Alcohol

2010 Federation of European Psychophysiology Societies
Journalof Psychophysiology
C. Tomberg: Alcohol
2010; Vol.
Hogrefe
Pathoph
24(4):215230
Publishing
ysiology
Article
Alcohol Pathophysiology
Circuits and Molecular Mechanisms
Claude Tomberg
Brain Research Unit, Faculty of Medicine and CENOLI, Free University of Brussels, Belgium
Abstract. There is no specialized alcohol addiction area in the brain; rather, alcohol acts on a wide range of excitatory and inhibitory
nervous networks to modulate neurotransmitters actions by binding with and altering the function of specific proteins. With no hematoencephalic barrier for alcohol, its actions are strongly related to the amount of intake. Heavy alcohol intake is associated with both
structural and functional changes in the central nervous system with long-term neuronal adaptive changes contributing to the phenomena
of tolerance and withdrawal. The effects of alcohol on the function of neuronal networks are heterogeneous. Because ethanol affects
neural activity in some brain sites but is without effect in others, its actions are analyzed in terms of integrated connectivities in the
functional circuitry of neuronal networks, which are of particular interest because of the cognitive interactions discussed in the manuscripts contributing to this review. Recent molecular data are reviewed as a support for the other contributions dealing with cognitive
disturbances related to alcohol acute and addicted consumption.
Keywords: molecular mechanisms of alcohol actions, alcohol addiction, hippocampal theta rhythm, long-term neuronal adaptive changes,
alcohol withdrawal
Because alcohol is distributed by the bloodstream to all

tissues in a vascularity and water-content-related amount
(Norberg, Jones, Hahn, & Gabrielsson, 2003), it has specific actions on a wide range of excitatory and inhibitory
nervous systems. This explains the diversity of symptoms
found with alcohol intoxication, varying directly with the
speed of alcohol intake, especially if the alcohol level in
blood is on the increase. Most people feel euphoric, appear excited, are excessively talkative, and loosen their
social restraints. Others can become aggressive. And
some people are not euphoric at all but become sleepy,
even after moderate doses of alcohol.
Because alcohol, compared to other drugs, which usually act at much lower concentrations (nMM range), affects the brain only under enormous concentrations (mM),
the effects of ethanol should be caused by a summation of
effects on a number of different receptors affected at doses
much higher than those needed for light intoxication (e.g.,
after drinking half a glass of wine) (Wallner, Hanchar, &
Olsen, 2006). It is now generally accepted that ethanol acts
by binding with and altering the function of specific proteins, particularly voltage-dependent ion channels (calcium-activated potassium channels) (Dopico, Anantharam,
& Treistman, 1998), voltage-gated calcium channels
(Wang, Wang, Lemos, & Treistman, 1994; Widmer, Lemos, & Treistman, 1998), whose expression or function
seems to be modified following alteration of protein kinase
C by ethanol exposure (Walter, McMahon, Dadgar, Wang,
& Messing, 2000), rectifying potassium channels (Brodie
Hogrefe Publishing
& Appel, 1998)), and membrane-bound ligand-gated ion

channels including -aminobutyric acid (GABAA,
GABAB), N-methyl-D-aspartate (NMDA) and kainate
glutamate, glycine, nicotinic acetylcholine, and 5-hydroxytryptamine type 3 (5-HT3) receptors.
Evaluation of these actions is closely related to the
concentration of alcohol in the brain and thus the quantity
of alcohol in cerebral blood. Ethanol is fully absorbed by
the digestive tract, 25% being absorbed by the stomach
and 75% by the bowels. Ethanol may be detected in the
blood in the minutes following its ingestion. The speed
of alcohol absorption can be modified by numerous factors. For example, the presence of food in the stomach
reduces the speed of gastric absorption of alcohol. Ethanol easily goes trough biological membranes, even
through the lipid bilayer of cells, and there is no hemato-encephalic barrier for alcohol. Thus, a short time after
intake alcohol concentration in the brain is raised to a
level very close to that in the blood. Elimination is independent of alcohol concentration, which is done to
9098% by the liver, the rest being disposed of by the
kidney, the lungs, and the skin. For a man with 70 kg
body weight, metabolism eliminates 15 to 20 mg/dl per
hour. Common alcohol drinks contain about 12 to 15
grams of alcohol per liter, so that the concentration of
alcohol in blood increases when the amount disposed of
by the metabolism is exceeded. The level of blood (and
brain) alcohol steadily increases when the alcohol intake
exceeds the capacities of metabolic disposal.
Journal of Psychophysiology 2010; Vol. 24(4):215230
DOI: 10.1027/0269-8803/a000035
216
C. Tomberg: Alcohol Pathophysiology
Acute Alcohol Consumption

Enzymes Involved in Alcohol Metabolism
Alcohol is oxidized into acetaldehyde by alcohol dehydrogenase (ADH). ADH is responsible for the facial flush
reaction of redness, facial heat, dizziness, and sometimes
even loss of consciousness. The acetaldehyde is then transformed into acetate by acetaldehyde dehydrogenase
(ALDH). The activity of ALDH varies among human
groups, which reflects onto well-known inequalities between humans in relation to the capacity to drink alcohol.
Numerous polymorphisms exist for ALDH. ALDH*2 allele code is a quite inactive ALDH, which means that ADH
concentration is accumulated and produces facial flush reactions shortly after even little alcohol ingestion (Yamamoto, Ueno, Mizoi, & Tatsuno, 1993; Yin, 1994). For example, 50% of the Japanese and many Asiatics of Mongolian
ethnic strains possess an ALDH*2 allele with a gene mutation of an isoenzyme of the ALDH resulting in a decrease
of that enzyme activity. Shortly after ingesting alcohol,
these people have an increased concentration of acetaldehyde in the blood and develop a flush reaction to alcohol
with vasodilatation (facial flush), a hot feeling, tachycardia,
and hypotension (Nakamura et al., 1996; Thomasson,
Crabb, Edenberg, & Li, 1993).
The GABAergic System

Among the neurochemical systems proposed to be involved in the reinforcement of the reward profile of alcohol, the modulation of the GABA receptors is one of the
most well known and the best studied, as GABAergic circuits sculpt the temporal and spatial aspects of synaptic
integration (Akerman & Cline, 2007). GABAergic agonists
reinforce many of alcohol behavioral effects, while GABAergic antagonists reverse them. GABAA antagonists reverse the motor-impairing effect of alcohol (Frye & Bresse,
1982; Lijequist & Engel, 1982).
Acute ethanol exposure alters or modulates GABAergic
transmission in the brain through various mechanisms.
There are still controversies and conflicts about them (Lovinger & Homanics, 2007), but there is now strong evidence for at least the contribution of the following. Behaviorally relevant low-dose alcohol action seems to be preferentially mediated by a form of nonsynaptic
GABAergic inhibition (Kaneda, Farrant, & Cull-Candy,
1995; Olsen, Hanchar, Meera, & Wallner, 2007), which
gives rise to a tonic form of inhibition that can potently
suppress neuronal excitability (Santhakumar, Wallner, &
Otis, 2007). These GABAA receptors are highly sensitive
to ambient GABA present in the brain, alcohols, and anesthetics. Two possible locations of these extrasynaptic
GABAA-Rs are currently being discussed. One could be an
extrasynaptic site in neighboring synapses, activated via
GABA spillover escaping from the synaptic cleft and thereby hyperpolarizing the neural cell. Another possibility
could be a positioning at presynaptic nerve endings, where
they might contribute to the regulation of synaptic function
through their synapse onto dopaminergic neurons as those
located in the ventral tegmental area, one of the key brain
regions for reward that project to the nucleus accumbens
and prefrontal cortex (Beckstead, Domesick, & Nauta,
1979; Xiao, Zhou, Li, & Ye, 2007). Activation of these
GABAA presynaptic receptors produces depolarization of
nerve presynaptic ending, which elevates the intracellular
calcium concentration and increases GABA neurotransmitter release (Xiao et al., 2007), thereby also increasing
GABA receptor-mediated Cl flux (Allan, Huidobro-Toro,
Bleck, & Harris, 1987; Suzdak, Schwartz, Skolnick, &
Paul, 1986). Yet, Kelm, Criswell, and Breese (2007) suggested that ethanol acts presynaptically to increase spontaneous GABA release by a mechanism involving calcium
release from an internal store. The extrasynaptic GABAA
receptors appear to contain subunit (excluded from
GABAergic synapses) associated with 4 or 6 subunits,
the last one being expressed only in cerebellar granulate
cells, whereas 4 subunits have a more widespread distribution (Saxena & Macdonald, 1994; Sieghart et al., 1999;
Wallner, Hanchar, & Olsen, 2003). Doses of ethanol as low
as 13 mM appear to be effective (Sundstrom-Poromaa et
al., 2002).
Ethanol potentiation of GABAergic synaptic transmission is limited by presynaptic GABAB receptors, thereby
suggesting that they play a role in regulating behavioral
sensitivity to ethanol (Ariwodola & Weiner, 2004).
The more abundant postsynaptic GABAA receptors
(containing 2 subunit) have their activity increased by alcohol, albeit only at high, anesthetic concentrations of
more than 30 mM (Mihic et al., 1997). These GABAA
receptors have a phasic activity that opens only briefly
(10 ms) (Wallner et al., 2003) and enhance the temporal
resolution of neuronal integration according to the behavioral state (Pouille & Scanziani, 2001).
Single acute ethanol exposure stimulate spontaneous
dose-dependent GABA release, which increases the frequency of spontaneous miniature inhibitory postsynaptic
currents in the ventral tegmental area neurons (Melis, Camarini, Ungless, & Bonci, 2002) in basolateral and central
amygdala neurons (Roberto, Madamba, Moore, Tallent, &
Siggins, 2003; Zhu, & Lovinger, 2006), in the Purkinje
cells (Ming, Criswell, Yu, & Breese, 2006), in hippocampal
neurons (Carta, Ariwodola, Weiner, & Valenzuela, 2003),
the brain stem (Sebe, Eggers, & Berger, 2003) and spinal
motoneurons (Ziskind-Conhaim, Gao, & Hinckley, 2003),
and in the frontal cortex (Marszalec, Aistrup, & Narahashi,
1998; Moriguchi, Zhao, Marszalec, Yeh, & Narahashi,
2007).
Because ethanol affects neural activity and sensitivity to
GABA in some, but not all, brain sites (Criswell, Ming,
Kelm, & Breese, 2008), and because the effects of ethanol
on the function of GABAergic interneurons are heterogeHogrefe Publishing
neous both in terms of mechanism and impact, they should

be analyzed in terms of connectivities and integrated in the
functional circuitry of each sub-system (see below).
The Mesolimbic Dopaminergic System

The mesolimbic dopaminergic system plays a key role in
mediating the rewarding properties of drugs of abuse
(Wise, 1987) and is strongly involved in the influence of
motivational, emotional, and contextual information on behavior (Mnte et al., 2008; Pierce & Kumaresan, 2006).
Yet this system does not work in isolation (Gonzales, Job,
& Doyon, 2004).
The system originates in dopaminergic neurons located
in the ventral tegmental area (VTA) in the midbrain, which
in turn innervate several forebrain regions including the
nucleus accumbens (NAcc), amygdala, hippocampus, medial prefrontal cortex (mPFC), and ventral pallidum (Carr,
ODonnell, Card, & Sesack, 1999; Jay, 2003; Napier &
Maslowski-Cobuzzi, 1994; Wise, 2002).
Ethanol enhances extracellular dopamine by increasing
dopamine release in the nucleus accumbens (Di Chiara &
Imperato, 1988; Gonon, 1988; Imperato & Di Chiara,
1986; Yim, Schallert, Randall, & Gonzales, 1998), though
not by inhibition of dopamine uptake (Gonzales et al.,
2004; Yim & Gonzales, 2000). Rather, it is probably due
to an increase in the firing rate of dopaminergic neurons in
the ventral tegmental area (VTA), which send dopaminergic projections on the nucleus accumbens (Brodie, Shefner,
& Dunwiddie, 1990; Bunney, Appel, & Brodie, 2001; Gessa, Muntoni, Collu, Vargiu, & Mereu, 1985). This ethanolinduced excitation of VTA neurons could at least partly be
due to direct electrophysiological effects of ethanol as
membrane depolarization, a decrease in after action potential hyperpolarization (Appel, Liu, McElvain, & Brodie,
2003; Brodie, McElvain, Bunney, & Appel, 1999), and enhancement of function of an inward rectifying channel
(Brodie & Appel, 1998). As VTA dopaminergic cells receive inhibitory inputs from GABAergic interneurons innervated by GABAergic afferents from Nacc and the ventral pallidium, ethanol-induced excitation of VTA dopaminergic neurons could also be result from inhibition of
tonic inhibitory regulation by GABAergic input to the
dopamine cell (Kalivas, Duffy, & Eberhardt, 1990; Klitenick, DeWitte, & Kalivas, 1992). However, Stobbs et al.
(2004) claim that the inhibitory effect of ethanol on electrically coupled networks of VTA GABA neurons is due
primarily to the inhibition of NMDA receptor-mediated excitation and not the enhancement of GABA receptor-mediated inhibition. This is of interest because the increased
firing of the VTA neurons is thought to be important for
ethanol reinforcement (Harris, 1999). Serotonin potentiates
ethanol-induced excitation of dopaminergic VTA neurons
(Brodie, Trifunovic, & Shefner, 1995).
The nucleus accumbens (Nacc) also receives glutamaergic inputs from mPFC, the amygdala, and the hippocampus
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(Sesack & Pickel, 1992; Somogyi, Bolam, & Smith, 1981;

Totterdell & Smith, 1989). The Nacc has two main inhibitory outputs trough the GABAergic medium spiny neurons
(MSN), which send projections to the ventral pallidum and
the ventral tegmental area (VTA) (Chang & Kitai, 1985).
The MSN are thought to play a major role in integrating
various afferent signals that innervate the NAcc. Dopaminergic projections from the VTA to the NAcc and the convergence of these afferents with descending excitatory
glutamatergic synapses from cortical areas are key cellular
and molecular contributions to the expression of motivated
behaviors (Gonzales et al., 2004).
Both ventral pallidum and VTA send GABAergic efferents to the medial dorsal thalamus. Glutamatergic projections from the medial dorsal thalamus to the mPFC close
this limbic circuit (Heimer, 2003; Pierce & Kumaresan,
2006).
It is known that lower doses of ethanol produce CNS stimulation and may enhance cognitive activities (see chapter below on effects of alcohol on memory processes), whereas
higher doses induce CNS depression. The hypothesis that
alcohol in low doses produces CNS stimulation is proposed
to be due to differential sensitivity of GABAergic and dopaminergic neurons in the VTA to GABAA agonists (Pierce &
Kumaresan, 2006). Stimulation of GABAA receptors located
on GABAergic interneurons by lower doses of ethanol disinhibits dopaminergic neuronal activity (Mereu & Gessa,
1985), whereas GABAA receptors expressed by dopaminergic cells in the VTA are inhibited by the local administration
of higher doses of a GABAA agonist (Westerink, Kwint, & de
Vries, 1996).
Changes in dopaminergic transmission play a critical
role in modulating the flow of information through the limbic circuit comprising these interconnected nuclei, something that could be of high importance in ethanol reinforcement.
The Glutamaergic System

Acute ethanol exposure reduces excitatory glutamatergic
input (Allgaier, 2002; Dodd, Beckmann, Davidson, &
Wilce, 2000; Roberto et al., 2004; Woodward, 1999) and
has NMDA antagonist properties. As with GABA receptors, ethanol alters the effects of the NMDA receptors in
some brain regions but is without effect in others. Ethanol
sensitivity of NMDA receptors is influenced by subunit
composition. Ethanol more efficiently blocks NMDA receptor containing the NR2A or NR2B subunits, but has less
effects at receptors containing the NR2C and NR2D subunits (Woodward, 2000; Yamakura, Mori, Masaki, Shimoji, & Mishina, 1993). It is also apparent that factors such
as phosphorylation and protein-protein interactions are important in modulating this sensitivity (Woodward, 2000).
The actions of ethanol may also result in changes in the
interaction between NMDA receptors and its binding partners (Ron, 2004).
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It has been proposed that mechanisms similar to synaptic

plasticity come into play for ethanol-induced behavioral
changes. The modulating functions of dopamine in the nervous system often involve regulation of or by glutamate (Sesack, Carr, Omelchenko, & Pinto, 2003). In particular, the
convergence between dopamine and glutamate signaling in
the nucleus accumbens provides a cellular site for the modulation of synaptic plasticity by dopamine. Ethanol enhances
functional interaction between dopamine and NMDA receptor function. Dopaminergic inputs alter the ethanol sensitivity
of NMDA receptors, and dopamine receptor-1 (D1) activation strongly decreases ethanol inhibition of NMDA responses (Maldve et al., 2002). An intriguing new hypothesis in the
field is that this type of interaction may promote the plasticity
that occurs during the development of ethanol reinforcement
(Gonzales et al., 2004).
Ethanol and the Cerebellum

The cerebellum is involved in the control of balance as well
as the motor coordination, skills, fine regulation of voluntary movement, and in affective cognitive functions (see
below on alcohol and motor control).
Ethanol increases action potential firing in Golgi
GABAergic interneurons, thereby increasing GABAergic
phasic and tonic inhibition of cerebellar granule cells (Botta et al., 2007; Carta, Mameli, & Valenzuela, 2004; Freund,
Wang, & Palmer, 1993). Low-dose alcohol intoxication impairs motor coordination by enhancing tonic inhibition mediated by extrasynaptic GABAA receptors, 63, expressed exclusively in cerebellar granule cells (CGNs)
(Hanchar, Dodson, Olsen, Otis, & Wallner, 2005). CGNs
send excitatory connections to Purkinje neurons, the
unique output of the cerebellar cortex.
Several studies report that ethanol acutely depresses Purkinje cell firing (Basile, Hoffer, & Dunwiddie, 1983; George
& Chu, 1984; Sorensen, Palmer, Dunwiddie, & Hoffer, 1980)
but excites at low doses (917 mM and 0.251 g/kg) (George
& Chu, 1984; Sinclair & Lo, 1986). It seems that, when synaptic inputs are removed from the Purkinje cells, ethanol increases their firing rate by mechanisms that alter their intrinsic pacemaker activity (Edgerton & Reinhart, 2003; Ming et
al., 2006). Yet, ethanol seems to have two conflicting actions
of on the cerebellar Purkinje neuron: an increased inhibition
due to a presynaptic increased GABA release and a postsynaptic action of ethanol to increase the intrinsic excitatory
drive. Interplay of these two actions may underlie a part of
the complex effect of ethanol on the firing rate of cerebellar
Purkinje neurons (Ming et al., 2006; Satake, Saitow, Rusakov, & Konishi, 2004).
Ethanol and the Hippocampus

Memory, learning, and emotions are hippocampal-dependent functions. Declarative and episodic memories systems
are suggested as being centered on the hippocampus

(Squire, 1992; Tulving, 1983). Anterograde memory performance appears to be closely related to hippocampal efficiency, while memory of older events and procedural
memory can be spared in hippocampal dysfunction as revealed in the first stage of Alzheimer disease and by the
patient H. M., who had surgical bilateral removal of hippocampus and amygdala for treatment of epilepsy. More specifically, the dentate gyrus appears to be involved in working memory performance (Hernandez-Rabaza, Barcia,
Llorens-Martin, Trejo, & Canales, 2007). The posterior
hippocampus supports spatial memory and learning processes (Doeller, King, & Burgess, 2008). In rats, the ventral
hippocampus plays a role in brain processes associated
with anxiety-related behaviors (distinct from fear, which
more plausibly depends on amygdalar function) (Bannerman et al., 2004). The hippocampus seems to work as a part
of a memory network: It is closely wired to the dorsolateral
prefrontal cortex via the parahippocampal gyrus, subiculum, presubiculum, and adjacent transitional cortice. Reciprocal projections may allow retrieval by prefrontal cortex of memories stored in the hippocampus (Goldman-Rakic, Selemon, & Schwartz, 1984; Heinemann, Schmitz,
Eder, & Gloveli, 2000). These could be both spatial and
temporal contexts associated with a particular event (episodic memory traces) constituting indices of the locations
in the neocortex where more detailed sensory/perceptual
detail may be found (Morris et al., 2003).
Exposure to ethanol impairs performance on explicit
memory but not impair implicit memory tasks (Lister,
Gorenstein, Fisher-Flowers, Weingartner, & Eckardt,
1991). Ethanol exposure also impairs spatial working
memory and contextual fear conditioning (Matthews, Simson, & Best, 1995, 1996; Melia, Ryabinin, Corodimas, Wilson, & LeDoux, 1996).
Adult mammalian brain could produce neurogenesis, at
least in two brain regions: the subventricular zone and the
dentate gyrus of the hippocampus. Learning increases the
survival of adult-born cells (Leuner et al., 2004). They are
thought to memorize bindings between items (Shastri,
2002) or to store a memory index (Teyler & DiScenna,
1986) for linking representations of distinct experiences
(Abrous, Koehl, & Le Moal, 2005). Exposure to ethanol
inhibits neural progenitor cell proliferation and survival in
adult hippocampal dentate gyrus (Herrera et al., 2003; Nixon & Crews, 2002). The effects of alcohol on hippocampal
neurogenesis seem to be highly dependent on dosage, intake patterns, and length of exposure (Canales, 2007). It
has also been found in binge ethanol exposure (Nixon &
Crews, 2002). Reduced adult hippocampal dentate gyrus
neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information (Hernandez-Rabaza et al., 2008).
Acute alcohol exposure inhibits NMDA-evoked neuronal excitatory activity in the hippocampus (Simson, Criswell, & Breese, 1993). Acute ethanol impairs astroglial
regulation of the functional coupling between NMDA reHogrefe Publishing
ceptors and Kv2. 1 channels, principal components of voltage-sensitive K+ currents, which are critical regulators of
somatodendritic excitability (Mulholland, Carpenter-Hyland, Woodward, & Chandler, 2009; Murakoshi & Trimmer, 1999).
Ethanol increases the size of the after-hyperpolarization
(AHP) in CA1 hippocampal pyramidal neurons (Carlen,
Gurevich, & Durand, 1982) and in dentate granule neurons
from rats (Niesen, Baskys, & Carlen, 1988), thereby reducing their firing rate. On the other hand, ethanol paradoxically increases excitability of CA1 pyramidal neurons indirectly by inhibiting the kainate receptor-dependent drive
of GABAergic interneurons (Breese et al., 2006).
Long-term potentiation (LTP) is a mechanism by which
brief high frequency stimulations induces long-lasting increases in synaptic efficacy. It is thought to be involved in
memory formation, the type of memory depending of the
brain area and circuit in which plasticity is observed. Ethanol decreases hippocampal long-term potentiation (Sinclair & Lo, 1986) even at low concentrations (Blitzer, Gill,
& Landau, 1990) due to ethanol inhibition of synaptically
NMDA receptor-mediated responses (Morrisett & Swartzwelder, 1993). This could contribute to the amnesic actions
of ethanol seen both after acute administration and following chronic high consumption. (Little, 1999).
Hippocampal theta rhythm (410 Hz) (Vanderwolf,
1969) represents the online state of the hippocampus
(Buzski, 2002). It is thought to play a functional role in
the temporal linking of widely separated neuronal assemblies activities involved in the memory building process.
The firing timing of hippocampal pyramidal cells and interneurons has been shown to be differentially related to
the theta phase oscillation; the interneurons provide a spatio-temporal GABAergic control regulating the integration
of pyramidal cells activities, thereby contributing to the
representations in hippocampus (Somogyi & Klausberger,
2005). In rats, hippocampal theta rhythm has been reported
to be suppressed by low to moderate doses of ethanol (Kaheinen, Korpi, Pyykk, Mntysalo, & Ignatius, 1988) in
conjunction with deficits in working memory (Givens,
1995).
Heavy drinkers exhibit increased EEG synchronizations
in the theta (48 Hz) and gamma (3045 Hz) bands that are
suggested to be indicative of changes in hippocampal-neocortical connectivity (de Bruin et al., 2004).
Ethanol and the Prefrontal Cortex

The prefrontal cortex (PFC) is the largest brain region and
is estimated to constitute 29% of the entire cortex (Goldman-Rakic et al., 1984; Moselhy, Georgiou, & Kahn,
2001). It contains two main cell types: glutamatergic pyramidal projection neurons and GABA interneurons that
exert local inhibitory control through input onto the pyramidal cells, thus regulating the pyramidal output of the prefrontal cortex (Gabbott, Dickie, Vaid, Headlam, & Bacon,
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219
1997; Leriche, Mndez, Zimmer, & Brod, 2008; Somogyi,

Tams, Lujan, & Buhl, 1998). GABA-immunoreactive
neurons were found to constitute approximately 16% of all
medial PFC (mPFC) neurons in rat (Gabbott et al., 1997)
and 24.9% in monkey (Gabbott & Bacon, 1996).
Prefrontal glutamatergic projections are proposed as
mediating executive top-down control of behavior (Montag, Schubert, Heinz, & Gallinat, 2008). Symptoms consistent with dysfunction of the frontal lobes following brain
injury can include problems with disinhibition, impulsivity,
short-term memory, attention, planning, problem solving,
and poor motivation (Kraus & Maki, 1997). Working memory tasks are also mediated by the prefrontal cortex. Longterm potentiation (LTP)-related learning and memory
mechanisms were shown in mPFC following stimulation
of mPFC layers II/III (Nowicky & Bindman, 1993) and
stimulation of the hippocampalprefrontal cortex pathway
by an NMDA receptor-dependent process (Jay, Burette, &
Laroche, 1995).
Acute ethanol intake may simultaneously activate
GABAergic interneurons and glutamatergic projection
neurons of the medial prefrontal cortex, and this coordinated effect may contribute to a narrow selection of the activated glutamatergic cortical output (Leriche et al., 2008).
Ethanol and the Thalamus

Thalamic intralaminar nuclei are known to play a role in
arousal, vigilance (Kinomura, Larsson, Gulys, & Roland,
1996) and in intrinsic alertness (Mottaghy et al., 2006).
Ethanol affects arousal with stimulation at lower doses and
sedation at high doses. Ethanol was found to inhibit thalamocortical relay neurons at moderate (50 mM) but not low
(10 mM) concentrations, via increased tonic inhibition mediated by extrasynaptic GABAA receptors (Jia, Chandra,
Homanics, & Harrison, 2008). In contrast, ethanol at low
concentrations could potentially enhance thalamocortical
burst firing by facilitating the rebound calcium spikes of
thalamic relay nucleus induced by GABAergic inhibitory
currents (Jia, Pignataro, & Harrison, 2007). Low concentrations of ethanol (2.5, 5, and 10 mM) enhance T-type
low-threshold calcium current in thalamus, whereas higher
concentrations of ethanol (20 and 50 mM) decrease T-type
current (Mu, Carden, Kurukulasuriya, Alexander, & Godwin, 2003).
These thamalic alcohol actions have consequences on
sleep quality as the thalamus is involved in the regulation
of sleep states (Tinuper et al., 1989). Alcohol disrupts normal sleep; the time spent in deep (slow-wave) sleep is increased probably via potentiated tonic inhibition, whereas
the time spent in the dreaming state (REM sleep) is decreased (Jia et al., 2007). The sedative effects of alcohol
promote sleep onset but also cause fragmentation of sleep
patterns, and the resulting insomnia may lead to recurrent
problem drinking (Kubota, De, Brown, Simasko, & Krueger, 2002). During alcohol withdrawal, sleep patterns reJournal of Psychophysiology 2010; Vol. 24(4):215230
220
main disrupted, though in an opposite way of that during

alcohol exposure: Time to sleep onset is increased, slow
wave sleep is reduced, and REM sleep is enhanced (Drummond, Gillin, Smith, & DeModena, 1998).
Alcohol Addiction
Alcohol exposure has a myriad of consequences: Heavy
alcohol intake is associated with both structural and functional changes in the central nervous system. Long-term
neuronal adaptive changes within the brain due to chronic
ethanol intake contribute to the phenomena of tolerance
and withdrawal. Yet little is known about the mechanisms
that lead to the development of alcohol reinforcement, and
it is difficult to identify the one playing a causal role. Moreover, research developments seemed to converge on the
idea that, even in the alcoholic brain without apparent
structural brain changes, some cognitive impairment exists
(Akine et al., 2007). In chronic alcoholics without patent
neurological and psychiatric complications, hypometabolisms were found in the mediofrontal (MF) and in the left
dorsolateral prefrontal (DPF) cortex which may account for
reduced verbal fluency (MF) and lower reaction time
(DPF) (Dao-Castellana et al., 1998; Samson, Baron, Feline,
Bories, & Crouzel, 1986).
Computed tomography (CT) and magnetic resonance
imaging (MRI) studies revealed reductions in brain volume
in chronic alcoholism: reduced gray and white matter volumes (Badsberg-Jensen & Pakkenberg, 1993; Pfefferbaum
et al., 1992), losses in the frontal lobes (Dally et al., 1988;
Melgaard et al., 1990) as well as in medial temporal and
parietal cortices, in subcortical structures (thalamus, caudate nucleus) (Brewer & Perrett, 1971; Jernigan et al.,
1991; Sullivan, Rosenbloom, Serventi, Deshmukh, &
Pfefferbaum, 2003), in the cerebellar cortex (Shear, Sullivan, Lane, & Pfefferbaum, 1996), and in the cerebellar vermis (Sullivan, Deshmukh, Desmond, Lim, & Pfefferbaum,
2000), thinning of the corpus callosum (see the section on
alcohol and motor control) (Hommer et al., 1996; Pfefferbaum, Lim, Desmond, & Sullivan, 1996), reduced volume
in the pons (Sullivan & Pfefferbaum, 2001), and reduction
in hippocampal volume (Geuze, Vermetten, & Bremner,
2005). Neuropathological studies revealed reduced numbers of glial cells, particularly astrocytes and oligodendrocytes (Korbo, 1999), in the hippocampus of alcoholics,
while hippocampal pyramidal neurons were relatively
spared (Harding, Wong, Svoboda, Kril, & Halliday, 1997).
The volume reductions of cortical and subcortical cerebral structures reveal correlations with large increases in
subarachnoid cerebrospinal fluid (CSF) volume and mild
ventricular enlargement (Jernigan et al., 1991). The age at
first drinking was found to be significantly correlated with
the decrease in gray matter volume in the middle frontal
cortex, the cerebellum, and the brainstem (Chanraud et al.,
2007).
Loss of cortical neurons found in the frontal lobe (but

not in the motor cortex) may correspond to the abnormalities in working memory commonly seen in chronic alcoholics see the section on alcohol and memory (Kril, Halliday, Svoboda, & Cartwright, 1997). Perfusion deficits in
frontal areas measured by SPECT proved to be correlated
with impaired control process of inhibition and with working memory deficits in a task involving the ability to coordinate storage and processing (Chen et al., 2007; Noel et
al., 2001).
Significant differences in hippocampal volumes were
found between patients consuming various beverages with
the smallest volumes in the wine group, followed by the
spirits group; the extent of brain atrophy in beer-consuming
patients seems to be more moderate (Wilhelm et al., 2008).
Enzymes and Biochemical Phenomena

Involved in Alcohol Addiction
One of the most impressive consequences of heavy drinking is that direct and indirect ethanol metabolites are detectable in the blood days or even weeks after alcohol withdrawal well after the disappearances of alcohol in the
blood. Chronic alcohol consumption causes, among other
things, elevation of serum carbohydrate-deficient transferrin (CDT) levels, serum gamma-glutamyltransferase
(GGT), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), glutamate dehydrogenase (GDH),
and an increase in mean corpuscular erythrocyte volume
(MCV) that have longer half-live in blood than ethanol.
These can be used as biological markers to detect heavy
drinking when a lack of cooperativeness is suspected, when
the history is not available, or as tool to control abstinence
compliance in alcoholic treatments. They may also be useful to the physician before operations when alcohol abuse
is denied by the patient. CDT is the only test approved by
the US Food and Drug Administration (FDA) for detection
of heavy drinking.
Carbohydrate-deficient transferrin (CDT) is raised in
many alcohol abusers (Stibler, 1991; Stibler & Kjellin,
1976). Plasma half-life of CDT was found to be around 14
days (Allen, Litten, Anton, & Cross, 1994; Stibler, 1991)
and has been reported to remain significantly high for at
least 6 weeks after alcoholics stop drinking (Glasinovic et
al., 2001). During detoxification period CDT decreases
progressively after cessation of alcohol intake with a halflife of 16 5 days, though it fluctuates and remains abnormal in the remaining 6 days (Behrens, Worner, & Lieber,
1988). Increased CDT could be due not only to excessive
alcohol intake, but also to carbohydrate-deficient glycoprotein syndrome, a hereditary disorder of glycoprotein synthesis. It appears that the critical alcohol intake for a CDT
increase is almost the same as for alcohol-induced liver
cirrhosis (Gressner & Manns, 1995). CDT as biomarker for
Hogrefe Publishing
alcohol addiction has a diagnostic sensitivity of around

3050% for women and 5070% for men (Arendt, 2001).
Alcohol has toxic effects on blood cells and their functions in the production of structurally abnormal blood cell
precursors and enlarged erythrocytes (macrocytosis). Mean
corpuscular volume (MVC) is an average estimate of erythrocytes volume. MCV was found to increase significantly and linearly with age (Mundle, Ackermann, Munkes,
Steinle, & Mann, 1999). Moreover, increased MCV was
found in heavy drinkers due to a deficiency in B vitamins
and the direct toxic effects of alcohol on erythropoese. If
a long period of abstinence is suspected, MCV may be measured to detect evidence of earlier heavy drinking (Mundle
et al., 1999). Measurement of MCV, however, is not as reliable for an abstinence survey as the reed globules have a
quite long lifetime.
The serum enzyme gamma-glutamyltransferase (GGT)
is the most frequently used marker of alcohol intake, partly
because of low detection cost. GGT serum levels are raised
under heavy alcohol consumption but also in hepatic dysfunction. GGT is a regulating glutathione (GSH) metabolism. GSH is an important antioxidant against free radicals
and oxidative stress. Conditions that increase serum GGT,
such as high alcohol consumption, lead to increased free
radical production and the threat of glutathione depletion
(Whitfield, 2001). Acetaldehyde is thought to induce mitochondria oxidative stress by depleting mitochondrial levels
of glutathione (Farfn Labonne et al., 2009). During abstinence, GGT levels decrease by half within 2 weeks and
then usually return to the average range over a period of
68 weeks (Das, Dhanya, & Vasudevan, 2008). However,
GGT is also raised in a variety of non-alcohol-related liver
diseases, so that it is not related solely to alcohol consumption. The combination of CDT and GGT as markers yield
a sensitivity of over 90% (Behrens et al., 1988; Hietala,
Koivisto, Anttila, & Niemel, 2006; Mundle et al., 1999).
Phosphatidylethanol (PEth) is an abnormal phospholipid
formed in cell membranes only in the presence of ethanol
(Gustavsson & Alling, 1987; Kobayashi & Kanfer, 1987).
The reaction is catalyzed by phospholipase D, an enzyme
that normally catalyzes the hydrolysis of phospholipids
leading to the formation of phosphatidic acid. However,
phospholipase D also utilizes short-chain alcohols instead
of water as substrates, resulting in the formation of phosphatidylethanol in an manner dependent on alcohol concentration. By this mechanism, ethanol could interact with
cell function (Gustavsson, 1995). Phosphatidylethanol in
cell membranes may induce disturbances in cell function.
Acutely low ethanol concentrations were shown to impair
intestinal barrier function by induction of apoptosis in intestinal epithelial cells (Asai, Buurman, Reutelingsperger,
Schutte, & Kaminishi, 2003). Chronic alcohol consumption is associated with increased risk of gastrointestinal
cancer. High concentration of ethanol triggers mucosal hyperregeneration, disrupts cell adhesion, and increases sensitivity to carcinogens. Phosphatidylethanol accumulation
after chronic alcohol consumption disrupts signals that norHogrefe Publishing
221
mally restrict proliferation in intestinal cells, thus facilitating abnormal intestinal cell proliferation (Pannequin et al.,
2007). Cellular localization of PEth in blood is mainly in
erythrocytes (Varga, Hansson, Johnson, & Alling, 2000).
Substantial alcohol intake is needed to elevate blood PEth:
No PEth was detected for 25 mmol/liter in blood after 30
to 60 min of a single alcohol intake (32 to 47 g of alcohol)
of normal consumers, while prolonged alcohol consumption for 3 weeks (total estimated intake: 1334 488 g) produced PEth detectable level in blood (Varga, Hansson,
Lundqvist, & Alling, 1998). The time course of PEth disappearance varied among individuals. PEth is detectable in
chronic alcohol-dependent patients for more than 2 weeks
after sobriety-sustained alcohol intake, while in sober persons who had abstained from ethanol for 4 days no PEth
was found (Hansson, Caron, Johnson, Gustavsson, & Alling, 1997). Blood concentrations are highly correlated to
alcohol intake with nearly no false positives or negatives,
making PEth a promising new marker for detecting longterm alcohol intake and abuse with excellent sensitivity and
specificity (Aradottir, Asanovska, Gjerss, Hansson, & Alling, 2006; Hansson et al., 1997; Nissinen et al., 2008;
Wurst et al., 2003, 2004).
Fatty acid ethyl esters (FAEE) can be detected in serum
and erythrocytes up to 24 h after drinking. They are not
stable in blood because of enzymatic activity, but do become incorporated into hair and thus can be analyzed in
this medium even after several months (Pragst, Auwrter,
Sporkert, & Spiegel, 2001). The incorporation was found
to occur mainly from sebum into the completed hair (Auwrter et al., 2001). Differential concentrations of FAEE
(sum of concentrations of four esters: ethyl myristate, ethyl
palmitate, ethyl oleate, ethyl stearate) were found in the
hair of alcoholics who were social/moderate drinkers: A
FAEE cut-off of 1.0 ng/mg (Auwrter et al., 2001; Hartwig,
Auwrter, & Pragst, 2003) and 0.4 ng/mg (both in hair)
(Wurst et al., 2004) were suggested for establishing heavy
alcohol use. After 19 months of claimed abstinence of a
subject convicted of driving under influence of alcohol,
ethyl glucuronide (EtG) was found only in distal parts of
hair, whereas the proximal parts were negative and FAEE
concentrations were found over hair length and showed
values typical for either moderate social drinking or abstinence (Wurst et al., 2008).
The GABAergic System

In chronic drinkers, higher alcohol concentrations in blood
are required to produce symptoms and signs of alcohol intoxication. The increased tolerance of chronic alcoholics
appears to some extent to be related to a compensatory
downregulation of the GABAergic system (Grobin, Matthews, Devaud, & Morrow, 1998). Chronic alcohol exposure produces changes in GABAAR subunit expression
(Grobin, Papadeas, & Morrow, 2000; Morrow, Montpied,
Lingford-Hughes, & Paul, 1990) and functions in a differJournal of Psychophysiology 2010; Vol. 24(4):215230
222
ent way related to cerebral structures (Follesa et al., 2006).

GABAA-Rs -subunits were found to be downregulated in
rat cerebellum and hippocampus, but neither in the cerebral
cortex nor in cerebellar granule neurons (Follesa et al.,
2005; Marutha Ravindran, Mehta, & Ticku, 2007). Chronic
alcohol consumption reduces GABAergic function by altering the density or affinity of GABAA-Rs (Fadda & Rossetti, 1998). Restructured GABAA-R subunit composition
(newly formed synaptic 4 and 2 subunits) and localization were found after chronic intermittent ethanol treatment
in hippocampal CA1 pyramidal neurons and dentate gyrus
granule cells with a switch of alcohol actions from extrasynaptic to synaptic hippocampal GABAA-Rs (Liang et al.,
2006). This could contribute to alcohol tolerance, because
synaptic GABAA-R are activated at higher alcohol concentrations than extrasynaptic GABAA-Rs. Hypothesized
mechanism of alcohol-induced GABAAR plasticity is an
internalization of overactivated extrasynaptic receptors,
which may explain the decreased magnitude of tonic inhibitory currents (Liang et al., 2007). GABAA receptors are
currently therapeutic targets for the treatment of alcoholism
via their close interactions with neuroactive steroids that
potentiate the GABA currents (Enoch, 2008). GABAergic
drugs are suggested as acting primarily via the potentiation
of extrasynaptic GABAARs (Liang, Spigelman, & Olsen,
2009) and could by this mechanism restore the inhibitory
control of GABAergic neurons and more specifically their
anxiolytic action.
The Dopaminergic System

Alcohol addiction may be regarded as a disease of the brain
reward system (Vetulani, 2001). Clinical descriptions show
that addiction translates emotions into sensations. Addiction is a phenomenon involving motivational functions of
nucleus accumbens and discriminative and executive functions of the medial prefrontal cortex, the extended amygdala, and the hippocampus.
Increases in dopamine (DA) are associated with subjective reports of drug reinforcement (Volkow, Fowler, Wang,
& Goldstein, 2002). More specifically, the rate of DA increases in the striatum (and NAcc) seems to be a key point
in reinforcing drug effects (Balster & Schuster, 1973)
more than just the DA concentration increase itself. Neuronal circuitry involving glycine receptors in the nucleus
accumbens and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area are involved in the mesolimbic dopamine reinforcing effects of ethanol (Sderpalm,
Lf, & Ericson, 2009).
Despite the fact that alcohol-induced DA release within
the nucleus accumbens is critically involved in the initiation of alcohol reinforcement processes (Di Chiara & Imperato, 1988), it seems to have a less important role in
maintaining alcohol consumption (Rassnick, Stinus, &
Koob, 1993; Vengeliene, Bilbao, Molander, & Spanagel,
2008).
Repeated alcohol exposure leads to long-lasting changes

that alter synaptic communication between neurons in the
mesolimbic dopamine system; these mechanisms may contribute to the ethanol-seeking behavior that occurs in alcoholism (Gonzales et al., 2004; Maldve et al., 2002). Longterm drug use seems to be associated with decreased dopaminergic function, as evidenced by reductions in striatal
DA release and D2 dopamine receptors density of addicted
subjects. The latter has been associated with reduced activity of the orbitofrontal cortex (involved with salience, motivation, and compulsive behaviors) and of the cingulate
gyrus (involved with inhibitory control and impulsivity),
which implicates deregulation of frontal regions by DA in
the loss of control and compulsive drug intake that characterizes addiction (Volkow, Fowler, Wang, Swanson, & Telang, 2007). A significant association was reported between the A1 allele of the D2 dopamine receptor (DRD2)
gene, substance misuse, and personality traits of impulsivity and novelty seeking, and the DRD2 TaqI A polymorphism was suggested as being implicated in alcohol dependence (Pinto et al., 2009).
The Glutamaergic System

Chronic ethanol administration produces a chronic blockade of NMDA receptors. Their sensitivity to ethanol is then
reduced, contributing to ethanol tolerance. Ethanol dependence may be associated with upregulation of NMDA receptors and tolerance to the actions of NMDA antagonists
(Krystal, Petrakis, Mason, Trevisan, & DSouza, 2003).
This induces increased ligand binding to the NMDA receptor, raising protein levels of the NR1, NR2A, NR2B subunits, and mRNA levels for NR2 subunits (Kumari, &
Ticku, 2000; Trevisan et al., 1994) and an increase in the
phosphorylation of the NR2B (Miyakawa et al.,1997) or
NR2A subunits (Anders et al., 1999).
Alcohol Withdrawal
When alcohol is abruptly withdrawn, symptoms are usually
opposite to the effects of acute intoxication: a state of hyperexcitability emerges, perceived by the subject as a disagreeable state of arousal, anxiety, and sleeplessness (Kiefer & Mann, 2005). Repeated withdrawal produces the
kindling phenomenon with a lowered threshold for convulsions (Ballenger & Post, 1978). EEG recordings disclosed
seizures with epileptiform-type characteristics that increase in prevalence and severity with multiple detoxifications (Becker, 1994). Increased spike and sharp wave activities are observed, varying with both the length of ethanol exposure and the number of withdrawal episodes
(Veatch & Gonzalez, 1996).
Glutamatergic upregulation, resulting from the combination of increased NMDA receptor function and increased
Hogrefe Publishing
glutamate release, contributes to the ethanol withdrawal

symptoms (Allgaier, 2002; Krystal et al., 2003) and seems
to play a major role in withdrawal hyperexcitability and the
production of convulsions (Little, 1999). The amplitude of
GABAA-mediated IPSP/Cs as well as the frequency and
amplitude of spontaneously occurring mIPSCs were found
to be robustly enhanced, suggesting enhanced basal
GABAergic transmission (Breese et al., 2006). Significant
reductions in DA D2 receptors, in DA release and in the
firing rate of dopaminergic neurons were revealed as well
as changes in their firing pattern (Molleman & Little, 1995;
Volkow et al., 2002). This could contribute to the dysphoric
effects of alcohol withdrawal. Upregulation of L-type calcium channels was found with increased density of channels regulated by protein kinase C (PKC) (Walter et al.,
2000).
Brain damage in alcoholics is potentially reversible
since preserved nerve-cell bodies might allow lost or malfunctioning axons to re-established and restored to function
after prolonged abstinence and/or treatment; by contrast,
lost neocortical neurons cannot be replaced (Badsberg-Jensen & Pakkenberg, 1993). These plastic changes in the
brain brought about by changes in protein synthesis are only slowly reversible (Kiefer & Mann, 2005). Frontal brain
abnormalities (hypoperfusion) in alcoholics may subside
with extended abstinence (Gansler et al., 2000).
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Claude Tomberg
Brain Research Unit CP 630
Faculty of Medicine
University of Brussels
808, route de Lennik
1070 Bruxelles
Belgium
Tel. +32 2 555-6405
Fax +32 2 555-6403
E-mail ctomberg@ulb.ac.be
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2010 Federation of European Psychophysiology Societies

Because alcohol is distributed by the bloodstream to all

& Appel, 1998)), and membrane-bound ligand-gated ion

C. Tomberg: Alcohol Pathophysiology

Acute Alcohol Consumption

The GABAergic System

C. Tomberg: Alcohol Pathophysiology

neous both in terms of mechanism and impact, they should

The Mesolimbic Dopaminergic System

(Sesack & Pickel, 1992; Somogyi, Bolam, & Smith, 1981;

The Glutamaergic System

C. Tomberg: Alcohol Pathophysiology

It has been proposed that mechanisms similar to synaptic

Ethanol and the Cerebellum

Ethanol and the Hippocampus

are suggested as being centered on the hippocampus

C. Tomberg: Alcohol Pathophysiology

Ethanol and the Prefrontal Cortex

1997; Leriche, Mndez, Zimmer, & Brod, 2008; Somogyi,

Ethanol and the Thalamus

C. Tomberg: Alcohol Pathophysiology

main disrupted, though in an opposite way of that during

Loss of cortical neurons found in the frontal lobe (but

Enzymes and Biochemical Phenomena

C. Tomberg: Alcohol Pathophysiology

alcohol addiction has a diagnostic sensitivity of around

The GABAergic System

C. Tomberg: Alcohol Pathophysiology

ent way related to cerebral structures (Follesa et al., 2006).

The Dopaminergic System

Repeated alcohol exposure leads to long-lasting changes

The Glutamaergic System

C. Tomberg: Alcohol Pathophysiology

glutamate release, contributes to the ethanol withdrawal

rons is blocked by quinidine. Journal of Pharmacology and

C. Tomberg: Alcohol Pathophysiology

electroencephalographic study. British Journal of Addiction to

C. Tomberg: Alcohol Pathophysiology

Purkinje neurons in cerebellar slices in vitro. Neuroscience

dylethanol formation: Specific effects of ethanol mediated via

C. Tomberg: Alcohol Pathophysiology

Irwin, M., . . . Cermack, L. S. (1991). Reduced cerebral gray

C. Tomberg: Alcohol Pathophysiology

Melia, K. R., Ryabinin, A. E., Corodimas, K. P., Wilson, M. C., &

astroglial EAAT2 modulation of Kv2. 1 potassium channels in

C. Tomberg: Alcohol Pathophysiology

of drugs of abuse? Neuroscience and Biobehavioral Reviews,

tions. Annals of the New York Academy of Sciences, 1003,

C. Tomberg: Alcohol Pathophysiology

relaxometry reveals central pontine abnormalities in clinically

C. Tomberg: Alcohol Pathophysiology

nence. International Journal of Legal Medicine, 122, 235239.

Journal of Psychophysiology 2010; Vol. 24(4):215230

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