Not only are cytokines associated with the presence of
neuritic plaques, but they may also contribute to plaque
maturation. Although the presence of neuritic plaques in AD
patients correlates with clinical dementia, the earlier, pre-
sumably less mature, diffuse plaques do not correlate well with
cognitive decline (Ding et al., 2007; von Gunten et al., 2006).
One intriguing hypothesis that has been offered is that
cytokines, in fact, drive the evolution of the plaques into their
more mature dense core forms (Griffin et al., 2006; Liu et al.,
2005). Thus, IL-1 and IL-6 may contribute to AD pathology by
increasing b-amyloid deposition and dystrophic neurite
formation (Griffin et al., 2006). Evidence in favor of this
hypothesis is supported by reports indicating that IL-1b
released from microglia may provoke the release of the
neurotrophin S100b from adjacent astrocytes, which may then
contribute to the development of dystrophic neurites and other
pathological alterations in neuronal elements associated with
the plaques (Liu et al., 2005). Other cytokines, including TNF-
a and IFN-g, may also contribute to b-amyloid deposition. In
fact, both of these cytokines enhanced b-amyloid production
43
from co-cultures of astrocytes and microglia, whereas
inhibition of IFN-g reduced b-amyloid accumulation and
gliois in a genetic model of AD involving mutation of the b-
amyloid precursor protein (Yamamoto et al., 2007). In addition,
cytokines may promote AD pathology by interfering with the
production of growth factors critical for the proper maintenance
of neurons. For instance, IL-1b inhibited BDNF signaling in
cultured neurons by blocking activation of the ERK MAP
kinase pathway (Tong et al., 2007). Taken together, these data
suggest that cytokines, through their actions on b-amyloid and
growth factor functioning, may influence the course of AD.
Besides acting in a provocative capacity in b-amyloid
induced neurodegeneration, cytokines may also function in a
protective manner. For instance, pretreatment of neuronal
cultures with TNF-a reduced hippocampal neuronal death and
hyperphosphorylation of tau protein provoked by b-amyloid
(Orellana et al., 2007). However, as already mentioned, TNF-a,
together with IL-1b and other pro-inflammatory cytokines,
served to enhance b-amyloid accumulation and augmented its
neurodegenerative effects (Chiarini et al., 2006). In fact, it was
reported that activation of TNF-R1 and the subsequent
induction of apoptotic protease-activating factor (APAF) were
required for b-amyloid induced neuronal death to occur (Li
et al., 2004a,b). The duality of functioning of TNF-a in
neuronal survival may stem from the differential activation of
its two receptor subtypes, TNF-R1 and TNF-R2. Whereas TNF-
R1 has pro-death effects that are mediated by its intra-cellular
death domain and associated apoptotic caspases, TNF-R2
mainly has pro-survival and proliferative functions (Dopp et al.,
2002; Neta et al., 1992). Indeed, TNF-R2 activation typically
stimulates several intra-cellular adapter proteins that influence
the production of a number of neuroprotective proteins by
NFkB (Baud and Karin, 2001; Fernyhough et al., 2005). As
well, the degree of activation of microglial cells may influence
the neurodegenerative effects of TNF-a. Indeed, this cytokine
had neurotoxic effects in neuronal cultures exposed to b-
amyloid in the presence of microglia, but not in those treated
with the glial suppressor Ara-C (Chao et al., 1993; Takeuchi
et al., 2006; Orellana et al., 2007). These findings suggest that
the TNF-a exposed glia may be releasing toxic factors that
counteract any effects that the cytokine may have on
neuroprotective pathways.
In addition to the direct central actions of cytokines,
infectious agents may influence systemic cytokines and
immune cell functioning that may, in turn, contribute to AD
pathology. Indeed, LPS-provoked elevations of circulating IL-
1b and IL-6, coupled with that of several chemokines,
augmented neuronal damage associated with reduced cerebral
blood flow and was posited to contribute to the pathology
observed in cases of AD involving neurovascular changes
(McColl et al., 2007). Variations of circulating cytokines may
also contribute to the progression from pre-clinical states,
characterized by mild cognitive impairment, to the AD
syndrome. Peripheral blood monocytes derived from elderly
individuals experiencing mild cognitive impairments displayed
higher levels of mitogen stimulated IL-6, IL-8 and IL-10
compared to healthy age-matched controls (Magaki et al.,
44 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
2007). As well, serum TNF-a levels were elevated in AD and in
patients with mild cognitive impairment, and levels of the
cytokine were negatively correlated with concentration of the
protective growth factor IGF-1 (Alvarez et al., 2007).
Although several genes have been implicated in the
development of AD, it seems that APOe E4 may be particularly
important in this respect (Mahley et al., 2006). Moreover,
recent findings also suggested that cytokine gene polymorph-
isms may have predictive power with regard to AD. For
instance, a polymorphism in the promoter region of the IL-10
gene was found in an Italian sample to predict increased risk of
AD (Bagnoli et al., 2007). Additionally, a polymorphism of the
IL-18 gene ( 137 C/C) was associated with a faster rate of
cognitive decline in AD patients (Bossù et al., 2007).
In addition to cytokines, insulin and IGF-I may be involved
in AD, as the peptide was reported to regulate amyolid
precursor protein (APP) processing and hence central levels of
b-amyloid (Adlerz et al., 2007). A role for IGF-I in the disease
has also been suggested by the finding of a polymorphism of the
IGF-I receptor in a subset of female AD patients (Garcia et al.,
2006). Similarly, disturbances of the IGF-I receptor were
reported in transgenic animal models of AD, as well as in
diabetic mice that displayed signs of dementia (Wu et al., 2006;
Li et al., 2007). As might be expected, administration of IGF-I
prevented cognitive and vascular dysfunction, and increased
central IGF-I receptor levels in AD-like mutant mice that over-
express amyloid precursor protein/presenilin genes (Lopez-
Lopez et al., 2007).
Many of the functions of IGF-I in AD may be associated
with the ability of the peptide to influence neuroinflammatory
cascades. In this regard, IGF-I attenuated the behavioral effects
of LPS (Bluthe et al., 2006), and conversely, exposure to TNF-a
induced neuronal apoptosis by inhibiting IGF-I pro-survival
signals (Venters et al., 1999). Similarly, reduced IGF-I
expression was associated with increased IFN-g levels, along
with deficits in hippocampal long-term potentiation (Maher
et al., 2006). Thus, pro-inflammatory cytokine activity may be
negatively coupled to IGF-I expression, and hence interactions
between these factors may have important modulatory effects
upon cognitive neuronal processes. Moreover, the insulin
receptor substrates 1 and 2 (IRS-1 and -2), which are adaptor
proteins essential for IGF signaling, require the anti-inflam-
matory cytokine, IL-4, in order to induce proliferation of B and
T lymphocytes (Hartman et al., 2004). Together, these data
suggest that IGF-I may act to suppress the deleterious central
consequences of pro-inflammatory stimuli (TNF-a, IFN-g),
while interacting with anti-inflammatory elements (IL-4) to
provide pro-cellular functions.
16. Cytokines mediate the comorbidity between
depression and neurodegenerative conditions
As indicated earlier, comorbidity between psychiatric
illnesses and neurological conditions is fairly common, and
not surprisingly, the presence of depression may also hinder
alleviation of symptoms related to these disorders. Despite the
complications associated with dealing with comorbid illnesses,
and the difficulties in the choice of treatments given different
comorbidities (Goodnick and Hernandez, 2000), knowledge of
the processes that lead to a given disturbance may facilitate the
identification of the mechanisms that promote a second
disturbance, and might also be instrumental in the development
of more effective treatment strategies for both.
In some instances the development of comorbid depression
that occurs in conjunction with physical illness might be a result
of the distress attributable to the disease or it may be secondary
to the psychosocial stress associated with it. Yet, it has also been
reported that at least some of these comorbidities cannot be
attributed to such factors, but instead might reflect the
possibility that the illnesses involve similar underlying
processes or etiologies (Leentjens et al., 2003; McDonald
et al., 2003). For instance, as mentioned earlier, stressor-
provoked elevations of corticosterone may instigate hippo-
campal neuronal damage (McEwen, 1994; Sapolsky et al.,
2000), as well as inhibition of neurogenesis (Kozorovitskiy
et al., 2004; Montaron et al., 2006), and as such could contribute
to both depression and chronic neurodegenerative diseases. In
addition to hippocampal variations, a chronic variable stressor
regimen was shown to provoke cortical cell loss, and this
outcome was synergistically enhanced by cortical administra-
tion of LPS, and attenuated by the glucocorticoid inhibitor RU-
486 (de Pablos et al., 2006). Likewise, stressor-induced
alterations of glutamate and DA activity within the basal
ganglia were suggested to have neurotoxic consequences that
might be relevant for PD (Smith et al., 2002; Zigmond et al.,
1998). Conversely, antidepressants or other agents that mitigate
the deleterious effects of stressors or provoke beneficial growth
factors may have neuroprotective actions (Hayley et al., 2005;
Manji and Chen, 2002; Peng et al., 2007). In fact, in addition to
pharmacological treatments, manipulations such as exercise,
which have positive effects on mood, had neuroprotective
consequences through the activation of GDNF and subsequent
signaling of ERK kinases (Smith and Zigmond, 2003).
Comorbid illnesses may be promoted by similar experiential
factors (e.g., protracted distress), or they may be subject to
several common underlying biological features. The specific
pathology that develops in response to a chronic stressor might
largely be determined by genetic dispositions, coupled with a
constellation of experiential and environmental factors. As
depicted in Fig. 3, there is reason to believe that activation of the
inflammatory immune system may be pivotal for the expression
of each of these pathologies discussed to this point. As shown,
multiple overlapping CNS processes may act in a feed-forward
manner, in which one illness may influence other co-morbid
conditions by acting upon common or parallel biological
processes. Of course, co-morbid psychiatric pathology may stem
from the psychosocial or prognostic burden of coping with the
aftermath of neurological disability (Sobel et al., 2005).
16.1. Depression and comorbid cardiovascular (heart and
stroke) disturbances
Of the pathologies that have been linked to major depression,
particular attention has been devoted to cardiovascular diseases
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
Fig. 3. Stressors induce depressive illness, which may be associated with
several comorbid conditions, namely vascular illness (e.g., stroke and myo-
cardial infarction), as well as neurodegenerative conditions, including Parkin-
son’s and Alzheimer’s diseases. Inflammatory processes activated in response to
stressors may be a common denominator for these varied illnesses. Indeed,
several common cytokines have been associated with these pathologies,
although in several respects they may involve different processes. Specifically,
these cytokines might contribute to comorbid pathologies through several
divergent routes, including activation of microglia (release of oxidative and
inflammatory factors), the promotion of plaque/protein aggregate formation,
and by altering vascular factors that contribute to arterial blockage (e.g., clot
formation).
(heart attack and stroke). There is, indeed, ample literature
showing that depression was a predictor of later cardiovascular
disease and illness recurrence (Frasure-Smith and Lesperance,
2005; Lespérance et al., 2004; Pratt et al., 1996; Zellweger et al.,
2004). Conversely, myocardial events were predictive of
subsequent depression (Frasure-Smith and Lesperance, 2005).
It is of interest, as well, that the covariation of depressive
symptoms and coronary artery disease may involve a common
genetic vulnerability (McCaffery et al., 2006). Inasmuch as C-
reactive protein, and other inflammatory factors (e.g., IL-6 and
soluble intracellular adhesion molecule: sICAM-1) are asso-
ciated with heart disease (Dibbs et al., 1999; Gullestad and
Aukrust, 2001) and with depression, and are also increased in
response to chronic stressors (Black, 2002; Pasic et al., 2003), the
possibility has been explored that CRP may be an underlying
factor for both these illnesses. Indeed, the presence of depression
and elevated levels of CRP were predictors of major adverse
cardiac events over a 2-year period, and the occurrence of these
events were especially frequent when individuals displayed both
elevated CRP and depression (Frasure-Smith et al., 2007).
Furthermore, it has been reported that antidepressants (SSRIs)
are not only effective in the treatment of depression among
myocardial infarction patients, but that this treatment may
facilitate management of coronary artery disease (Parissis et al.,
2007). Likewise, there is reason to believe that the inflammatory
45
immune system could serve as a therapeutic target in the
treatment of cardiovascular disease, and that anti-inflammatory
agents may play a positive role in the treatment of depression
(Brustolim et al., 2006).
Despite the impressive evidence suggesting that CRP may be
pertinent to the comorbidity that exists between cardiovascular
illness and depression (Frasure-Smith and Lesperance, 2005;
Miller et al., 2005), other reports indicated that the relation
between CRP and depression was generally weak or entirely
absent (Steptoe et al., 2003). This was especially the case when
other comorbid factors were controlled, such as body mass index
(Douglas et al., 2004). Thus, as tempting as it might be to focus
heavily on this acute phase protein, it may be a bit premature to
suggest a causal role for CRP in the evolution of depression.
As in the case of heart attack, depression is often co-morbid
with cerebral stroke following ischemia or hemorrhagic insult
(Nuyen et al., 2006). Although post-stroke depression has been
successfully treated with a variety of antidepressants (Goodnick
and Hernandez, 2000), treatment resistance is more frequent in
comparison to that evident in absence of co-morbidity
(Iosifescu et al., 2004). It appears, as well, that anxiety often
co-occurs in stroke patients already experiencing depression.
Indeed, generalized anxiety disorder co-existed with depression
in 20% of patients assessed 3–4 months after stroke, and in
addition to affecting mood symptoms, antidepressant treatment
(nortriptyline) significantly diminished anxiety, and enhanced
overall patient functioning (Kimura et al., 2003). It seems that
co-morbid depression or anxiety may be related to the severity
of functional impairment and progression of pathology
associated with stroke.
Several common biological processes may contribute to
stroke and co-morbid depression, including variations of
central monoamines and neuropeptides that are thought to
contribute to depressive illness and that may be altered by the
neurological damage that occurs following stroke (Kato et al.,
2000; Behan et al., 1996). Moreover, as shown in Fig. 3,
activation of neuroinflammatory processes occur in both stroke
and depression and as such, inflammatory signaling factors may
play a role in perpetuating the co-morbidity. In particular, IL-
1b, TNF-a and IL-6 are markedly altered within the brain and
periphery following an ischemic event, as well as in response to
psychological stressors (Dantzer, 2006; Minami et al., 1991,
2006; Spalletta et al., 2006). In fact, it was proposed that stroke-
induced elevations of IL-1b, TNF-a and IL-18 may enhance
activity of enzymatic pathways, including IDO, resulting in 5-
HT depletion at limbic brain regions, hence promoting
subsequent depressive symptoms (Spalletta et al., 2006).
Conversely, stressors that normally provoke depressive-like
pathology enhanced the damaging effects of an ischemic insult
and this outcome was thought to stem from the actions of pro-
inflammatory cytokines. In particular, stressor exposure
increased infarct size caused by later MCAO, whereas
inhibition of IL-1b or TNF-a prevented the augmenting
effects of the stressor (Caso et al., 2006, 2007). In effect, these
findings suggest that stressors might contribute to both
depressive and neurodegenerative pathology through their
actions on cytokines.
46 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
16.2. Depression and comorbid Parkinson’s disease
Depressive illness is co-morbid with 40–50% of PD cases
and often precedes the development of motor disturbances or
PD diagnosis. Beyond motor disabilities that characterize PD,
the disease is frequently associated with neuropsychiatric
symptoms, including depression, anxiety and memory dis-
turbances (McDonald et al., 2003). Given the temporal relations
between these disease states, depression has even been
suggested as a risk factor for PD development (Leentjens
et al., 2003; McDonald et al., 2003). Although PD is typically
considered a disease that involves substantia nigra DA neurons,
degeneration or dysfunction of other brain regions (e.g., those
associated with depression, such as the locus coeruleus,
hippocampus, prefrontal cortex) have indeed been reported
(Chan-Palay, 1993; Leentjens et al., 2003). Given that
inflammatory factors might influence both depressive and
PD syndromes, cytokines may contribute to the high degree of
co-morbidity that exists between these conditions (Hayley and
Anisman, 2005).
As already indicated, pro-inflammatory cytokines, such as
TNF-a and IFN-g, may contribute to PD pathology, whereas
peptides, including VIP and PACAP, may have neuroprotective
actions. Just as peptide-induced anti-inflammatory effects may
protect DA neurons, several antidepressants may gain some of
their beneficial actions by promoting anti-inflammatory out-
comes. Indeed, in addition to their mood elevating properties,
antidepressants such as rolipram and buproprion, enhanced the
production of the anti-inflammatory cytokine IL-10 while
reducing levels of the pro-inflammatory cytokines TNF-a and
IFN-g (Brustolim et al., 2006; Zhu et al., 2001). As well, the
tricyclic antidepressant imiprimine protected hippocampal
neurons from the apoptotic consequences of high doses of
LPS and these effects were related to the anti-inflammatory
actions of the antidepressant (Peng et al., 2007). Consistent
with the view expressed here, cytokine inhibitors used in
treating inflammatory disease, diminished comorbid depressive
symptoms (Kulmatycki and Jamali, 2006). Thus, it seems that
anti-inflammatory treatments might not only be useful in
mitigating neural injury and offset the development of
neurodegenerative conditions in already depressed individuals,
they might also limit the onset of depressive symptoms in
neurological patients. For instance, glatiramer acetate, a
synthetic polypeptide used to treat multiple sclerosis, was
hypothesized to have antidepressant effects through its
stimulatory actions on the anti-inflammatory cytokine IL-10,
as well as on BDNF (Tsai, 2007). From the available evidence,
it would seem likely that anti-inflammatory treatments might be
useful in the management of co-morbid neurodegenerative and
depressive pathologies, as occurs in PD.
16.3. Depression and comorbid Alzheimer’s disease (AD)
AD patients frequently (25–40%) present with co-morbid
depression (Caballero et al., 2006), and a recent meta-analysis
indicated that depression may be a significant risk factor for AD
(Ownby et al., 2006). Moreover, the presence of anxiety and
depressive symptoms among individuals with mild cognitive
impairment greatly increased the probability that they would
develop AD symptoms measured 3 years later (Palmer et al.,
2007). Similarly, co-morbid anxiety and depression additively
increased the severity of cognitive decline in AD patients
(Starkstein et al., 2007). In general, elderly individuals that
experience depressive illness appear to be particularly sensitive
to the cognitive aspects of the disorder, such that it may be
difficult to disentangle the affective disturbances from
symptoms of AD or dementia. In fact, underlying clinical
depression might be masked by a primary AD syndrome, hence
resulting in under-diagnosis of affective disturbances in the
elderly (Starkstein and Mizrahi, 2006).
As we have repeatedly emphasized, related neurobiological
and psychological (e.g., exposure to stressors) mechanisms
may give rise to depression and neurodegenerative processes. In
this respect, an increased number of hypothalamic CRH
neurons were reported in both AD and depression (Meynen
et al., 2007) and it was postulated that a hyperactive HPA axis,
characteristic of certain depressive subtypes, may engender
vulnerability to AD pathology. Conversely, disturbances of
CRH signaling stemming from loss of neurons in AD might
promote negative mood states (Raadsheer et al., 1994; Meynen
et al., 2007). Similarly, widespread degeneration within the AD
brain has been associated with monoamine deficiencies in
several brain regions (including the hippocampus, locus
coeruleus and brainstem raphe) that have been linked to
depressive symptoms (Engelborghs and De Deyn, 1997). As
such, treatments that influence common neurochemical
processes may be beneficial for both depressive and AD co-
morbid states and may even be used in a prophylactic capacity.
For instance, pretreatment with the SSRI paroxetine improved
cognitive performance and reduced the accumulation of b-
amyloid and abnormal tau protein in a transgenic rodent model
of AD (Nelson et al., 2007). As well, the proposition was
advanced that new therapies aimed at targeting cytokines and
growth factors (e.g., BDNF), together with their downstream
effectors, might be important for treatment of AD and co-
morbid depression (Kuipers and Bramham, 2006).
In addition to playing an important role in various pathologies,
inflammatory processes likely contribute to the co-evolution of
AD and depression. For instance, as seen in Fig. 3, augmented
pro-inflammatory cytokine levels may influence neuronal
functioning in brain regions (e.g., prefrontal cortex and
hippocampus) that are normally aligned with both MDD and
AD. Likewise, neurotransmitters and inflammatory factors, such
as oxidative radicals and COX-2 products, might act as triggers
for the co-evolution of these illnesses (Hussain and Mitra, 2000;
Melnikova et al., 2006). In fact, COX-2 activation was shown to
enhance b-amyloid toxicity and, as in the case of depression,
inhibition of COX-2 signaling attenuated pathology in an animal
model of AD (Liang et al., 2005; Melnikova et al., 2006).
Moreover, altered cytokine (TNF-a, IL-1b) and histamine serum
levels were correlated with the incidence of depression among
AD patients (Alvarez et al., 1996). Finally, it was reported that
co-morbid AD and depression were associated with common
genetic polymorphisms of cytokine genes (McCulley et al.,
 H. Anisman et al. / Progress in Neurobiology 85 (2008) 1–74
2004). Indeed, AD patients that were heterozygous for a
polymorphism in the promoter region of IL-1b (-511 variant)
were much more likely to develop depression relative to
individuals that were homozygous for the genetic variant
(McCulley et al., 2004). Ultimately, it may be that certain genetic
factors engender inflammatory responses to stressful or
neurotoxic insults that may favor the evolution of pathology
within multiple CNS regions.
17. Summary and conclusion
In this review, we have emphasized the importance of
considering depressive disorder in terms of endophenotypes,
rather than as a uniform illness. We indicated, as have others,
that major depression represents a cluster of features, and in
analyzing the neurochemical disturbances that characterize
depression, it is important to distinguish not only on the basis
of illness severity and chronicity but also as a function of the
symptoms that characterize the disorder. To be sure, a lengthy
list of neurochemical processes (and genes governing these
processes) have been identified in relation to MDD, and in
some instances these could be tied to specific features of the
disorder. However, tying behavioral and neurochemical
endophenotypes to one another may prove exceedingly
difficult given that neurochemical processes may interact
with one another, as well as with environmental and
experiential factors, in promoting a given symptom (or set
of symptoms).
The neurochemical features associated with the MDD
symptom profile span neurotransmitters, peptidergic factors,
inflammatory processes, and factors that influence neuronal
plasticity and neurogenesis. Some of these same features are
also prominent in illnesses that are comorbid with MDD,
most notably cardiovascular related events (including stroke
and its aftermath), PD and AD. In effect, it seems that
inflammatory processes are a common denominator for these
disorders, and it may well be that they contribute to the
provocation of these different pathological states. This is not
to say that cytokines necessarily subserve all instances of
depression (or other pathologies), but rather that immune
activation that involves inflammatory processes may give rise
to depressive features, and that these effects might be
particularly pronounced when superimposed on a backdrop of
stressful experiences. Likewise, it seems that both stressful
events and activation of inflammatory processes may promote
the sensitization of neuronal functioning so that subsequent
similar experiences give rise to more rapid and more
pronounced neurochemical changes, thereby favoring the
emergence of MDD. Whether sensitization of neurochemical
processes and synergies between stressors and inflammatory
factors contribute to the emergence of neurodegenerative
disorders and cardiovascular illness has not been examined
thoroughly. Yet, the data that are available appear to support
this view. Indeed, there is reason to believe that attenuating
depression, or the stress associated with depression, may have
positive effects on the course of illnesses comorbid with
MDD.
47
Acknowledgements
This work was supported by the Canadian Institutes of
Health Research and by the Natural Sciences and Engineering
Research Council of Canada. HA and SH hold Canada
Research Chairs in Behavioral Neuroscience and Neu-
roscience, respectively. SH also holds a NARSAD Young
Researchers Award. None of the authors have any direct or
indirect conflicts of interests of a financial nature relevant to the
present work.
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