INTRODUCTION

Endocrine responses constitute an integral component of the stress response

which involves hypothalamic-pituitary-adrenal (HPA) axis. Depending on the type of

stress, other factors such as angiotensin II, various cytokines and lipid mediators of

inflammation are secreted and act on different components of the HPA axis to

potentiate its activity (Holmes et al. 1986; Phillips, 1987). Life exists by maintaining

a complex dynamic equilibrium or homeostasis that is constantly challenged by

intrinsic or extrinsic adverse forces, the stressors (Chrousos and Gold, 1992). Under

favourable conditions, individuals can invest in vegetative and pleasurable functions

that enhance their emotional and intellectual growth, development and the survival of

their species, such as food intake and reproduction. In contrast, activation of the stress

response during threatening situations that are beyond the control of the individual,

can be associated with depression and eventually emotional or somatic disease

(Chrousos, 1992; Tsigos and Chrousos, 1994). The central control stations of the

stress system are located in the hypothalamus and the brain stem and include the

parvocellular corticotropin releasing hormone (CRH) and arginine vasopressin (AVP)

neurons of the paraventricular nucleus (PVN) of the hypothalamus, and the locus

ceruleus (LC)norepinephrine system (Chrousos and Gold, 1992; 1998).

The HPA axis, together with the efferent sympathetic/adrenomedullary system,

represents the effector limbs, via which the brain influences all body organs during

exposure to threatening stimuli (Gold et al. 1988a, b). The brain also differentially

activates a subset of vagal and sacral parasympathetic efferents that mediate the gut

responses to stress (Habib et al. 2001). There are mutual interactions of the central

stress stations with three higher brain control areas that influence and affect

anticipatory phenomena (mesocortical/mesolimbic systems); the initiation,

 Introduction

propagation and termination of stress system activity (amygdala/hippocampus

complex); and the setting of the pain sensation (arcuate nucleus) (Nikolarakis et al.

1986; Roth et al. 1988; Gray, 1989).

The response pattern of the HPA axis to stressful stimuli depends upon the

type of stress. Thus, exposure to sustained or repeated-intermittent physical-

psychological stimuli results in various degrees of adaptation to the primary

glucocorticoid responses to a novel superimposed stress (Aguilera et al. 1993; Hauger

et al. 1990). A spectrum of conditions may be associated with increased and

prolonged activation of the HPA axis, including anorexia nervosa with or without

malnutrition, obsessivecompulsive disorder, panic anxiety, chronic active

alcoholism, alcohol and narcotic withdrawal, excessive exercising, poorly controlled

diabetes mellitus, childhood sexual abuse and hyperthyroidism (Chrousos and Gold,

1992; Chrousos, 1998; Tsigos, 1993).

It is obvious that, various components of brain and HPA axis are integrated in

various ways and different downstream pathways seem to be involved in the stress

response. On the other hand, stressors are also of various types such as environmental,

metabolic/physiological and neural/psychological stressors including pollutants,

endocrine disruptors etc. In spite of many reports on stress and stress responses, there

is no specific study compiling and comparing the response of HPA axis to different

kinds of stressors. Hence purpose of this study was to understand if the effect of

different stressors are funnelled through the same mechanism and modulate the same

parameters? Another specific point to undertake this study was to test and compare

the effect of hypothalamic peptide CRH and AVP in view of the fact that pituitary

corticotrophs have receptors for both of these neuropeptides. Hence, it was though

worthwhile to study the expression of both Corticotropin releasing hormone and

Arginine vasopressin in mouse hypothalamus under different types of stress to

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 Introduction

understand when these peptides couple and uncouple to activate adrenal axis and

other stress related parameters/ molecules. In view of the above background

information, present study was designed with the following specific objectives:

Objective 1. To study the effects of environmental stressors (water and food

deprivation, pollutant) on the hypothalamic-pituitary-adrenal

(HPA) axis of laboratory mouse, Mus musculus.

Objective 2. To evaluate the effects of antineoplastic drug and herbicide on the

HPA axis.

Objective 3. To investigate the effect of neuromodulator (Cannabis sativa leaf

extract - Bhang) on the HPA axis.

Objective 4. To evaluate the xenobiotic effects of various stressors with special

reference to GST gene.

The thesis is compiled into four chapters each dealing with one objective. It is

expected that outcome of this study will be able to explain the involvement of other

mechanism(s) such as free radicals, modulation of Hsp70, nitric oxide (NO) and NF-

B during stressful conditions. Moreover, the findings will explain the differential

aspects of CRH and AVP in controlling their common target ACTH following

exposure to different types of stressors and will also strengthen our understanding in

the field of stress biology.

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