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100

ETHANOL ABUSE, DEPENDENCE, AND WITHDRAWAL: NEUROBIOLOGY AND CLINICAL IMPLICATIONS

JOHN H. KRYSTAL BORIS TABAKOFF

Ethanol produces a striking array of behavioral effects in patients and to prevent their relapse to ethanol use. Al- humans that are dependent on the dose of ethanol adminis- though the most severe consequences of withdrawal appear tered, whether ethanol levels are rising or falling, and the during the initial week of sobriety, protracted components rate of change of ethanol levels (1). The euphoric, , of withdrawal persist for many months (8). Protracted with- and anxiolytic effects of ethanol contribute to its wide recre- drawal symptoms include insomnia, anergia, and depressed ational use, whereas its sedative effects contribute to its con- mood. The effort to rid oneself of withdrawal symptoms sumption as a nonprescription hypnotic. Yet, at intoxicating may be an important motivator for relapse to ethanol use. doses, ethanol clouds memory and judgment (2), slows in- As will be reviewed later, this phase of recovery is also associ- formation processing and reaction time (3), impairs coordi- ated with gains in cognitive function, cortical activity, and nation (4), and disinhibits impulsive or aggressive behavior brain structure. (5). Perhaps, then, it is not surprising that some of the most Nutritional deficits complicate the natural history of al- damaging consequences of ethanol abuse reflect the impact coholism (9). If thiamine-deficient individuals ingest glu- of ethanol intoxication on behaviors, such as driving, that cose before thiamine repletion, the resulting demand on place a high demand on these cognitive functions (6). thiamine pyrophosphate-dependent metabolic processes With chronic administration, ethanol produces both ad- compromises neuronal metabolic functions and may pro- aptation and in the brain, accounting for tol- duce cell death associated with the Wernicke-Korsakoff syn- erance and dependence. The ethanol withdrawal syndrome drome (10). This eponym refers to a constellation of learn- (7) includes anxiety, insomnia, and symptoms of sympa- ing and memory impairment, psychosis, and motor findings. thetic nervous system arousal. With more severe levels of This chapter provides a brief and selective overview of dependence and repeated episodes of withdrawal, absti- the basic and clinical neuroscience of . Ethanol nence may be associated with substantial sympathetic is now known to have multiple specific actions in the brain arousal, agitation, perceptual changes, confusion, and sei- that contrast with the historical focus on its nonspecific zures. These symptoms may emerge together in the context perturbation of neuronal membrane bulk (11,12). of , a potentially -threatening complica- This chapter discusses the acute and chronic effects of tion of ethanol dependence that generally develops within ethanol at its targets in the brain, and the neural the initial week of sobriety. Another syndrome, alcoholic circuitry of human alcoholism that has become the focus hallucinosis, may develop during any phase of the cycle of of structural and functional neuroimaging studies. intoxication and withdrawal. It is associated with persisting hallucinations that may or may not remit with extended MOLECULAR TARGETS OF THE ACTION OF sobriety. ETHANOL: RELEVANCE TO INTOXICATION Acute and protracted abstinence are important contexts AND DEPENDENCE for treatment to ensure the medical safety of recovering Amino Glutamate John H. Krystal: Department of Psychiatry, Yale University School of Glutamate Receptors as an Ethanol Target in the Medicine, VA Research Center, VA Connecticut Healthcare System, Brain West Haven, Connecticut. Boris Tabakoff: Department of , University of Colorado Glutamate is the major excitatory in the School of Medicine, Denver, Colorado. (CNS) and glutamate utilizes both 1426 : The Fifth Generation of Progress

FIGURE 100.1. The relative potency of ethanol for its protein targets in the brain. Shown is the relationship between amounts of alcohol consumed and neurotransmission, neuroexcitatory components, and behavioral actions.

ionotropic and metabotropic receptors to transduce its sig- A–D). The relative affinity of ethanol for NMDA nal. The ionotropic receptors, receptor-gated ion channels, subtypes may be important to its dose-related effects in the include the N-methyl-D-aspartate (NMDA) ␣-amino-3-hy- brain (18), but this issue remains under intensive investiga- droxy-5-methyl-4-isoxazoleproprionate (AMPA), and kai- tion (19). nate receptors (13). NMDA receptors are gated by mem- The inhibition of NMDA receptor function by ethanol brane potential and the simultaneous binding of both has direct neuroprotective consequences (20). NMDA an- and glutamate (14). Ethanol at concentrations as tagonist effects of ethanol may influence its modulation of low as 5 mM (20 mg%) inhibits ion flux through the the release of other (21,22), perhaps re- NMDA receptor-gated ion channels, making NMDA re- flecting the capacity of low-dose NMDA antagonism to ceptors one of the highest affinity ethanol targets in the preferentially attenuate the activation of local inhibitory cir- brain (Fig. 100.1) (see ref. 15 for review). It shows lower cuits (23). affinity for AMPA and kainate glutamate receptors (15). The subjective effects of ethanol are tested in animals by Ethanol effects on the NMDA receptor function are de- measuring their ability to discriminate the effects of ethanol pendent on the concentration of glycine and the phosphory- and other . NMDA antagonists substitute for ethanol lation status of the receptor. In cultured cerebellar granule in these experiments, where they resemble the effects of cells, ethanol lowered the NMDA receptor affinity for gly- higher doses of ethanol than ethanol doses that are most cine, and ethanol effects were partially reversed by raising similar to the effects of ␥-aminobutyric acid (GABA) ago- glycine levels (16). A C (PKC)-mediated nists (24). Supporting the importance of the NMDA site, event may gate the effects of ethanol on WSP (withdrawal prone) and WSR (withdrawal sei- glycine affinity at the NMDA receptor (16). Other protein zure resistant) mice differ in their NMDA receptor kinases (e.g., kinases such as Fyn and Src) may also in several brain regions (25) and in their capacity to discrim- play a role in ethanol’s actions on the NMDA receptor (17). inate ethanol from other substances (26). Regional variations in NMDA receptor subunit compo- sition contribute to distinctions in ethanol effects on NMDA Receptor Adaptations with Ethanol Tolerance NMDA receptor function across brain regions (see ref. 14 and Dependence for review). Functional NMDA receptors are composed of Multiple lines of evidence implicate NMDA receptor up- an NR1 subunit, with at least eight splice variants, and one regulation as a mechanism contributing to acute ethanol NR2 subunit from among the four known subtypes (NR2 withdrawal. Chronic ethanol administration up-regulates Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1427

NMDA receptor number, particularly in the cerebral cortex 0.1 mg/kg. did not stimulate ethanol craving in and hippocampus (27). During acute ethanol withdrawal, patients, although craving was associated with the ethanol- NMDA receptor increases are associated with tremors, anxi- like effects of another NMDA antagonist dextromethor- ety, , and convulsions (27). Similarly, the increased phan (36). hippocampal NMDA receptor density in WSP mice is re- Clinical studies examining the interactive effects of keta- lated to their increased expression of withdrawal mine and other drugs may provide insights into the NMDA relative to WSR mice (25). Additionally, NMDA antago- antagonist component of ethanol effects in the brain. The nists given during withdrawal suppress withdrawal seizures NMDA antagonist-induced does not yet appear (28). Lastly coadministration of the ganglioside GM1 and dependent. For example, the euphoric properties ethanol prevents NMDA receptor up-regulation and the of ketamine are not blocked by pretreatment display of withdrawal seizures (29). (37) or markedly potentiated by pretreatment NMDA receptor up-regulation is subunit specific. In cul- (38). These findings parallel clinical findings describing the tured cells and whole animals, chronic ethanol administra- lack of interaction of ethanol and amphetamine (39). In tion increases the levels of the NR2A and NR2B protein contrast, the euphoric effects of ketamine (40), like ethanol subunits and their subunit messenger RNA (mRNA) levels (41), are attenuated by pretreatment with the ␮ opiate re- (30). Some, but not all, studies also suggest that NR1 sub- ceptor antagonist . Ethanol may possess actions unit protein level increases may be accompanied by increases at other brain targets that attenuate the dysphoric properties in NR1 mRNA levels (31). In cultured cells, the increases arising from its blockade of NMDA receptors including the in NMDA receptor subunit are associated with facilitation of GABAA receptor function (42) or blockade increased NMDA receptor function (32). of voltage-gated cation channels (43,44). The consequences of NMDA receptor up-regulation during dependence are compounded by increases in gluta- Dysregulation in Ethanol Dependent Pa- mate release associated with the initiation of abstinence tients: Relationship to the Familial Riskto Develop Alco- (33). Perhaps as a result, ethanol withdrawal is associated holism. Postmortem studies of brain tissue from ethanol- with seizures and neurotoxicity (see ref. 34 for review). dependent individuals suggest that the Bmax or Kd of NMDA receptors are increased in cortical structures alco- Glutamate: Clinical Correlates holics (45,46). In vivo, ethanol withdrawal increases cere- Glutamate and the Complex Discriminative Stimulus Ef- brospinal fluid (CSF) glutamate levels. The combination of fects of Ethanol. As is seen in Fig. 100.2, the NMDA an- increased glutamate release during withdrawal and NMDA tagonist, ketamine, produced dose-related ethanol-like ef- receptor up-regulation promotes withdrawal-related neural fects in recently detoxified alcoholic patients (35). As with plasticity and neurotoxicity (47). With repeated episodes of the preclinical studies (24), both the intensity and the degree withdrawal, patients show increased seizure risk (48) and of similarity of the ethanol-like effects of ketamine were hyperreflexia (49). greater at a higher subanesthetic dose (0.5 mg/kg) than at NMDA receptor function in recovering ethanol-depen-

FIGURE 100.2. Similarity of the effects of placebo (open circles), ketamine 0.1 mg/kg (solid cir- cles), and ketamine 0.5 mg/kg (solid squares) to ethanol (left), marijuana (middle), and standard error of the ע Values are expressed as mean .(20 ס right) in alcoholic patients (n) mean (SEM). Ketamine effects were significantly more similar to ethanol than both marijuana (.Data are from ref. 70) .(02. ס p ,6.7 ס and cocaine by post-hoc contrast (F1 1428 Neuropsychopharmacology: The Fifth Generation of Progress dent patients also may shift the reward valence of the ularly , , and (15). NMDA antagonist component of ethanol response from The similarity between the behavioral effects of GABA ago- dysphoria to euphoria, promoting further alcohol use. Re- nists and ethanol is dose-dependent, with the greatest simi- cently detoxified ethanol-dependent patients show reduc- larity between these classes observed with relatively tions in their sensitivity to the perceptual, mood, and cogni- low training doses of ethanol (15). tive effects of ketamine (50) and the glycine-B partial Ethanol has effects at the GABAA receptor at concentra- D- (51). In contrast, preliminary data tions of 10 to 100 mM. In one study, ethanol acted similarly suggest that these patients exhibited preserved euphoric re- to benzodiazepines by potentiating the effects of GABA sponses to ketamine relative to a healthy comparison group (58), whereas in another study ethanol resembled barbitu- (Krystal, unpublished data). Thus, NMDA receptor altera- rates by increasing the entry of without the addition tions associated with ethanol dependence might contribute of GABA (59). The microsac preparation employed in these to relapse to ethanol use in two ways: (a) by contributing studies, however, would be expected to contain certain suffi- to the signs and symptoms of ethanol withdrawal, and (b) cient amounts of endogenous GABA to influence their in- by enhancing the rewarding properties or reducing the dys- terpretation. phoric properties of ethanol during the early phases of re- Ethanol actions at GABAA receptors vary across brain lapse to ethanol use. regions and may be related to the differential expression of GABAA receptor subunits (60). This receptor is composed מ -Healthy individuals at increased familial risk for develop ing alcoholism, relative to a ‘‘family history negative’’ group, of five subunits that associate to form a Cl channel. Sub- unit families (e.g., ␣, ␤, ␥, ␦) and isoforms within each show reductions in the dysphoric effects of NMDA receptor ␣ ␣ antagonists resembling the changes seen in ethanol depen- family (e.g., 1– 6) have been identified (61). Variation in subunit composition imparts functional distinctions in dent patients (52). Thus, inherited differences in NMDA GABA receptor subtypes relevant to ethanol action (61). receptor function may contribute to alterations in the set A For example, isoforms of the ␥ subunit [i.e., ␣ or ␣ point for sensitivity to ethanol effects that promote the de- 2S 2L (62)] that differ in their sensitivity to PKC isoforms differ velopment of the abuse of ethanol. Further research is in their sensitivity to ethanol (63). However, studies now needed to clarify the impact of ethanol dependence and question the importance of these particular GABAA receptor alcoholism vulnerability on glutamatergic function. subunits (64). Some of these differences between studies The mechanism through which ketamine sensitivity is may reflect the importance of a particular PKC isoform, altered in individuals at increased familial risk for alcoholism PKC-⑀. is not yet clear. In individuals without a family history of The adenylyl cyclase signaling system and protein kinase alcoholism, antagonism of voltage-gated cation channels A (PKA) also modulate ethanol’s actions at GABAA recep- clearly reduces the dysphoric effects of ketamine and may tors. Ethanol potentiates GABA inhibition of cerebellar enhance its euphoric effects (43,44); i.e., these pretreat- Purkinje cell firing, but only when there is concomitant ments may produce changes in the reward valence of keta- stimulation of ␤-adrenergic receptors (65) and activation mine effects that are similar to the alterations associated of PKA (66). with a family history of ethanol dependence. The genes underlying altered ketamine response in individuals at risk Chronic Actions of Ethanol on GABAA Receptor for alcoholism are not yet known. Function Changes in the levels of GABAA receptor subunits occur in : A Putative Glutamatergic Pharmacother- animals treated chronically with ethanol (67). It consistently ␣ apy for Alcoholism. Acamprosate is a deriva- decreases the mRNA and protein for the 1 subunit of the tive without ethanol-like behavioral effects that reduces al- GABAA receptor, whereas other subunits may show no cohol consumption in animals (53). This drug is a change or even increases (67). In vitro studies form ethanol- promising agent for treating alcoholism (54,55). It reduces treated animals demonstrated a reduced ability of ethanol NMDA receptor function, contributing to its capacity to to potentiate GABA-mediated chloride flux, suggestive of suppress ethanol withdrawal (56). However, it also has pro- the development of ethanol tolerance (58). In vivo, hyper- motes some NMDA receptor-mediated effects (57). The site excitability, fear behaviors, and convulsions during acute ethanol withdrawal may reflect decreases in GABAergic of action of acamprosate is not known and the mechanisms neurotransmission (68). WSP and WSR mice, noted earlier related to its are not fully understood. to differ in NMDA receptor regulation, also differ in pre- dicted directions with respect to their GABAA receptor char- acteristics and their vulnerability to withdrawal seizures GABA (69). GABA Receptors as Targets for Ethanol Action GABA: Clinical Correlates Ethanol produces sedative-hypnotic effects that resemble GABA Systems and Alcoholism Vulnerability. To date, other drugs that facilitate GABAA receptor function, partic- the genes underlying the GABA-related vulnerability for Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1429 alcoholism are unknown. A haplotype relative-risk study symptoms. These changes may in part reflect ethanol depen- ␣ ␣ did not find evidence associating either the 1-or 3-sub- dence and withdrawal-related effects on the levels or func- unit genes with alcoholism, although suggestive data sup- tion of enzymes regulating GABA synthesis and degradation porting further study was obtained for the latter gene in an (80). association study (70). The strongest tie between GABAA Reductions in GABAA receptor binding in postmortem receptor involvement and the vulnerability to alcoholism and antemortem neuroimaging studies may reflect the com- has come from studies evaluating ethanol and benzodiaze- bined effects of vulnerability, ethanol dependence, and alco- pine effects in populations at high-risk for developing alco- holism-related neurotoxicity. Some postmortem studies holism. Most (71,72), but not all (73), studies found that found reductions in GABAA/ (BZ) binding, male offspring of alcoholics have reduced sensitivity to the but other studies had conflicting results (81–83). Variability cognitive, behavioral, and motor effects of both benzodiaze- between studies may reflect a compensatory up-regulation pines and ethanol. Similarly, individuals at risk for alcohol- in BZ/GABAA binding that follows alcoholism-related neu- ism exhibited blunted cerebellar metabolic inhibition, but rotoxicity (84) or the failure to employ that differen- not cortical metabolic inhibition, following a dose of lora- tiate between subtypes of GABAA receptors. In vivo, posi- zepam (74). However, there may be greater sensitivity to tron emission tomography (PET) and single photon or preference for the euphoric effects of benzodiazepines in emission computed tomography (SPECT) neuroreceptor this population (71), although these effects are not uni- imaging has provided evidence of reductions in BZ binding formly replicated (75). The rewarding effects of alcohol and (Fig. 100.3) (85,86). Neurotoxicity contributed to, but did benzodiazepines in humans may be increased in anxious not account for, reductions in BZ receptor binding in pa- individuals, who tend to experience more pronounced anxi- tients (87). Reductions in BZ binding may be consistent olytic effects of these drugs (76). with evidence of reduced regional brain metabolic sensitivity to in ethanol-dependent individuals (88). How- Clinical Evidence of GABA Dysregulation in Alcohol- ever, metabolic blunting did not rapidly recover with sobri- ism. GABAergic regulation differs in alcoholic and nonal- ety (89), raising the possibility that this deficit reflected coholic populations. GABA levels are reduced in plasma, genetic vulnerability or irreversible . CSF, and brain in recently detoxified alcoholics during the Psychopharmacologic studies also implicate GABA sys- first month of detoxification (77,78). In patients, low tems in withdrawal and relapse. Clearly, drugs facilitating plasma GABA levels predicted relapse (79), perhaps because GABAA receptor function including BZs, barbiturates, and low GABA levels were associated with protracted abstinence suppress acute ethanol withdrawal (90).

FIGURE 100.3. Transaxial slice of regions where benzodiazepine receptor distribution volume in alcoholic patients was significantly lower than in comparison subjects based on a statistical parametric mapping analysis (yellow). Single photon emission computed tomography (SPECT) data were superimposed on an MRI template. (From Abi-Dargham A, Krystal JH, Anjivel S, et al. Alterations of benzodiazepine receptors in type II alcoholics measured with SPECT and [123I]ioma- zenil. Am J Psychiatry 1998;155:1550–1555, with permission.) See color version of figure. 1430 Neuropsychopharmacology: The Fifth Generation of Progress

The BZ antagonist may reduce ethanol intoxica- to signs of ethanol withdrawal (109,110), perhaps in part, tion in humans at doses greater than required to antagonize by partially depolarizing cell membranes and recruiting BZ effects (91). However, this drug does not produce NMDA receptors. ethanol withdrawal symptoms in ethanol-dependent indi- Electrophysiologic studies with transformed cells or pi- viduals (92). It is not yet clear whether flumazenil exposure tuitary terminals also indicated that both N and T during ethanol withdrawal alters the course of recovery from channels could be inhibited by an ethanol concentration of ethanol dependence. 50 mM (111,112). Recent evidence (113) also indicates that chronic administration of ethanol to mice up-regulates the number and function of N-type calcium channels. There is growing interest in the role of neuroactive interme- diates in sex steroid synthesis and in alcoholism VSCCs: Clinical Correlates (93). , a coagonist of the steroid anesthetic site of the GABAA receptor, shares discriminative stimulus Ethanol actions at VSCCs may modulate its behavioral ef- properties with ethanol and suppresses the ethanol absti- fects in humans. Despite the apparent similarities between nence syndrome in animals (94,95). Allopregnanolone also the effects of ketamine and ethanol, ketamine produces may potentiate the effects of ethanol (96). Allopregnanolone more profound perceptual effects than ethanol at doses stud- levels, like those of its precursor , vary markedly ied to date (114). However, the perceptual effects of keta- during the menstrual cycle. In the late luteal phase, drops mine are attenuated in humans by both the L-type VSCC in allopregnanolone levels may contribute to premenstrual antagonist nimodipine (44) and by , a drug with mood disturbances (97) and increase the intensity of the multiple effects on cation channels, including an antagonist discriminative stimulus properties of ethanol (98). These action at P- and N-VSCCs (43). These studies suggest that factors may increase ethanol consumption during this phase the combination of NMDA and VSCC antagonist proper- of the menstrual cycle (99). Supporting this view, higher ties of ethanol enhance its . allopregnanolone levels in the late luteal phase are associated The relevance of adaptations in VSCCs for the clinical with reduced self-administration in women (100). phenomenology of ethanol withdrawal is not yet clear. Thus, cyclical variation in levels may be a focus L-channel antagonists may reduce the severity of some with- for future pharmacotherapies for female alcoholics. drawal symptoms, but they do not clearly suppress with- drawal seizures (115). However, the existing studies are lim- ited by shortcomings in their study design and the selection Voltage-Sensitive Calcium Channels of agents with limited CNS penetration. (VSCCs) Preclinical Studies (5-HT) In the brain, VSCCs play a major role in gating synaptic 5-HT systems contribute to the discriminative properties calcium influx and thereby modulating a range of calcium- of ethanol in animals and humans. Ethanol facilitates that dependent intracellular processes, membrane potential, and activity of 5-HT1B, 5-HT2C, and 5-HT3 receptors, and it neurotransmitter release (101,102). There are six known shares discriminative stimulus properties with drugs acting VSCC classes: L-type (dihydropyridine-sensitive), N-type at these sites (15,116). (‘‘neuronal’’), P-type (‘‘Purkinje’’), Q-type, R-type, and T- The administration of the 5-HT partial agonist, m-chlo- type (‘‘transient’’) channels (103,104). rophenylpiperazine (mCPP), produces a euphoric effect that Ethanol blocks L-type channels. Supporting this hypoth- is perceived as ethanol-like in early-onset alcoholic patients esis, L-type VSCC antagonists show some ethanol-like ef- (117–119). However, mCPP effects were not specifically fects in rats (105). Ethanol, at concentrations over 50 mM, similar to ethanol, i.e., the effects were similar to several ם inhibited [45Ca2 ] influx in in vitro preparations (106). substances of abuse (117). The two mCPP studies that ad- These studies suggested a wide range of L-type channel sen- ministered mCPP intravenously also reported the induction sitivity to inhibition by ethanol, ranging from 10 to Ͼ200 of craving (117,119), whereas the study administering this mM, perhaps reflecting differences in channel subunit com- drug orally found the opposite (120). mCPP also produced position. The variability in L-type channel sensitivity to anxiety and irritability (117). The induction of dysphoria by ethanol may depend on the characteristics of its subunits, this drug may have contributed to the elicitation of craving. post-translational modifications, and other regulatory Several studies report that the cortisol or prolactin response mechanisms (107,108). to mCPP is reduced in early onset patients (118,119,121). Chronic exposure to ethanol in vivo or cultured cells up- Further, the cerebral metabolic response to mCPP was re- regulates L-type channels via a PKC-dependent mechanism duced in early-onset alcoholics (122). In contrast, the eu- (108). The up-regulation of L-type channels may contribute phoric responses to mCPP were enhanced in early-onset Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1431 patients relative to patients with a later onset of alcoholism properties of ethanol and other drugs (146). Doses of (119). ethanol that produce motor stimulation or ataxia increase The site of action of the ethanol-like effects of mCPP is the firing rate of midbrain dopamine of unanesthe- not clear. Its partial 5-HT2C agonist action appears to figure tized rats (147). In vitro, ethanol added to brain slices in most prominently in its general discriminative stimulus ef- concentrations of 20 to 320 mM also stimulated the activity fects (123). mCPP also has activity at 5-HT3 (124) and 5- of ventral tegmental dopamine neurons (148). HT7 receptors (125). Preliminary data suggested that ritan- Ethanol increases dopamine release in brain regions in- serin, a drug that blocks 5-HT (5-HT2A, 5-HT2C, 5-HT6, volved in the reinforcing effect of ethanol, such as the ven- 5-HT7, 5-HT1D) and dopamine (D2) receptors, reduced tral tegmental area and (21). Further, mCPP effects in healthy humans (125–129). The lack of rats bred to drink ethanol, compared to ethanol nonprefer- specificity regarding the site of action of both mCPP and ring animals, show increased dopamine release associated ritanserin limits the interpretation of the mechanisms un- with ethanol consumption (149). In addition, dopami- derlying the ethanol-like and craving effects of mCPP. Also, nergic drugs alter ethanol self-administration in animals the failure of ritanserin as an alcoholism pharmacotherapy (150). Ethanol also has effects on dopamine release that (130) further raises concerns about the therapeutic applica- may be mediated by and nicotinic cholinergic sys- bility of the mCPP studies. tems (151,152). During ethanol withdrawal, there are re- Molecular genetic studies further increased interest in ductions in dopamine release in the ventral striatum and in genetic variation associated with the function of the 5-HT the nucleus accumbens (153). These decreases may contrib- transporter and the regulation of central 5-HT turnover. ute to withdrawal-related dysphoria. Ethanol, NMDA re- Although the findings have not been replicated (131,132), ceptor antagonists, and L-type VSCC antagonists attenu- two groups have associated 5-HT transporter alleles with ated these dopamine deficits (153–155). reduced central 5-HT function or poor impulse control in alcoholic individuals (133,134). However, one study failed to find that alleles of the 5-HT transporter were associated with alcoholism (131). One hypothesis guiding these studies The (LC) contains the cell bodies for the was that reduction in the efficacy or availability of synaptic brain dorsal noradrenergic system (156). LC basal activity 5-HT resulting from enhanced density or function of the and activation are reduced by ethanol, an action that may 5-HT transporter would contribute to the constellation of contribute to sedative effects of ethanol (157,158). Ethanol behaviors associated with early-onset alcoholism (135,136). also produced biphasic effects on norepinephrine turnover Alternatively, reduced density of 5-HT transporter binding in the brain, with low doses increasing turnover and higher in the brain might reflect reductions in the density of 5- doses depressing turnover. The sensitivity of noradrenergic HT terminals that might contribute to reduced central 5- systems to ethanol effects varies among brain regions (159). HT function (137,138). Studies suggest that 5-HT trans- porter antagonists have limited efficacy for alcoholism and : Clinical Correlates may make some early-onset patients worse (139,140). How- ever, 5-HT–related vulnerability may be reflected in comor- Modulation of function modulates the stim- bid conditions. Ethanol-dependent patients with depression ulant and intoxicating effects of ethanol. Catecholamine may benefit from treatment with 5-HT transporter antago- synthesis inhibition, produced by ␣-methyl-para-tyrosine, nists (141), and patients with comorbid anxiety may benefit modestly reduced ethanol intoxication in healthy humans from the addition of the 5-HT1A agonist buspirone (142). (160). Similarly, dexamphetamine and Preclinical research suggests that ethanol stimulates 5- pretreatment either had no effect or modestly potentiated ␣ HT3 receptors and that 5-HT3 antagonists may attenuate ethanol intoxication in humans (39). In contrast, the 2- the discriminative stimulus properties of ethanol and adrenergic antagonist yohimbine potentiated the intoxicat- ethanol self-administration in animals (143). In humans, ing effects of ethanol, but did not substantially alter the the 5-HT3 antagonist odansetron did not robustly attenuate subjective sense of euphoria associated with intoxication the discriminative stimulus effects of ethanol (144). How- (161). These data may conflict with other studies suggesting ever, a clinical trial employing odansetron found evidence that ␤-adrenergic stimulation attenuates ethanol intoxica- of efficacy in early-onset ethanol-dependent patients (145). tion, whereas ␤-adrenergic blockade enhances intoxication (162,163). In recently detoxified early-onset alcohol-depen- dent patients, yohimbine effects have a low degree of simi- Catecholamines larity to ethanol effects and it reduced ethanol craving levels below baseline (117). Dopamine Several studies document reduced sensitivity of both do- Dopamine-mediated neurotransmission has received much pamine and noradrenergic receptors in recently detoxified attention due to the involvement of dopamine in rewarding patients. Reduced sensitivity of dopamine receptors is sug- 1432 Neuropsychopharmacology: The Fifth Generation of Progress gested by blunted growth hormone responses to dopamine density and function of striatal and accumbens ␮ opioid (164). These data are consistent with neuroimaging receptors (190). In contrast, chronic ethanol administration data, suggesting that the density of dopamine transporter also modulates the binding and function of ␦ opioid recep- binding is preserved but striatal D2 receptor density is de- tors (191,192). creased in ethanol-dependent patients (137,165). Down- ␣ regulation of postsynaptic 2-adrenergic receptors is sug- gested by blunted growth hormone responses to clonidine Opiates: Clinical Correlates and increased cortisol responses to yohimbine (121,166). Naltrexone appears to reduce the rewarding effects of In contrast, presynaptic noradrenergic activity appears to ethanol and ethanol consumption in social drinkers (41, normalize rapidly following withdrawal, as measured by the 193). Also, naltrexone maintenance appears to reduce the CSF levels of the norepinephrine metabolite 3-methoxy-4- pleasurable aspects of ethanol consumed during treatment hydroxyphenethyleneglycol (MHPG) (167). Similarly, the for alcoholism (194,195). This property appears to contrib- presynaptic component of the noradrenergic response to ute to the capacity of opiate antagonists to reduce ethanol yohimbine, reflected by plasma MHPG levels, is normal in consumption in alcoholic patients (196,197). patients sober for approximately 1 month (121). The contributions of endogenous opiate systems to the Genetic studies relating catecholamine receptor alleles to rewarding effects of ethanol are further supported by evi- the vulnerability to alcoholism have been a promising but dence of abnormalities in these systems in alcoholic patients. controversial research strategy that has not yet born fruit. However, the current data do not yield a clear picture of Initial studies suggested that D2 receptor alleles were associ- these abnormalities. Postmortem studies have described ated with alcoholism (168,169). However, more definitive both increased ␮-receptor density (198) and decreased ␮- subsequent studies were negative (170). Reanalysis of pub- receptor affinity (199). CSF and plasma studies have also lished studies suggested that the positive findings reflected suggested the existence of reductions in ␤-endorphin levels ethnic differences between the patient and control popula- and ethanol-stimulated increases in plasma ␤-endorphin tion (171). A subsequent study also suggested that D2 re- levels (200,201). Naltrexone reductions in ethanol effects ceptor alleles predicted an anticraving response to bromo- appear to be particularly evident in individuals at high risk criptine (172). However, studies using dopamine agonists for developing alcoholism (202). These data suggest a ge- to treat alcoholism have so far had limited promise (173, netic component underlying the efficacy of naltrexone treat- 174). A tentative association between versions of the D4 ment for alcoholism. To date, there have been negative stud- receptor and novelty-seeking (175) was reported. However, ies evaluating the association of the proenkephalin A gene this finding was not replicated, and studies of other dopa- and ␮ opiate receptor gene with alcoholism (203,204). mine receptor genes to alcoholism have been negative (133, 176–182). THE NEURAL CIRCUITRY OF AND DEPENDENCE: INSIGHTS Opiates FROM NEUROIMAGING AND Preclinical Studies NEUROPSYCHOLOGY

Ethanol modulates opioid in regionally spe- Structure (Computed Tomography, cific ways. Acute ethanol administration to animals or Magnetic Resonance Imaging, ethanol perfusion of cultured pituitary or hypothalamic tis- Postmortem) sue increased (183) or had no effect on (184) tissue content or release of ␤-endorphin. Ethanol also raised enkephalin Preclinical studies describe alcoholism-related neurotoxic- and dynorphin levels in some brain regions in some studies ity. These toxic effects appear to reflect a combination of (183,185). Chronic ethanol administration to rodents de- the neurotoxic effects of ethanol, the interaction of ethanol creased pituitary ␤-endorphin processing and reduced hy- with nutritional deficiencies, and the neurotoxic conse- pothalamic mRNA levels of the precursors proopio- quences of ethanol withdrawal (205). In rats, extended con- melanocortin (POMC) and prodynorphin (186,187). sumption of an ethanol did not produce anatomic defi- In vitro, ethanol has a biphasic effect on ␮ opioid recep- cits. However, ethanol withdrawal was associated with tor binding. Ethanol concentrations, in the range of 10 to reductions in dendritic arborization and neuronal loss 25 mM, produce a small, but significant, increases in the (206). binding of ␮ receptor ligands, whereas higher concentra- Brain shrinkage and neuronal loss has been documented tions of ethanol inhibit binding to the ␮ receptor in the brain tissue from individuals with alcoholism in both (188). Under physiologic conditions, the ␮ receptor may cortical and limbic regions (207). With respect to brain be more sensitive to ethanol-induced inhibition than the ␦ volume, postmortem research suggests that white matter receptor (189). Chronic ethanol administration reduces the loss appears to be more prominent than gray matter loss Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1433

(208). Neuronal loss appears to be primarily loss of pyrami- Structural neuroimaging studies are consistent with the dal neurons, with relative sparing of (208). findings in postmortem research. Cortical and limbic volu- Another study was unable to replicate neuronal loss using metric losses in ethanol-dependent patients have been de- uniform sampling and unbiased neuron counting methods scribed using computed axial tomography (CAT) and mag- (209). However, even when neurons are extant, they may netic resonance imaging (MRI) (212,213). Gray and white exhibit structural deficits consistent with neurotoxicity matter volumetric losses are progressive with heavy drinking (210). Generally, cortical and limbic brain shrinkage and and are most prominent in frontal and temporal cortex neuronal loss may be more prominent in individuals whose (213–215). Ethanol-dependent individuals also show sulcal is complicated by Wernicke’s encepha- and ventricular enlargement (215), as well as hippocampal lopathy and Korsakoff’s psychosis (211). The Wernicke- volume reduction (216). Reductions in the volume of the Korsakoff syndrome has been associated with abnormalities corpus callosum has also been described (217). Brain atro- in frontal cortex, as well as in several subcortical structures phy documented in structural neuroimaging studies is most including the thalamus, hippocampus, mamillary bodies, more prominent with advancing age in adults (Fig. 100.4) and amygdala (10). (218). This age-related effect may reflect an age-related vul-

FIGURE 100.4. The top two panels illustrate the relationship between drinking severity and duration with gray and white matter volume loss in ethanol-dependent patients. The bottom two panels illustrate the interaction between alcoholism and volume loss with age. Top figures: The relationship between cortical gray matter rate of change and the amount of alcohol consumed and between the cortical (04. ס p ,0.52מס during the follow-up period (left) (Spearman rho gray matter rate of change and the estimated amount of time during past 5 years that alcoholic patients (group 1) met Diagnostic and Statistical Manual ofMental Disorders , third edition revised ס DSM-III-R) criteria for alcohol dependence during the follow-up period (right) (Spearman rho) One alcoholic patient who reported 950 kg of alcohol consumption is omitted .(04.ס p ,0.53מ from the left panel so as not to distort scaling. The darker circle represents two patients with overlapping values. (From Pfefferbaum A, Sullivan EV, Rosenbloom MJ, et al. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen Psychiatry 1998;55:905–912.) Bottom figures: Cortical gray (left) and white matter (right) volume changes with age in ethanol-dependent patients. Data from individual ethanol-dependent pa- tients are expressed as age-corrected Z-scores plotted as a function of age. (From Pfefferbaum A, Lim KO, Zipursky RB, et al. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 1992;16:1078–1089, with permission.) 1434 Neuropsychopharmacology: The Fifth Generation of Progress nerability to ethanol in older populations, the interaction FindingsFrom Functional Neuroimaging of aging processes, and the neurotoxicity of alcoholism, i.e., Functional neuroimaging studies described reductions in the ‘‘premature aging of the brain’’ (219), as well as the cortical blood flow and metabolism associated with ethanol accumulated impact of long-standing alcoholism on older withdrawal. There is a limited understanding of the extent populations. Thus, atrophy may not be detectable in young to which these studies also reflect genetic or alcohol-related healthy ethanol-dependent populations (220). In contrast, structural abnormalities. Studies of ethanol intoxication ethanol-dependent adolescents show hippocampal volumet- suggest that it reduces cortical metabolism in humans (233). ric changes not seen in the studies of healthy young adults Clinical studies of withdrawal, mostly conducted during (221). The study in adolescents raises the possibility that or following medications for detoxification, predominately adolescents show disruptive effects on brain development or describe reductions in regional cerebral perfusion or an increased sensitivity to the neurotoxic effects of ethanol. metabolism in frontal and temporal cortex (234,235). More Over the initial years of sobriety, there is recovery in the pronounced deficits were observed in patients with evidence volumes of gray and white matter and reductions in sulcal of cortical atrophy based on structural neuroimaging (236), and ventricular volume (222). There are differences in the years of ethanol use, age (237), and multiple ethanol detoxi- rate of particular brain regions and particular tissue types fications (238). Cerebral perfusion and metabolic deficits with regard to the rate of recovery (222,223). The relatively may attenuate over the initial months of sobriety (237), rapid recovery of white matter volume with sobriety does and improvement may continue over several years (239). not appear to reflect the return of tissue displaced by Antisocial personality (240), a risk factor for developing ethanol, i.e., tissue rehydration (224). alcoholism, but not family history of alcoholism (241), was Nutritional status, neurologic complications of ethanol associated with more pronounced volumetric deficits. withdrawal, and hepatic function appear to be related to Across several studies, reductions in resting frontal corti- findings in structural neuroimaging studies. Ethanol with- cal perfusion and metabolic rate is associated with reduced drawal seizures have been linked to neurotoxicity in these performance on cognitive tests that engage the frontal cortex patients (225). Supporting this association, temporal cortex (242). Similarly, cerebellar metabolic deficits are associated white matter loss was particularly associated with ethanol with behavioral evidence of cerebellar dysfunction (236). withdrawal seizures (226). Although cortical atrophy has been described in ethanol-dependent patients with good nutritional status (227), the Wernicke-Korsakoff syndrome Behavioral Studies and hepatic are generally associated with more prominent MRI volumetric deficits in cortical and limbic The most profound cognitive deficits associated with alco- structures than ethanol-dependent patients who are other- holism are the memory impairments arising from nutri- wise healthy (228). tional deficiency, as in Korsakoff syndrome (10), or hepa- To date, there has been very little study of structural toxicity, as in hepatic encephalopathy (243). Although the factors that might predispose individuals to develop alcohol- most severe consequences of alcoholism for cognition may ism. One risk factor, antisocial personality disorder, appears not reflect the direct toxic effects of ethanol on the brain, to be independently associated with reductions in frontal many patients exhibit cognitive deficits independent of cortex gray matter volume (229). Thus, the observation that these factors that reflect the combined impact of age, famil- frontal gray matter volume loss is present in young ethanol- ial vulnerability for alcoholism, adaptations to ethanol dependent patients could reflect a combination of the vul- effects on the brain, perhaps degree of injury (244), nerability to alcoholism and atrophic effects of ethanol de- presence of comorbid depression, and ethanol-related neu- pendence (214). rotoxicity (245). Cognitive function is further compromised in those patients who continue to drink, due to the direct effects of ethanol on cognition (246). Magnetic Resonance The familial vulnerability to alcoholism and traits associ- ated with that vulnerability are associated cognitive deficits Magnetic resonance spectroscopy (MRS) has been applied and educational achievement (247). Although reductions to the evaluation of structural deficits in alcoholic patients in attention, planning, visual-spatial learning, and impulse in a limited fashion. Proton-MRS ([1H]MRS) enables the control have been described in children of alcoholics (248), measurement of N-acetyl-aspartate (NAA), a constituent of these findings are not universal (249). These findings may viable neurons. One study found reductions in the NAA/ be largely accounted for by comorbid traits such as antisocial ratio in the frontal cortex and cerebellum of personality, similar to both MRI and event-related potential ethanol-dependent patients (230,231). A phosphorus-MRS (ERP) findings in alcohol dependent patients (250,251). ([31P]MRS) study found reductions in phosphodiester and Consistent with this view, the familial risk for cognitive levels in cortical white matter in ethanol- deficits associated with alcoholism is particularly associated dependent patients (232). with poor prognosis of the parent in alcoholism treatment, Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1435 a characteristic of antisocial alcoholism (252). Familial his- these effects contribute to its complex array of behavioral tory of alcoholism appears to compound the negative conse- effects in animals and humans. Direct effects of ethanol on quences of social drinking on cognitive function (253). excitatory and inhibitory neurotransmission also are modu- However, children of alcoholics exhibit attenuated impair- lated by direct and indirect effects of ethanol on ion chan- ment in attention and memory relative to individuals with nels. Further, the cellular consequences of exposure to a familial alcoholism history (254). Thus it is possible that ethanol are modulated by ethanol-sensitive regulatory en- cognitive responses to ethanol may also contribute to the zymes, such as PKA and PKC. risk for making the transition from social drinking to alco- The diversity of ethanol targets in the brain and frequent holism. co-localization of the neural circuitry bearing the sites of Although traits associated with the vulnerability to alco- ethanol action raise the possibility of convergent mecha- holism contribute to cognitive deficits seen in ethanol- nisms underlying the rewarding effects of ethanol in the dependent patients, they do not account for the deficits brain. In this regard, there is growing evidence that the in patients (255). Ethanol-dependent patients show many interplay of the prefrontal cortex (PFC) and limbic struc- impairments in cognitive function. Deficits in the level of tures including the nucleus accumbens (NAc) and amygdala performance and efficiency of verbal skills, learning and generally plays an important role in reward (266,267). memory, problem-solving and abstracting, and perceptual- Ethanol has many component actions that directly inhibit motor skills have been described (256). Cognitive deficits the output of the NAc including NMDA receptor antago- may reflect in part the degree of neurotoxicity related to nism, GABA facilitation, and enhancement in 5-HT and alcoholism. For example, young ethanol-dependent patients dopamine release (267). Drugs that antagonize the inhibi- may show normal brain volumes on MRI and normal cogni- tory effects of ethanol in the NAc, such as naltrexone (268), tive function (257,258). With repeated episodes of ethanol may play an important role in the treatment of alcoholism withdrawal and advancing age, cognitive deficits become even if ␮ opiate receptors are not a major site of action for more pronounced (259). many of the behavioral effects of ethanol. Cognitive function improves over the initial year of so- Abnormalities in PFC development may be an important briety; however, the domains of cognitive function do not factor influencing the vulnerability to alcoholism, in part recover at the same rate and recovery may be partial (260, by altering the interplay of PFC and NAc that underlies 261). Poor cognitive function at the time that treatment is reward. As noted above, the vulnerability to alcoholism, initiated appears to predict improved alcohol-related treat- particularly in the case of individuals with antisocial person- ment outcomes (262). However, progress in treatment may ality disorder or impulsive traits, appears to be associated be reflected in improved cognitive function (263). Consis- with behavioral, physiologic, and structural evidence of PFC tent with the view that treatment may modulate cognitive dysfunction. An important and unanswered question is, recovery, some cognitive deficits in recovering patients ap- How does PFC dysfunction contribute to the vulnerability pear to respond to cognitive rehabilitation (264). to alcoholism? Hypotheses have been presented that suggest In summary, the behavioral studies describe the display that alcoholism is just one of several forms of impulsive of deficits in cognitive functions that may have implications behavior that these individuals fail to inhibit due to a general for circuitry dysfunction in alcoholism: executive function deficiency in behavioral inhibition or as a consequence of deficits associated with the prefrontal cortex, visual-spatial the failure to anticipate the negative consequences of alco- deficits associated with the parietal cortex, and learning/ holism (269,270). memory deficits that may involve the hippocampus and These cognitive hypotheses may be complemented by a related temporal cortical structures. Overall, these studies reward dysfunction hypothesis resting on a consideration of are consistent with the findings related to reduced tissue the impact of PFC dysfunction on mechanisms underlying volume on MRI, reductions in cortical metabolism with reward. The PFC input into limbic structures responsible (FDG)-PET (242), and information for reward is critical to the experience, anticipation, and processing deficits in ERP studies (265). This overlap im- seeking of reward (271,272). The activation of PFC outputs plies a connection between alterations in brain structure, to limbic structure causes a release of glutamate that may function, and behavior related to alcoholism. serve to activate, for example, the GABAergic output neu- rons of the NAc, and this action opposes direct effects of ethanol (268). From this perspective, PFC activation serves THE INTERPLAY OF THE NEURAL as a ‘‘brake’’ on reward mechanisms. In fact, it is tempting CIRCUITRY AND NEUROCHEMISTRY OF to think of this PFC-NAc interplay as a pathway contribut- ALCOHOLISM: IMPLICATIONS FOR ing to the capacity of human judgment to restrain impulsive TREATMENT reward-related behavior. Yet abnormal PFC input would also be expected to disturb NAc function with respect to Ethanol has multiple specific effects on , mono- both the processing of rewarding stimuli generally and drugs , and neurotransmitter systems, and of abuse in particular. Thus, it may not be surprising that 1436 Neuropsychopharmacology: The Fifth Generation of Progress the familial vulnerability to alcoholism is associated with ality disorder and alcohol-induced aggression. Alcohol Clin Exp both PFC functional deficits and alterations in the capacity Res 1998;22:1898–1902. 6. Linnoila M. Effect of drugs and alcohol on psychomotor skills of drugs representing multiple component actions of related to driving. 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Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, and Charles Nemeroff. American College of Neuropsychopharmacology ᭧ 2002.