Chapter 8 Neurobiology of Alcohol

 

Chapter 8. Neurobiology of Alcohol

NEUROBIOLOGY OF ALCOHOL: INTRODUCTION

Ethanol is a small molecule that readily distributes into highly perfused tissues such as the brain.

Peak levels of ethanol are attained approximately 30 minutes after ingestion of an alcoholic drink.

A single drink of ethanol produces a biphasic effect with a rapid stimulatory phase associated with

an increase in blood ethanol concentrations followed by a depressant phase as the blood

concentration diminishes. Although the ethanol from a single drink is readily metabolized in two

steps involving the enzymes alcohol dehydrogenase and aldehyde dehydrogenase, this process

follows zero-order kinetics. Accordingly, there is a decrease in the percentage of ethanol

metabolized per given unit of time, as the dose of this agent is increased.

Because of its comparatively low toxicity per unit volume, ethanol can be consumed in large

amounts and, consequently, individuals with impaired control over their drinking may remain

highly intoxicated for extended periods. Serious disruption in the performance of many of the

activities of daily living can occur as a result of the behavioral disinhibition and impairments of

judgment, cognition, and fine motor skills associated with high levels of intoxication. Repeated

exposure to ethanol is associated with the development of tolerance to many of its effects. The

continual use of ethanol can also lead to the development of physical dependence and the

consequent onset of withdrawal symptoms following the discontinuation of ethanol consumption.

When compared with most pharmacological agents, the potency of ethanol is extremely low, with

its effects becoming apparent only in the millimolar range. Most drugs, in contrast, are active at

micromolar or even nanomolar concentrations. The low potency of ethanol raises questions as to

the specificity of its actions. The effects of ethanol on behavior appear to be mediated by its effects

on a variety of proteins in the nervous system. These include proteins associated with

-aminobutyric acid (GABA)A receptors, the glutamate receptors (including the

N-methyl-D-aspartate [NMDA], -amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA],

and kainate receptors), nicotinic receptors, cannabinoid CB1 receptors, voltage-gated calcium ion

channels, and calcium-activated potassium (BK) channels. The exact nature of the interaction of

ethanol with these proteins largely remains to be elucidated. There is limited evidence, however,

that ethanol may interact with specific amino acids at discrete locations on the sequence of amino

acids that form NMDA receptors (Honse et al. 2004; Smothers and Woodward 2006), the adenylyl

cyclase enzyme (Yoshimura et al. 2006), and possibly a particular subunit of the GABAA receptor

(Jung and Harris 2006).

Some authors have stressed the relationship between blood alcohol concentrations and the effects

of ethanol on specific neuronal systems in the brain as a key to understanding the behavioral

effects of ethanol (Wallner et al. 2006). The behavioral effects correlate with the concentration of

ethanol achieved in the brain, which is directly related to blood alcohol concentration. Mild

intoxication produced by the consumption of one or two standard drinks (a standard drink is a glass

of wine, a bottle of beer, or a shot of spirits) occurs with ethanol levels of 5–10 mmol/L and may

involve mild disruption of cognitive processing and mood changes, ranging from mild mood

elevation to dysphoria. Moderate drinking leads to ethanol concentrations as high as 20 mmol/L;

however, the legal limit for driving is now frequently set at blood levels of 17 mmol/L (0.08

mg/dL). Ethanol levels greater than 100 mmol/L may produce coma and death. Ethanol

concentrations in the range of 10–50 mmol/L might be most relevant in the identification of

proteins that mediate the actions of ethanol in all but the most severe states of intoxication. In

many studies, ethanol concentrations greater than 100 mmol/L have been used to assess thePrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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effects of ethanol on receptors and ion channels. This has led some investigators to question

certain claims that have been made in the past concerning the effects of ethanol on GABA and other

neurotransmitter systems (Krystal et al. 2006).

Recent evidence indicates that even small doses of ethanol (0.25–0.5 g/kg) can substantially

reduce glucose metabolism in the brain without producing detectable alterations in cognitive

performance (Volkow et al. 2006). The full implications of ethanol-induced alterations in brain

metabolism on neuronal function have still not been fully characterized. Chronic ethanol use

appears to have effects on glucose utilization that are evident during the detoxification of alcoholic

individuals. Volkow et al. (1994) showed that glucose metabolism in several brain regions,

including the frontal cortex, orbitofrontal cortex, and basal ganglia, was lower at the start of

detoxification of alcohol-dependent individuals than in control subjects. Over the course of a

30-day withdrawal period, glucose metabolism increased in frontal regions; however, metabolism

was found to remain lower than control levels in the basal ganglia.

Supported by National Institute on Alcohol Abuse and Alcoholism grant K24 AA13736 (Kranzler).

CAMP PATHWAYS

The second messenger cyclic adenosine monophosphate (cAMP) plays a key role in the regulation

of cellular activity by acting through cAMP-dependent protein kinase A (PKA) to phosphorylate a

host of proteins, including those that regulate gene expression, receptor function, and ion channel

function. The activation of G protein–coupled receptors can elevate or decrease intracellular

concentrations of cAMP by altering activity of the different types (isoforms) of adenylyl cyclase.

Alterations of cAMP levels within the cell, in turn, modulate PKA activity. PKA is composed of

different regulatory and catalytic subunits. Ethanol administration can enhance the activity of some

isoforms of adenylyl cyclase (Tabakoff and Hoffman 1998; Yoshimura et al. 2006) that have been

shown to enhance PKA activity (Ortiz et al. 1995). Recent abstinence from ethanol is associated

with a decrease in platelet adenylyl cyclase activity, but increases in the activity of these enzymes

occur in association with a history of alcohol dependence (Hoffman et al. 2002).

The selective deletion of the PKA regulatory RII subunit from mice resulted in an increase in

ethanol consumption and a decrease in the sedative effects of ethanol (Thiele et al. 2000b).

Infusion of a PKA inhibitor, Rp-cAMP, into the nucleus accumbens (NAcc) elevated ethanol intake in

rats (Misra and Pandey 2005). This inhibitor also reduced levels of the phosphorylated form of the

gene transcription factor, cAMP response element–binding protein (CREB), and protein levels of

neuropeptide Y (NPY) in the NAcc. This may be of significance because both CREB and NPY have

been implicated in the regulation of ethanol consumption (Hayes et al. 2005; Misra and Pandey

2003; Pandey et al. 2004). In mice that were haplodeficient for CREB (i.e., those with partial

deletion of the CREB gene), ethanol consumption increased (Pandey et al. 2004). These mice

showed decreased levels of phosphorylated CREB and expression of NPY in brain structures that

include the amygdala, hippocampus, and NAcc (Pandey et al. 2004).

Ethanol-induced PKA activity may have broad influences on neuronal function, many of which are

presently poorly understood. NMDA receptor function varies with the phosphorylation state of the

receptor, and PKA plays a major role in this variation. Activation of dopamine D1 receptors can

enhance the activity of PKA, which then leads to enhanced phosphorylation of CREB. The alteration

of CREB activity not only appears to influence the regulation of ethanol consumption but has also

been implicated in the reinforcing actions of many other abused substances, including cocaine and

morphine (McClung and Nestler 2003; Walters and Blendy 2001).

NEUROTRANSMITTER SYSTEMS AND ETHANOL

Dopamine

Dopaminergic neurons in the mesolimbic region project from the ventral tegmental area (VTA) to

the NAcc. The NAcc may be crucially important in producing the rewarding actions of ethanol

(Weiss and Porrino 2002). Ethanol administration enhances dopamine release in the NAcc (DiPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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Chiara and Imperato 1988; Yim and Gonzales 2000), which may result from ethanol-induced

increases in the firing rate of dopamine cells located in the VTA (Brodie et al. 1999; Gessa et al.

1985). The repeated administration of ethanol may result in sensitization of dopamine VTA neurons

to the effects of ethanol on dopamine cell firing (Brodie 2002). However, during acute withdrawal

from ethanol, spontaneous activity of dopamine cells in the VTA is decreased (Shen and Chiodo

1993), as is dopamine release in the NAcc (Weiss et al. 1996).

Dopamine D2 receptor–deficient mice, “knockout mice,” show less preference for ethanol than do

the wild-type mice that can express this receptor (Thanos et al. 2005b). Transfer of D2 receptor

deoxyribonucleic acid (DNA) by viral vector into the NAcc of mice lacking this receptor leads to an

increase in ethanol consumption and preference. In contrast, transfer of D2 receptor DNA into

wild-type mice and mice heterozygous for the D2 receptor gene reduces ethanol consumption.

These results suggest that the D2 receptor regulates ethanol drinking and that either high or

minimal receptor availability is associated with reduced levels of drinking.

There is some evidence that low D2 availability in the striatum may be related to alcohol use

disorders. Volkow et al. (2002) have shown that subjects with early-onset alcohol dependence have

lower D2 availability in the caudate and putamen than do control subjects. Individuals with alcohol

use disorders have also been shown to have lower D2 receptor levels in the ventral striatum than

do controls (Heinz et al. 2004). D2 receptor concentrations in the ventral striatum have been found

to correlate negatively with both alcohol craving and ethanol cue-induced activation of the medial

prefrontal cortex and the anterior cingulate (Heinz et al. 2004).

Serotonin

In monkeys, high rates of ethanol consumption are associated with low cerebrospinal fluid (CSF)

levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) (Higley et al. 1996).

Evidence implicating serotonin in the development of alcoholism includes the observation that

concentrations of 5-HIAA in CSF may be lower in early-onset alcoholic individuals than in those

whose alcohol use disorders had a late onset (Fils-Aime et al. 1996).

Extracellular serotonin levels are regulated by the activity of serotonin transporters, which mediate

the reuptake of this neurotransmitter into presynaptic neurons. Studies in rodents indicate that

ethanol administration may lead to significant elevations in serotonin levels in the hippocampus

(Daws et al. 2006) and striatum (Thielen et al. 2001). However, evidence from mutant mouse

models suggests that the effects of ethanol on serotonin levels in the hippocampus may not result

from a direct interaction of alcohol with serotonin transporters (Daws et al. 2006).

The availability of brainstem serotonin transporter sites, as labeled by the radioligand [I-123]2

-carbomethoxy-3 -(4-iodophenyl) tropane ([I-123] -CIT), was found to correlate positively with

the mean daily intake of ethanol by monkeys (Heinz et al. 2003). Binding of ligands to serotonin

transporters, however, was reduced in the brainstem of alcoholic individuals (Heinz et al. 1998;

Szabo et al. 2004) and in other regions, including the frontal cortex, midbrain, thalamus, and

amygdala (Szabo et al. 2004). However, Brown et al. (2007) showed that when a new

radioligand—[11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile—with high

specific binding for the serotonin transporter was used, there were no differences in binding to this

transporter protein between alcohol-dependent and control subjects. The extent of binding to

serotonin transporters in the raphe nucleus by [I-123] -CIT was dependent upon the genotype of a

polymorphic site in the promoter of the gene encoding the transporter (Heinz et al. 2000). Studies

that carefully control for genetic factors may be needed to clarify the relationship between

alcoholism and serotonin transporter availability.

Ethanol consumption may also be modulated by the serotonin type 3 (5-HT3) receptor.

Administration of the 5-HT3 antagonist ondansetron results in a reduction of ethanol consumption

by individuals with early-onset alcoholism (Johnson and Ait-Daoud 2000; Kranzler et al. 2003). The

administration of 5-HT3 antagonists, including ondansetron, also reduced ethanol intake in animals

(Tomkins et al. 1995). This effect is not seen when a 5-HT3 antagonist is administered to mice thatPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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are missing the gene for the 5-HT3A receptor subtype (Hodge et al. 2004). Infusion of the 5-HT3

antagonist tropisetron into the NAcc reduces ethanol-induced increases in dopamine release

(Yoshimoto et al. 1992) and ethanol consumption (Jankowska and Kostowski 1995). This suggests

5-HT3 receptors may modulate ethanol drinking via an action on dopamine release in the NAcc.

There is some evidence that 5-HT1B receptors can modulate the dopamine-releasing actions of

ethanol. Results of a study by Yan et al. (2005) suggest that infusion of 5-HT1B receptor agonists

into the VTA significantly prolong the time during which ethanol administration produces an

increase in dopamine levels in the NAcc. In contrast, their findings indicate that ethanol-induced

dopamine release is decreased by the intrategmental infusion of 5-HT1B antagonists. In animal

models of alcohol consumption, the administration of serotonin 5-HT1B receptor agonists can

suppress ethanol intake (Higgins et al. 1992; Tomkins and O’Neill 2000). Rats consume more

ethanol after being given an injection of a viral vector containing 5-HT1B DNA, which increases the

expression of 5-HT1B receptors in the NAcc (Hoplight et al. 2006). However, the effects of deletion

of 5-HT1B receptors from mice have been inconsistent. Some investigators (Crabbe et al. 1996), but

not others (Gorwood et al. 2002), have found that 5-HT1B knockout mice consumed more ethanol

than wild-type mice. Although these findings suggest that 5-HT1B receptors may play a role in

modulating ethanol self-administration, it is unclear how expression levels of 5-HT1B receptors are

related to this effect.

Nicotinic Receptors

The stimulant effects of ethanol are attenuated in healthy subjects who have been pretreated with

the nicotinic receptor antagonist mecamylamine (Blomqvist et al. 2002). This finding complements

those from animal studies that implicate nicotinic receptors in the mediation of the actions of

ethanol. In animals, the systemic administration of mecamylamine may decrease ethanol-induced

enhancement of locomotor activity (Blomqvist et al. 1992) and suppresses voluntary ethanol

consumption (Blomqvist et al. 1996). When infused into the VTA, mecamylamine may block

ethanol-induced dopamine release in the NAcc (Blomqvist et al. 1997; Tizabi et al. 2002) and may

also reduce ethanol consumption (Ericson et al. 1998). The voluntary intake of ethanol produces an

increase in acetylcholine levels in the VTA, an effect that may explain how ethanol may activate

nicotinic receptors in the VTA that regulate dopamine release in the NAcc (Larsson et al. 2005).

In addition to acting on nicotinic receptors by enhancing acetylcholine release, ethanol may also

have more direct effects on these receptors (Aistrup et al. 1999). Ethanol, through actions on

presynaptic nicotinic receptors, may enhance the release of GABA (Alkondon et al. 1997; Moriguchi

et al. 2007). Potential implications of this effect are discussed in the section after next, “GABAA

Receptor Systems.” Nicotinic receptors consist of different combinations of subunits, and the

precise subunit combination may determine the nature of the receptor response to ethanol

(Cardoso et al. 1999; Covernton and Connolly 1997). Nicotinic receptors containing 3 4 subunits

are either inhibited or potentiated by low concentrations of ethanol (Covernton and Connolly 1997).

Deletion of the 7 nicotinic subunit from mice increases their sensitivity to the hypnotic effects of

ethanol (Bowers et al. 2005). Even slight variations in the amino acid composition of the 4 subunit

may determine the extent to which 4 2-containing nicotinic receptors are activated by ethanol

(Butt et al. 2003). This suggests that genetic polymorphisms in nicotinic receptors may help

determine how individuals differ in their responses to ethanol.

Cannabinoid CB1 Receptors

The activation of cannabinoid CB1 receptors may promote the release of dopamine in the NAcc by

increasing firing rates of dopamine neurons in the VTA (Gessa et al. 1998; Tanda et al. 1997). The

administration of the CB1 receptor antagonist rimonabant blocks ethanol-induced firing of

tegmental dopaminergic neurons (Perra et al. 2005). This compound also inhibits

ethanol-stimulated dopamine release in the NAcc (Cheer et al. 2007). Administration of rimonabant

significantly reduces the intake of ethanol in wild-type mice, but not in mice in which the CB1

receptor is deleted (Thanos et al. 2005a). Compared with the ethanol consumption of wild-typePrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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mice, the ethanol consumption of mutant mice whose CB1 receptor has been deleted is significantly

reduced (Thanos et al. 2005a). These results suggest that the CB1 receptor may regulate the

rewarding actions of ethanol as part of the regulatory actions of CB1 receptor systems within the

mesolimbic system.

GABAA Receptor Systems

Many of the behavioral effects of ethanol appear to result from its interaction with GABAA

receptors. Barbiturates and benzodiazepines positively modulate the actions of GABA at these

receptors. These agents have several behavioral effects that parallel those of ethanol, including

anxiolytic, anticonvulsant, hypnotic, and sedative actions. Injection of the GABAA receptor agonist

muscimol into limbic areas produces stimulus properties that substitute for those of ethanol in drug

discrimination studies (Hodge and Alken 1996). The sedative and motor-impairing effects of

ethanol are potentiated by the concurrent administration of either GABAA receptor agonists, such

as muscimol, or positive modulators of the GABAA receptors, such as the benzodiazepines (Frye and

Breese 1982; Martz et al. 1983; Tauber et al. 2003). The administration of benzodiazepine inverse

agonists will block or reverse the depressant effects of ethanol, as well as suppress its

self-administration (Petry 1995; Suzdak et al. 1986). Sedation produced by the infusion of ethanol

into the brain is blocked by the administration of the GABAA receptor antagonist bicuculline (Givens

and Breese 1990). The hyperexcitability associated with withdrawal from chronic ethanol exposure,

including seizures, can be reversed or attenuated by the administration of benzodiazepines. Finally,

there is cross-tolerance of benzodiazepines or barbiturates to the depressant effects of ethanol

(Khanna et al. 1998).

Behavioral studies can only provide indirect evidence that ethanol interacts with GABAA receptor

systems. A large body of physiological and biochemical studies has examined the interactions

between ethanol and GABAergic systems. GABAA receptors consist of a family of structurally

related ionotropic receptors. This family includes a variety of pentameric complexes consisting of

subunits that differ in their amino acid structure. Common subunits found to exist in the brain

include the types (including subtypes 1, 2, 4, and 6), (subtypes 2 and 3), , and (subtypes 1,

2, and 3). The most abundant GABAA receptors identified in the brain consist of two , two , and

one subunit (Pritchett et al. 1989). GABAA receptors containing the 1 subunit may mediate the

sedative-hypnotic actions of benzodiazepines and new hypnotic agents, such as zolpidem (Blednov

et al. 2003). The presence of 2 subunits in GABAA receptors has been linked to the mediation of

the anxiolytic effects of the benzodiazepines (Morris et al. 2006). Deletion of the 1 subunit gene

attenuates the sedative actions of ethanol in male mice (Blednov et al. 2003), although this effect

has not been seen in some strains of 1 subunit knockout mice (Kralic et al. 2003). In rats, infusion

of a selective

1 subunit antagonist into the ventral pallidum, which receives extensive output from

the NAcc, blocks both the sedative and reinforcing effects of ethanol (Harvey et al. 2002; June et al.

2003). In humans, genetic variation in the amino acid composition of the 2 subunit has been

associated with differences in the subjective effects of ethanol (Pierucci-Lagha et al. 2005).

GABAA receptors containing 1 x 2 subunit combinations are abundant in the postsynaptic sites of

the brain and exhibit sensitivity to benzodiazepines. Of these, the 1 2 2 combination binds readily

to zolpidem, and brain sites that show dense binding of zolpidem have been linked to the actions of

ethanol (Criswell et al. 1993, 1995). Whether ethanol interacts directly with postsynaptic GABAA

receptors at concentrations that produce moderate levels of intoxication has been questioned

because several studies have shown that ethanol enhances the activity of GABAA receptors only at

concentrations associated with extremely high levels of intoxication (Krystal et al. 2006). An

alternative mechanism through which ethanol may indirectly interact with GABAA receptors may

involve the process of alcohol-evoked GABA release. Acute ethanol administration increases the

release of GABA from presynaptic sites in some brain regions, including the central nucleus of the

amygdala, a structure implicated in the rewarding effects of ethanol (Siggins et al. 2005).

Electrophysiological data also suggest that ethanol can promote GABA release in the cerebellum

(Carta et al. 2004). In some regions, such as the hippocampus, this effect may be regulated byPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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presynaptic GABAB receptors, which may limit GABA release as part of a negative feedback system.

A second mechanism through which ethanol may interact with GABAA receptors is by increasing

neurosteroid concentrations in the brain (Morrow et al. 1999). Neurosteroids, such as

allopregnanolone, are synthesized in the brain from cholesterol (Hu et al. 1987). They may increase

the activity of GABAA receptors by binding to specific sites on the and subunits of these

receptors (Hosie et al. 2006). The acute administration of ethanol can increase concentrations of

allopregnanolone in the plasma, cerebral cortex, and hippocampus (Barbaccia et al. 1999; Morrow

et al. 2001; VanDoren et al. 2000). This may occur through the stimulation of neurosteroid

synthesis, an effect that may, at least in part, involve the effects of ethanol on the

hypothalamic-pituitary-adrenal (HPA) axis (Follesa et al. 2006). In humans, the administration of

finasteride, a compound that inhibits neurosteroid synthesis, attenuates the subjective effects of a

moderate dose of ethanol (Pierucci-Lagha et al. 2005).

GABAA receptors containing 4 3 , 6 3 , and 4 2 subunit combinations have been shown by

some investigators to be sensitive to the effects of low concentrations of ethanol

(Sundstrom-Poromaa et al. 2002; Wallner et al. 2003), though in a recent study this effect could

not be replicated for the 4 3 subunit combination (Borghese et al. 2006). GABAA receptors

containing subunits and either 4 or 6 subunits have extrasynaptic locations and regulate tonic

(rather than phasic) currents (Hanchar et al. 2004). These extrasynaptic receptors represent a

smaller proportion of GABAA receptors in the brain than do those located in the synapse. Receptors

containing the 6 3 combination are present in cerebellar granule cells, whereas those composed

of the 4 3 combination are more widespread in the brain and appear in areas such as the

hippocampus, striatum, and frontal cortex (Wallner et al. 2006). GABAA receptors containing 4 or

6 subunits in combination with the subunits may mediate the anxiolytic motor coordination,

impairment, and the sedative effects of low-dose ethanol.

Prolonged exposure to ethanol may result in decreased sensitivity (i.e., tolerance) to the sedative

and many other actions of ethanol. Tolerance to the action of ethanol may occur in association with

a decrease in GABAA-mediated function (Grobin et al. 1998). Acute forms of tolerance to the

sedative-hypnotic effects of ethanol, which occur in a single drinking session, may be related to the

phosphorylation of the isoform of protein kinase C (PKC) (Wallace et al. 2007). Chronic tolerance,

it has been suggested, may result from an alteration in the subunit composition of GABAA receptors

that are present in the brain. Such changes in subunit expression are seen in animal studies that

either examined the presence of subunit proteins by immunoreactivity or measure levels of

messenger ribonucleic acids (mRNAs), which are responsible for the synthesis of the subunits

(Grobin et al. 1998; Mahmoudi et al. 1997). These changes include a decrease in the expression of

2 subunits in the cerebral cortex and the cerebellum, and an increase in 4, 6, and 1–3 subunits

in these regions. This pattern of change, however, has not been detected for humans with a history

of alcoholism. Evidence concerning the effects of chronic ethanol use on the relative amounts of

different GABAA subunits in the human brain is not consistent. One group of researchers has

reported that levels of mRNA for the 3 receptor subunit may be increased in the frontal cortex of

alcoholic individuals (Mitsuyama et al. 1998). Another group found increases in the 1 subunit

levels in this region (Lewohl et al. 1997) but failed to see this change when tissue from the

superior frontal cortex of noncirrhotic alcoholic patients was examined (Lewohl et al. 2001). In

another study, levels of 2 subunit mRNAs were decreased in the superior frontal cortex (Lewohl et

1. 2000). Some researchers, however, have been unable to find changes in the frontal cortex in the

expression of mRNA for any GABAA receptor subunits (Flatscher-Bader et al. 2005; Mayfield et al.

2002).

The significance of findings on the nature of GABAA subunit expression in alcoholic individuals is

confounded by postmortem studies in which investigators are unable to control for genetic

differences between control and alcoholic groups, and variables such as between-group differences

in the cause of death and the state of health before death. Examination of the effects of chronic

ethanol on GABAA subunit expression in nonhuman primates allows for the control of some of these

confounding factors. Chronic self-administration of ethanol decreased the expression of 2, 4, 1, Print: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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3, 1, 2, and 3 subunit mRNAs in the orbital frontal cortex of cynomolgus monkeys (Hemby et al.

2006). In the dorsolateral prefrontal cortex of these animals, mRNAs were decreased for 1, 2, 1,

and subunits, although no changes were observed for subunits in the anterior cingulate. These

reductions in GABAA subunits may contribute to the tolerance that develops to ethanol’s effects.

Tolerance to the effects of ethanol may also be related to alterations in the trafficking of GABAA

receptor subunits between the cell membrane surface and the interior of the cell. This is evidenced

by the finding that chronic exposure to ethanol enhances the internalization of 1 subunits in

cerebral cortical neurons (Kumar et al. 2003).

Glutamate Receptor Systems

NMDA receptors

Activation of NMDA receptors by glutamate and other excitatory amino acids enhances calcium and

sodium flow into neurons, with a resultant increase in excitatory postsynaptic potentials. NMDA

receptors contain four subunits: two NR1 and two NR2 subunits. NR2A and NR2B subtypes exist,

and, in some cases, other subunits, such as the NR3 subunit, may also be present. Glutamate may

activate NMDA receptors by binding to the NR2 or comparable subunit. The functioning of NMDA

receptors is dependent on the binding of the amino acid glycine to the NR1 subunit. NMDA

receptor–mediated flux is regulated by a voltage-dependent magnesium block. Consequently, these

receptors become active only when a certain level of neuronal depolarization is reached.

Competitive antagonists directly block the binding of glutamate to the NMDA receptor. Ketamine,

phencyclidine, and many other agents act as uncompetitive antagonists at the NMDA receptor by

binding to sites within the ion channel of the receptor complex.

Several studies indicate that there is overlap in the stimulus properties of ethanol and

uncompetitive NMDA receptor antagonists (Hodge et al. 2001; Hölter et al. 2000; Hundt et al.

1998). In animal studies, the administration of both competitive and uncompetitive antagonists

reduces responding for ethanol (Rassnick et al. 1992; Shelton and Balster 1997). However, these

agents will also reduce responding for saccharin solutions, which argues against the specificity of

their actions (Shelton and Balster 1997). The administration of both uncompetitive and competitive

NMDA receptor antagonists decreases ethanol consumption at doses that produced only small

changes in food intake (McMillen et al. 2004), which is consistent with the idea that NMDA

receptors regulate ethanol consumption.

From a functional standpoint, acute ethanol administration appears to inhibit NMDA receptor

activity. At concentrations as low as 10 mmol/L, ethanol can inhibit NMDA receptor–mediated

influx of calcium in cultured cerebellar granule cells (Hoffman et al. 1989). The acute

administration of ethanol may reduce excitatory postsynaptic potentials mediated by NMDA

receptors in the hippocampus (Lovinger et al. 1989, 1990), with significant inhibition being

detected at an ethanol concentration of 25 mmol/L. In the core of the NAcc, NMDA currents are

reduced by ethanol at concentrations ranging between 11 and 200 mmol/L (Nie et al. 1994).

Ethanol in concentrations of 25–75 mmol/L inhibits NMDA excitatory postsynaptic potentials in

medium spiny neurons of the shell of the NAcc (Zhang et al. 2005). There is limited evidence that

the inhibitory effects of ethanol are regulated by discrete sites located on NR1 (Smothers and

Woodward 2006) and NR2A (Honse et al. 2004) subunits.

The sensitivity of NMDA receptors to glutamate and other agonists is regulated by the

phosphorylation and dephosphorylation of receptor subunits. Kinases, such as PKA and tyrosine

kinases, phosphorylate the receptor, whereas phosphatases, such as PP1, can dephosphorylate the

receptor. The hypnotic effect of ethanol is greatly enhanced in mutant mice with deletions of the

gene for Fyn-tyrosine kinase (Miyakawa et al. 1997; Yaka et al. 2003). However, presence of the

Fyn mutation does not appear to alter voluntary ethanol consumption (Yaka et al. 2003). The NR2B

subunit may be a target of Fyn-tyrosine phosphorylation. Involvement of this subunit in mediating

ethanol’s sedative effects is suggested by the finding that the administration of ifenprodil, a

selective antagonist of the NR2B subunit, increases the duration of loss of the righting reflex inPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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wild-type mice (Yaka et al. 2003).

The presence of a dopamine D1 receptor agonist leads to a marked reduction in the inhibitory

actions of ethanol on NMDA-induced currents in the NAcc (Maldve et al. 2002). This may result

from D1 receptor–mediated phosphorylation of the NR1 subunit. In cAMP-regulated phosphoprotein

32KD (DARPP-32) knockout mice, D1 agonist stimulation fails to alter the sensitivity of NMDA

receptors to the inhibitory effects of ethanol (Maldve et al. 2002). The reinforcing effects of ethanol

are attenuated in DARPP-32 knockout mice (Risinger et al. 2001), which may indicate that

DARPP-32–mediated phosphorylation of the NMDA receptor is involved in the neuroadaptation that

promotes ethanol consumption.

NMDA receptors may be up-regulated during ethanol withdrawal (Haugbøl et al. 2005). In the

amygdala, chronic ethanol treatment produces an increase in NMDA-stimulated currents, possibly

indicating that NMDA receptor up-regulation is related to enhanced sensitivity of the NMDA

receptor systems (Floyd et al. 2003). Treatment with NMDA receptor antagonists such as

memantine reduces ethanol withdrawal seizures, suggesting a role for the NMDA receptor in the

onset of withdrawal symptoms (Bienkowski et al. 2001).

Chronic ethanol administration increases mRNA and protein levels for NMDA receptor subunits in

various brain regions, including the amygdala, cerebellum, frontal cortex, and hippocampus

(Darstein et al. 2000; Floyd et al. 2003; Kalluri et al. 1998). Similarly, in postmortem tissues, there

is greater density of putative NMDA receptor binding sites in frontal cortical tissues obtained from

alcoholic individuals than from controls (Freund and Anderson 1996). In rats treated chronically

with ethanol, concentrations of NMDA receptor subunits in the cerebral cortex and hippocampus

returned to near-control levels 48 hours after the start of withdrawal (Kalluri et al. 1998). Chronic

ethanol exposure increases the size and density of clusters of the NR1 and NR2B subunits in

synapses of hippocampal neurons (Carpenter-Hyland et al. 2004). Thus, chronic ethanol

administration appears to remodel the pattern of distribution of synaptic NMDA receptor subunits in

neurons.

A recent study by Zhou et al. (2007) indicates that, in addition to altering NMDA subunit expression

and NMDA receptor function, chronic ethanol administration may also alter the structure of

dendritic spines within the NAcc. Both continuous and intermittent access to ethanol reduced

dendritic spines of medium spiny neurons of the NAcc. Intermittent ethanol exposure was

associated with the appearance of large-sized spines. Continuous access to ethanol was also

associated with an up-regulation of NR1 subunits. Ethanol-induced alterations in dendritic spine

morphology may be related to changes in the postsynaptic proteins that regulate NMDA receptor

function. These proteins include Homer and Shank, which are involved in the anchoring of NMDA

receptors and regulate their function. Deletion of the Homer-2 protein in mice enhanced the

hypnotic effects of ethanol and increased place aversion to environments associated with ethanol

administration (Szumlinski et al. 2005).

Ethanol exposure may also alter the function of NMDA receptors by changing the trafficking of

NMDA receptor subunits. Treatment with ethanol increases the internalization of NR2A subunits

into hippocampal neurons. This, in turn, produces NMDA receptors that consist predominantly of

NR2B subunits, which are associated with the form of synaptic plasticity known as long-term

depression, which plays a role in memory (Liu et al. 2004).

The up-regulation of NMDA receptors that results from chronic ethanol exposure may be one factor

that contributes to the increased neuronal excitability that occurs during withdrawal from ethanol.

A second factor in the development of hyperexcitability during withdrawal may be increased

extracellular levels of excitatory amino acids in the brain. Glutamate may be elevated in both the

hippocampus (Dahchour and De Witte 2003) and the striatum (Rossetti and Carboni 1995;

Saellstroem et al. 2006) during ethanol withdrawal. These elevations may involve positive feedback

loops in which glutamate stimulates NMDA receptors to facilitate further release of this amino acid

(Rossetti et al. 1999). Interestingly, nicotine administration also increases glutamate release in the

NAcc in animals withdrawn from ethanol (Saellstroem et al. 2006).Print: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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AMPA/Kainate receptors

AMPA and kainate receptors are glutamate-activated receptors (GluRs) that regulate sodium

currents and in some cases also calcium currents. These receptors overlap in their sensitivity to

certain agonists, but are composed of distinct subunits, with GluR1–4 units forming the AMPA

receptors and GluR5–7 forming the kainate receptors in combination with kainic acid (KA) 1–2

subunits (Dingledine et al. 1999). Ethanol reduces non–NMDA glutamate receptor–mediated

currents in the central nucleus of the amygdala (Zhu et al. 2007). These currents are increased by

the repeated administration of ethanol. In the core of the NAcc, ethanol slightly reduces

kainate-induced currents but has no effect on AMPA-induced currents (Nie et al. 1994). In the

hippocampus, ethanol potently inhibits currents produced by kainate receptors, but not those

associated with the activation of AMPA receptors (Carta et al. 2003).

Although ethanol has not been shown to alter the activity of AMPA receptor systems, these

systems, nevertheless, may play a role in alcoholism. The AMPA receptor subunits GluR2 and GluR3

are elevated in tissues obtained from individuals with a history of alcohol abuse, when compared

with control subjects (Breese et al. 1995). Topiramate, which has AMPA/kainate-blocking

properties (Gryder and Rogawski 2003; Poulsen et al. 2004), reduces ethanol consumption in

alcohol-dependent individuals (Johnson et al. 2003). It is unknown whether this effect involves

actions at kainate receptors, AMPA receptors, or both types of receptor.

AMPA receptor systems may regulate ethanol-seeking behaviors. Reinstatement of responding for

ethanol, a measure of the motivation to seek ethanol, is blocked by the administration of an

AMPA/kainate receptor antagonist (Bäckström and Hyytiä 2004; Sanchis-Segura et al. 2006).

Reinstatement responding induced by ethanol-related cues is blunted in mice missing the GluR3

subunit (Sanchis-Segura et al. 2006). Mice missing this subunit, however, did not differ from

wild-type mice with respect to the self-administration of ethanol.

Metabotropic receptors

Metabotropic receptors are activated by glutamate, but in contrast to glutamatergic ionotropic

receptors, their actions are mediated by G proteins. Group I metabotropic receptors include the

metabotropic GluR1 (mGluR1) and mGluR5 subtypes, and Group II receptors include the mGluR2/3

subtypes. The Group II receptors are located on presynaptic glutamatergic neurons. The Group I

metabotropic receptors and NMDA receptors can each alter the activity of the other receptor type.

For example, activation of NMDA receptors can potentiate the activity of mGluR5 receptors

(Alagarsamy et al. 2005), and NMDA receptor–mediated synaptic transmission is dependent on

activation of mGluR5 receptors (Harney et al. 2006).

Ethanol may decrease the activity of mGluR5-type receptors via a mechanism involving the kinase

PKC (Minami et al. 1998; Netzeband and Gruol 1995). Both the mGluR1 and mGluR5 receptors have

been implicated in the regulation of the rewarding effects of ethanol. The drug acamprosate, which

is approved for the treatment of alcohol dependence, may act as an antagonist at the mGluR5

receptor (Harris et al. 2002). Ethanol-induced elevations of dopamine levels in the NAcc are

blocked by the administration of mGluR1 or mGluR5 antagonists (Lominac et al. 2006). In animal

studies, the administration of mGluR1 and mGluR5 antagonists may reduce ethanol

self-administration (Cowen et al. 2005; Lominac et al. 2006), although mGluR1 antagonists have

not consistently had this effect (Hodge et al. 2006; Schroeder et al. 2005). The mGluR5 antagonist

6-methyl-2(phenylethynyl) pyridine alters ethanol intake in wild-type mice but not in animals in

which the isoform of PKC has been deleted (Olive et al. 2005). This is consistent with other

findings implicating PKC-mediated phosphorylation in the inhibitory actions of ethanol on mGluR5

receptors (Minami et al. 1998).

Neuropeptides

Opioid receptor systems

The endogenous opioid system plays a role in the reinforcing effects of ethanol and a variety ofPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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other drugs that are self-administered by animals and abused by humans, including nicotine,

cocaine, amphetamines, and cannabinoids. Three classes of opioid receptors, , , and , interact

with opioid peptides to produce their biological effects (Kieffer 1995). The opioid receptor

mediates the effects of morphine and related opioid agonists (Yu 1996). It has a putative

secondary structure of seven transmembrane domains common to G protein–coupled receptors,

with functional coupling to adenylyl cyclase.

Ethanol, like nicotine, cocaine, amphetamines, and cannabinoids, releases dopamine in the NAcc (Di

Chiara and Imperato 1988; Tanda et al. 1997). In addition, opioid receptors in the VTA modulate

NAcc dopamine activity and ethanol-preferring (AA) rats have a significantly higher density of

opioid receptors in the VTA (and related limbic brain regions) than ethanol-avoiding (ANA) rats (De

Waele et al. 1995).

The opioid receptor is also a G protein–coupled receptor with functional coupling to adenylyl

cyclase, and it too has been shown to modulate ethanol consumption (Froehlich et al. 1991;

Krishnan-Sarin et al. 1995). In rats selectively bred for high levels of ethanol drinking, the selective

antagonist ICI 174864 was found to be more potent than naloxone in suppressing ethanol

consumption (Froehlich et al. 1991; Krishnan-Sarin et al. 1995). The more highly selective and

longer-acting antagonist, naltrindole hydrochloride, also produced a dose-dependent suppression

of drinking in rats selectively bred for ethanol consumption (Krishnan-Sarin et al. 1995).

In research done by Gianoulakis and Gupta (1986), concentrations of endogenous opioids, which

bind to and opioid receptors, are correlated with ethanol exposure. Acute ethanol treatment of

ethanol-drinking mice increased the hypothalamic release of -endorphin. In humans, individuals

with alcohol use dependency showed decreased basal plasma (Aguirre et al. 1990) and CSF

(Genazzani et al. 1981) concentrations of -endorphin. Furthermore, nonalcoholic adults with a

family history of alcoholism (i.e., high risk) had basal concentrations of -endorphin that were

comparable with those of abstinent alcoholic persons but significantly lower than those of low-risk

individuals (Gianoulakis et al. 1989). Following ethanol administration, -endorphin levels

increased among high-risk subjects, resulting in levels comparable with those seen following

ethanol administration among low-risk subjects (Gianoulakis et al. 1989). Furthermore, ethanol

induced a dose-dependent increase in plasma -endorphin levels in high-risk but not low-risk

subjects (Gianoulakis et al. 1996).

Enkephalins may also play a role in the reinforcing effects of ethanol (Li et al. 1998; Mendez and

Morales-Mulia 2006). The efficacy of opioid antagonists (i.e., naltrexone, nalmefene) in the

treatment of alcoholism (Srisurapanont and Jarusuraisin 2005) provides further evidence that the

rewarding properties of ethanol are, in part, mediated by the opioid system.

Neuropeptide Y

NPY is a 36-amino acid peptide neurotransmitter. Mice deleted for the gene encoding NPY showed a

preference for drinking ethanol-water solutions over water (Thiele et al. 1998). These mice were

also less sensitive to the hypnotic and sedative effects of ethanol than NPY wild-type mice. In

contrast, mice manipulated to overexpress NPY showed less preference for ethanol and greater

sensitivity to the sedative and hypnotic effects of ethanol (Thiele et al. 1998, 2000a). Studies of

specific NPY receptors show that Y1 receptors inhibit voluntary ethanol consumption and some of

ethanol’s intoxicating effects, such that mice deleted for the gene encoding this receptor show

increases on these measures (Pandey et al. 2003; Thiele et al. 2002). In contrast, the Y2 receptor

serves as a presynaptic autoreceptor that inhibits NPY release, so that mice deleted for the gene

encoding this receptor show reduced ethanol consumption (Pandey et al. 2003). These findings

have led to the suggestion that NPY Y1 agonists and Y2 antagonists may be of value in the

treatment of alcoholism (Cowen et al. 2004).

Other peptide neurotransmitters

Other peptides that have been linked to the actions of ethanol are corticotropin-releasing hormone

(CRH), urocortin, leptin, cholecystokinin, melanocortins, and galanin (reviewed in Cowen et al.Print: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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2004). Preclinical studies have linked the CRH system to the effects of a variety of substances of

abuse, including alcohol (Sarnyai et al. 2001). CRH, which plays a central role in the response to

stress by regulating the HPA axis, exerts its effects through CRH1 and CRH2 receptors. In an acute

free-choice paradigm, Sillaber et al. (2002) found that mice homozygous for a CRH1 receptor gene

deletion (CRH–/–) did not differ from wild-type mice with respect to their consumption of fluids,

including ethanol. However, following habituation to 8% ethanol and exposure to a repeated social

defeat stress, when tested again 3 weeks later, CRH–/– animals consumed more than twice the

volume of ethanol daily that did their wild-type littermates. Although subsequent exposure to a

swim stress slightly decreased ethanol consumption acutely in both groups of animals, CRH–/– mice

subsequently showed increased drinking, whereas there was no increase in drinking among the

wild-type mice. The doubling of ethanol intake persisted among the CRH–/– mice for more than 6

months. The rate of ethanol metabolism did not differ between the groups of mice, excluding this

as a possible explanation for the observed effects on drinking behavior. However, further analysis

did reveal increased expression of the NR2B subunit of the NMDA receptor, without alteration of

the expression of any other ionotropic glutamate subunit.

ETHANOL INTERACTIONS WITH ION CHANNELS

Voltage-gated calcium ion channels regulate neuronal excitability and neurotransmitter release by

regulating calcium flow into neurons in response to membrane potential changes. Several varieties

of voltage-gated calcium channels have been identified, including the L, N, P/Q, R, and T types.

Studies of the effects of ethanol on calcium channels in isolated cell preparations indicate that

ethanol can inhibit the activity of L-type (Mullikin-Kilpatrick and Treistman 1995), N-type (Solem et

1. 1997), P/Q-type (Solem et al. 1997), and T-type (Littleton et al. 1992; Mu et al. 2003; Twombly

1990) calcium channels. The functional implication of ethanol’s actions on voltage-gated calcium

channels is just beginning to be characterized. Dihydropyridine-sensitive (L-type) binding sites are

increased in ethanol-dependent rats (Dolin et al. 1987), and L-channel antagonists can prevent

withdrawal symptoms in these animals. N-type and P/Q-type channels have been implicated in the

regulation of neurotransmitter release (Reid et al. 2003). The hypnotic effects of ethanol are

diminished in mutant mice that lack the N-type calcium channel (Newton et al. 2004), which show

both decreased ethanol preference and levels of ethanol consumption compared with wild-type

mice.

In contrast to the other voltage-gated channels, T-type channels have low voltage thresholds for

activation. These channels have been implicated in the generation of burst responses in thalamic

neurons that produce spindle waves during Stage II sleep (Kim et al. 1995). Low concentrations of

ethanol may enhance T-type currents in the thalamus, although higher concentrations of ethanol

block these currents (Mu et al. 2003). The chronic self-administration of ethanol reduces T-type

calcium currents in dorsal-lateral geniculate nucleus cells in the thalamus of monkeys (Carden et

1. 2006), an effect that may play a role in the disruptive effects of ethanol on sleep (Carden et al.

2006).

Inwardly rectifying potassium channels can decrease neuronal excitability. G protein–coupled,

inwardly rectifying potassium channels (GIRKs) may be activated by intoxicating concentrations of

ethanol (Lewohl et al. 1999). Mutant mice, from which the GIRK2 type of potassium channel is

deleted, consume more ethanol than do wild-type mice (Blednov et al. 2001).

Large-conductance, BK channels are voltage-dependent potassium channels that are also activated

by increases in intracellular calcium. BK channels may be abundant in the medium spiny neurons of

the NAcc (Martin et al. 2004). BK channel subunits have been identified in several other brain

regions, including the amygdala, cerebellum, hippocampus, and neocortex (Edgerton and Reinhart

2003; Faber and Sah 2002; Hicks and Marrion 1998; Kang et al. 1996). These channels modulate

the shape and frequency of action potentials and control neurotransmitter release (Shao et al.

1999). Ethanol activates BK channels in the NAcc (Martin et al. 2004) at concentrations associated

with intoxication. Although the behavioral significance of ethanol-induced activation of BK channels

is not well understood, in the nematode Caenorhabditis elegans BK channels may be the onlyPrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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proteins through which ethanol acts to produce intoxication (Davies et al. 2003).

CONCLUSION

Ethanol can alter the activity of cAMP second messenger pathways by stimulating some isoforms of

adenylyl cyclase. This effect can alter the phosphorylation state of receptor systems, most notably

the NMDA receptor system. This action may also influence the function of CREB and NPY systems,

which may play a critical role in regulating drinking behaviors. Another neuropeptide, CRH, through

actions involving both the HPA axis and extra-HPA systems, may also play a key role in ethanol

consumption, possibly by interacting with the glutamate system through NMDA receptor effects.

Like many other drugs of abuse, ethanol promotes the release of dopamine within the mesolimbic

system. This action may be linked to the rewarding actions of ethanol. The dopamine-releasing

effects of ethanol may be enhanced as a result of repeated exposure to this agent. Nicotinic

receptors located in the VTA may mediate some of the dopamine-releasing actions of ethanol.

Cannabinoid CB1 and serotonin 5-HT3 and 5-HT1B receptors may also facilitate

mesolimbic-dopamine release associated with ethanol use. Whereas and opioid receptors also

appear to facilitate dopamine release following ethanol intake, the opioid receptor appears to

inhibit this effect.

The anxiolytic, hypnotic, motor-impairing, and sedative actions of ethanol most likely result from

activation of GABAA receptor systems. Mechanisms that mediate the actions of ethanol on these

systems remain a subject of intense investigation. Proposed mechanisms include ethanol-induced

presynaptic release of GABA, increases in neurosteroid concentrations in the brain, and direct

interactions between ethanol and GABAA receptors that contain 4 or 6 subunits in combination

with the subunit.

Each of the major types of glutamate receptors may play a role in alcoholism. The NMDA receptor

systems are subject to the inhibitory actions of ethanol. These actions produce some of the

stimulus effects associated with ethanol use and may be tied to the rewarding actions of ethanol.

mGluRs, particularly the mGluR5 receptor, may regulate ethanol self-administration, possibly

through an interaction with NMDA receptors. Although they may not directly interact with ethanol,

AMPA receptors may regulate ethanol-seeking behavior. Kainate receptors in select brain regions

are subject to the inhibitory actions of ethanol, but the behavioral implications of this effect remain

to be determined.

Ethanol exposure alters the functioning of L-, N-, P-, and T-type voltage-dependent calcium

channels. Ethanol-induced alterations of L-type calcium channels may play a role in the

development of ethanol withdrawal symptoms. N- and T-type calcium channels may mediate some

of the sedative effects of ethanol and its impact on the quality of sleep experienced. Recent

evidence suggests that BK channels may play an important role in ethanol intoxication.

The decreased sensitivity of GABAA receptors and the increased sensitivity of NMDA receptor

systems have been implicated in the development of neuronal hyperexcitability that occurs during

the early phases of ethanol withdrawal. Withdrawal symptoms can be attenuated by the

administration of either positive modulators of GABAA receptor systems, such as the

benzodiazepines, or NMDA receptor antagonists, such as memantine. Alterations in subunit

expression that occur with prolonged ethanol exposure may play a role in ethanol withdrawal.

Ethanol withdrawal, however, may also involve more subtle changes, such as alterations in the

local trafficking of receptors through the plasma membrane and in gene expression.

As discussed in this chapter, considerable knowledge has accrued concerning the neurobiology of

ethanol drinking behavior and ethanol’s behavioral effects. This growing understanding of the

neurobiology of alcohol can be expected to continue to inform the search for medications to treat

alcohol use disorders, reflecting an iterative process of preclinical and clinical development.

KEY POINTS

The antianxiety, motor-impairing, and sedative-hypnotic effects of ethanol may be produced by thePrint: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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activation of -aminobutyric (GABA)A receptors.

Ethanol may interact with GABAA receptors by enhancing GABA release, increasing brain neurosteroid

levels, and/or by directly acting on GABAA receptors that contain 4 or 6 subunits.

Decreased GABAA receptor sensitivity and N-methyl-D-aspartate (NMDA) receptor up-regulation may play

important roles in the development of physical dependence on ethanol.

Ethanol-induced dopamine release within the nucleus accumbens may produce the reinforcing effects of

alcohol.

Cannabinoid CB1, nicotinic, opioid, and serotonin 5-HT3 receptors may alter the reinforcing effects of

ethanol by facilitating dopamine release.

Endogenous opioid peptides, including the enkephalins, may promote ethanol consumption while other

peptides, such as neuropeptide Y, may have inhibitory effects on alcohol-seeking behaviors.

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SUGGESTED READING

Koob GF: Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243, 2003Print: Chapter 8. Neurobiology of Alcohol http://www.psychiatryonline.com/popup.aspx?aID=345891&print=yes…

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