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Home , Alcohol inhalation, Allopregnanolone, Nitrendipine, Physical dependence

Exploring Withdrawal Syndrome

DEBORAH A. FINN, PH.D., AND JOHN C. CRABBE, PH.D.

Alcohol withdrawal syndrome is characterized by hyperactivity of the . This hyperactivity represents the brain’s attempt to function normally despite the inhibitory effect of chronic alcohol consumption. The syndrome manifests when alcohol consumption ceases. Experimental, clinical, and genetic research have linked the development of withdrawal to alterations in the sensitivity of neuronal communication systems. Early treatment of the syndrome is advised, because the symptom severity may increase with each subsequent episode. KEY WORDS: AOD withdrawal syndrome; chronic AODE (alcohol and other drug effects); symptom; biological inhibition; neurotransmission; neurochemistry; ; receptors; animal model; animal strains; membrane channel; genetic mapping; biochemical mechanism; literature review

lcohol withdrawal syndrome teins, which bind to neurotransmitters, animal models to study the mecha- consists of unpleasant physical and ion channels through which ions1 nisms and genetics of withdrawal; and Aand mental symptoms follow- (e.g., sodium or calcium) enter the the involvement of neurotransmitters, ing the cessation of alcohol consump- cell. Following repeated administra- receptors, and ion channels in the tion. These symptoms may range from tion of alcohol, the brain attempts to syndrome. For a discussion on the role mild tremor to and restore normal functioning through convulsions. Repeated withdrawal adaptations (i.e., tolerance) that re- DEBORAH A. FINN, PH.D., is an episodes may contribute to the devel- duce alcohol’s initial perturbing ef- assistant professor in the Department opment of and to fects (figure 1). Long-term exposure of Behavioral Neuroscience, Oregon the negative health consequences of to alcohol can lead to physical depen- Health Sciences University, and a drinking. An increased understanding dence, in which neuronal adaptations research pharmacologist at the Dept. of Veterans Affairs Medical Center, of the genetic and biochemical corre- to alcohol become sufficiently pro- Portland, Oregon. lates of the syndrome may lead to nounced that the brain requires the improved treatments for withdrawal continued presence of alcohol to func- JOHN C. CRABBE, PH.D., is a professor as well as for other aspects of alcohol tion normally. When a person termi- in the Department of Behavioral dependence. nates a prolonged drinking session, Neuroscience, Oregon Health The symptoms of withdrawal rep- the adaptations that developed to Sciences University, director of the resent a phase in the alcohol-induced offset alcohol’s initial inhibitory ac- Portland Alcohol Research Center, cycle of neuronal inhibition and exci- tions are unopposed, resulting in a and a research career scientist at the tation. Research has demonstrated that rebound hyperexcitability, or with- Dept. of Veterans Affairs Medical short-term (i.e., acute) administration drawal syndrome. Center, Portland, Oregon. of alcohol can alter the release of This article describes the symp- toms of alcohol withdrawal; the use of Support for this work was provided by chemical messengers (i.e., neurotrans- grants from the National Institute on mitters) from neurons and can disrupt 1For a definition of this and other technical and the function of proteins in neuronal terms used in this article, see central glossary, (AA10760 and AA08621) and the membranes, including pro- pp. 177Ð179. Department of Veterans Affairs.

VOL. 21, NO. 2, 1997 149 Severe alcohol withdrawal is fre- quently complicated in its later stages Drug-free by the presence of tremens + (DT). Patients with DT are agitated, confused, and disoriented, with delu- sions and vivid hallucinations. DT may Acute Chronic Withdrawal persist until 96 hours after cessation of drinking (Victor and Adams 1953). 0

THE KINDLING MODEL OF ALCOHOL WITHDRAWAL Tolerance Last

Sedation SEVERITY dose

Central Nervous System Activity Several factors are associated with Time increased withdrawal severity, includ- ing increased alcohol consumption, a greater number of prior withdrawal episodes, the occurrence of medical Figure 1 Alcohol’s effect during exposure and withdrawal. The zero line represents problems, and the use of other drugs a hypothetical measure of overall brain excitability. For most physiological in addition to alcohol (Schuckit et al. or behavioral measures, acute alcohol administration produces short-term stimulation (i.e., points above the zero line), followed by or 1995). According to one hypothesis (i.e., points below the zero line). Continued alcohol adminis- (Ballenger and Post 1978), repeated tration causes neuronal adaptations that reduce alcohol’s initial perturbing withdrawal episodes increase the effects and result in tolerance. Physical dependence indicates that alcohol severity of subsequent withdrawal is needed to balance the neuronal adaptations and maintain normal brain syndromes as a result of “kindling.” function. Removal of alcohol from the body induces a rebound stimulatory In kindling, a convulsion-promoting effect, resulting in hyperexcitability of the nervous system (i.e., withdrawal drug or electric shock administered syndrome). repeatedly at doses below the effec-

SOURCE: Adapted from Metten and Crabbe 1996. tive level for a single administration eventually elicits a convulsion after a single administration. Thus, the neu- rochemical changes that occur during of withdrawal in the development of may occur within the first 2 days of alcohol withdrawal (i.e., reduced , see the article by Roberts abstinence in 5 to 10 percent of pa- function of inhibitory neurotransmis- and Koob, pp. 101Ð106. tients (Victor and Adams 1953; sion and increased activity of excitatory Schuckit et al. 1995; Yost 1996). neurotransmission) not only contribute SYMPTOMS OF ALCOHOL According to clinical studies, ap- to the withdrawal syndrome, but also WITHDRAWAL proximately 10 percent of alcoholics may cause long-term changes in brain may develop an additional set of with- excitability by a kindlinglike process Alcohol withdrawal is characterized by drawal symptoms. These symptoms (Glue and Nutt 1990). Consistent with symptoms of hyperactivity of the auto- represent a combination of marked the kindling hypothesis, the severity nomic nervous system, a division of autonomic nervous system hyperactiv- of withdrawal in mice, measured by the nervous system that helps manage ity, including large increases in blood handling-induced convulsions the body’s response to stress (Schuckit pressure, pulse, breathing rate, and (HIC’s), increases with repeated expo- et al. 1995; Yost 1996). Alcoholics heart rate, as well as elevated body sure to alcohol vapor and subsequent often continue to consume alcohol to temperature. Drenching sweats can withdrawal episodes compared with relieve or avoid withdrawal symptoms. cause severe dehydration, and tremor mice that received an equivalent dose The initial symptoms usually are can become sufficiently pronounced of alcohol vapor in a single adminis- relatively mild and include , to prevent the patient from performing tration (Becker and Hale 1993). , and tremors. These symp- such simple activities as manipulating Therefore, both animal and human toms may begin within 3 to 6 hours an eating utensil. Typically, these studies indicate a greater likelihood of following cessation of drinking and more severe symptoms peak in inten- severe withdrawal symptoms in pa- often before the blood alcohol concen- sity between the third and fourth days tients who have experienced a greater tration (BAC) has returned to zero. of abstinence and generally improve number of past withdrawal episodes. The symptoms usually abate within by the fifth day (Schuckit et al. 1995) These data suggest that early treat- 1 to 3 days. Severe convulsions also (figure 2). ment for alcohol withdrawal convul-

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sions may minimize increased with- and provide an overview of the main drawal severity in subsequent findings with each animal model. 70 episodes by preventing this kindling- 60 like process. Research is needed to Inbred Strains confirm this possibility. 50 An inbred strain is derived from 20 40 generations of brother-sister matings, 30 ANIMAL MODELS OF ALCOHOL resulting in a population of animals 20 WITHDRAWAL that is essentially genetically identical. 10

Thus, trait variation within an inbred Percentage of patients 0 Researchers have used various meth- strain can be attributed to environ- 123456714 ods to induce physical dependence in mental causes, whereas variation Days After Cessation of Drinking animals in order to define and quanti- between inbred strains can be attribut- fy the withdrawal syndrome. The ed to genetic causes. Studies docu- Convulsions (68 patients) most common paradigms utilize a Transient hallucinations menting differences in alcohol (50 patients) nutritionally balanced liquid diet con- withdrawal severity among inbred Tremors (50 patients) taining alcohol, inhalation of alcohol strains show clear evidence of genetic Motor and autonomic vapor, or multiple daily doses of alco- overactivity, confusion, and influence (Kakihana 1979; Crabbe et disordered sense perception hol administered either by injection or al. 1983). (44 patients) by a tube inserted into the esophagus One advantage of testing inbred (i.e., intubation). Although each pro- Figure 2 The relation of withdrawal strains is that genetic correlations symptoms to cessation of drinking. cedure has both advantages and disad- among alcohol-related traits can be vantages, each one attempts to estimated. Using 20 inbred mouse SOURCE: Adapted from Victor and Adams 1953. achieve relatively stable BAC’s over strains, Crabbe and colleagues (1983) time so that alcohol dose and duration correlated ratings of alcohol withdraw- of exposure can be determined. al severity with 13 different measures selection trait. This strategy has been Symptoms of alcohol withdrawal of alcohol sensitivity and found no used to generate lines of mice that in animals include tremors and other strong genetic correlations between differ in withdrawal severity following motor dysfunction as well as auto- withdrawal severity and other mea- chronic alcohol administration. With- nomic overactivity (reviewed in sures of alcohol sensitivity. Recently, drawal -prone (WSP) and -resis- Friedman 1980). One of the most the magnitude of acute withdrawal tant (WSR) mice were generated by commonly studied symptoms is con- severity in inbred animal strains fol- breeding for increased and decreased vulsions. Depending on the severity of lowing a single injection of alcohol HIC severity, respectively, after with- the withdrawal, convulsions can be was found to be similar to that result- drawal from 72 hours of exposure to spontaneous or induced by handling. ing from an injection of the alcohol vapor. Under these conditions, Susceptibility to chemically induced . That is, animals with WSP mice exhibited a 10-fold increase convulsions and audiogenic high pentobarbital withdrawal also in withdrawal severity compared to (i.e., seizures elicited by sound stim- exhibited high withdrawal to alcohol. WSR mice. uli) is also increased during alcohol This finding suggests that some genes During the past 15 years, the WSP withdrawal. Additional measures of may influence withdrawal severity and WSR lines have been tested using withdrawal include decreased body from multiple drugs. various behavioral tasks and with temperature (i.e., hypothermia), de- various drugs (Kosobud and Crabbe creased locomotor activity, increased Selective Breeding 1995; Metten and Crabbe 1996). anxiety, and increased change in be- Alcohol withdrawal tremors, in addi- havioral reactivity to stimuli. Another method for testing the role of tion to HIC, are more severe in WSP Since Goldstein (1973) initially genes in the expression of withdrawal mice compared with WSR mice. demonstrated that genetic factors can severity and its relation to other traits However, the lines do not appear to influence withdrawal severity, several utilizes selective breeding. For this differ with respect to other indicators genetic animal models—including purpose, researchers often use bidirec- of withdrawal severity, such as de- inbred strains, recombinant inbred tional selection, in which one line is creased activity. Acute withdrawal strains, and selectively bred lines— bred for maximal expression of a given severity following a single administra- have been used to study alcohol with- trait and the other is bred for minimal tion of an dose of alcohol drawal (for reviews, see Deitrich and expression of that trait. Bidirectional was also significantly greater in WSP Spuhler 1984; Kosobud and Crabbe selection for many generations pro- mice compared with WSR mice. 1995; Metten and Crabbe 1996). The duces animals that differ dramatically Consistent with results using in- following subsections focus on the in the selection trait and also differ bred strains, WSP and WSR mice not usefulness of genetic animal models with respect to the genes relevant to the previously exposed to alcohol did not

VOL. 21, NO. 2, 1997 151 differ from each other in sensitivity to brain. GABA functions by attaching ity of a genetic link between alcohol α several other effects of alcohol. to a binding site on GABAA receptors, withdrawal severity and decreased 1 thereby causing a pore in the cell subunit level. Overall, changes in the membrane to open and admit chloride level of GABAA receptor subunits QUANTITATIVE TRAIT LOCUS ions.2 The flow of these negatively following chronic alcohol administra- ANALYSIS charged ions into the neuron renders it tion may reflect an alteration in the less sensitive to further neurotrans- assembly of GABAA receptors, which, An additional strategy for understand- in turn, may underlie some of the ing mechanisms contributing to genet- mission. GABAA receptors—with binding sites for various molecules cellular and behavioral adaptations in ic differences in alcohol withdrawal alcohol dependence and withdrawal. severity involves the identification of and the chloride —form the specific genes that confer sensitivi- integrated complexes of five protein ty or resistance to a particular drug- subunits (Morrow 1995; Buck 1996). Steroidal GABA Various substances that bind to related behavior. Quantitative traits —a product of the GABA receptors (i.e., GABAergic (e.g., withdrawal severity) are continu- of the hormone proges- ligands) can reduce alcohol withdraw- ously distributed in a population—that terone—is the most potent steroidal al, including is, individual people or animals vary in modulator of GABA receptor activi- (e.g., Valium¨) and certain . A the degree to which they exhibit such ty. Found in the brain and in the traits. A quantitative trait locus (QTL) The effect of these bloodstream, allopregnanolone is is a small section of chromosomal substances is shown by reductions in thought to be synthesized by the DNA that has been demonstrated to both HIC and sensitivity to chemically adrenal glands and, in females, by the contain a gene or genes that influence induced convulsions. Depending on the ovaries; some synthesis also may a specific trait. Because of the high , experiments have demonstrated occur in the brain. Allopregnanolone both tolerance and to the degree of similarity between locations binds to GABAA receptors at a site of specific genes on mouse and human anticonvulsant effects of GABAergic distinct from the binding sites for chromosomes (Copeland et al. 1993), ligands during withdrawal. , , and when a QTL is mapped in mice, it is Although alcohol’s initial effects GABA. As a GABA , allopreg- highly likely that the human chromo- are inhibitory, chronic alcohol admin- nanolone’s overall effects are inhibito- istration decreases the ability of somal map site can be specified. ry, and its binding to GABAA recep- A recent QTL analysis of with- GABA, benzodiazepines, and barbitu- tors suppresses the development of drawal severity from a single injection rates to activate the inhibitory effect of convulsions. Chronic alcohol adminis- of alcohol (i.e., acute withdrawal) has GABAA receptors in alcohol- tration produces an increased respon- been successfully completed in three dependent animals (i.e., tolerance) siveness (i.e., sensitization) to the distinct genetic populations (Buck et (reviewed in Morrow 1995; Buck anticonvulsant effect of allopreg- al. 1997). Among other results, a QTL 1996). In addition, chronic alcohol nanolone. In addition, the allopreg- on chromosome 11 was mapped to a administration decreases chloride nanolone-induced augmentation of location near a cluster of genes that uptake induced by the GABAA activa- GABA-stimulated chloride ion uptake affect the synthesis of a receptor in- tor (i.e., agonist) and re- increased by 42 percent in alcohol- volved in alcohol’s effects (i.e., the duces the augmenting effect of withdrawing rats compared with rats gamma-aminobutyric acid [GABAA] benzodiazepines and barbiturates on not administered alcohol (Devaud et receptor). Studies are under way to muscimol-stimulated chloride ion al. 1996). Similar results were found link the function of specific genes to uptake. After alcohol withdrawal, the with another potent steroidal GABAA acute alcohol withdrawal severity reduced effectiveness of benzodi- agonist, tetrahydrodeoxycorticos- (Buck et al. 1997). azepines on agonist-stimulated chlo- terone, indicating that the sensitization ride uptake is reversed. of GABAA receptors to neuroactive Studies in mice, rats, and neuronal steroids during alcohol withdrawal is NEUROTRANSMITTERS AND cell cultures show that chronic alcohol not unique to allopregnanolone. This NEUROMODULATORS exposure alters the activity of genes enhancement of steroidal agonist The following subsections briefly that direct the synthesis of GABAA action during alcohol withdrawal summarize the effects of chronic receptor component subunits, increas- contrasts with the reduced effective- alcohol exposure on neurotransmitter ing the levels of some while decreas- ness of GABA, benzodiazepines, and receptors and ion channels (figure 3). ing others. In all studies, chronic alco- barbiturates during withdrawal. More hol administration decreased levels of importantly, evidence suggests that the subunit termed α . This subunit GABAA Receptor Complex 1 also was found to be decreased in 2 The GABAB receptor, which is another The amino acid GABA is the princi- alcohol-dependent WSP mice, but not GABA receptor subtype, has a different mode pal inhibitory neurotransmitter in the in WSR mice, suggesting the possibil- of action and is therefore not discussed here.

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the sites of action of benzodiazepines, barbiturates, and neuroactive steroids Figure 3 Ion channel adaptations revealed by alcohol withdrawal. Changes in are differentially modulated by the ion channel sensitivity or number during alcohol withdrawal results in decreased development of alcohol dependence. inhibitory and increased excitatory receptor function. Since allopregnanolone is a potent A. GABA receptor sensitivity is reduced modulator of GABAA receptors, and A Normal Acute alcohol Alcohol dependence because its levels in brain and plasma Cl- Cl- Cl- can reach physiologically active con- GABA GABA & alcohol GABA & alcohol centrations (see review by Paul and Exterior Purdy 1992), the possibility exists that alterations in the sensitivity or synthe- sis of this with anticonvulsant properties might modulate alcohol Interior withdrawal severity. For example, following 24 hours of alcohol vapor Cl- Cl- Cl- inhalation, plasma allopregnanolone decreased significantly (approximate- GABAergic inhibitory neurotransmission is reduced following chronic alcohol ly 40 percent) in WSP mice but not in administration. In the absence of alcohol (left), the neurotransmitter GABA opens GABA receptor-chloride (Cl-) channels, inhibiting neurotransmission. Alcohol WSR mice (Finn et al. 1994). A Separate studies did not find any increases GABA’s effect (middle), allowing more chloride to enter the neuron and increasing inhibition. In alcohol dependence (right), both GABA and alcohol have change in plasma allopregnanolone in smaller effects on GABAA receptors. Less chloride enters the neuron, increasing the alcohol-dependent male rats following activation of neurons previously inhibited by GABAergic neurotransmission. an alcohol-containing liquid diet (Devaud et al. 1996). However, in a B. NMDA receptor sensitivity is enhanced group of nine alcohol-dependent human Normal Acute alcohol Alcohol dependence subjects, plasma allopregnanolone and Ca++ Ca++ Ca++ NMDA NMDA & alcohol NMDA & alcohol tetrahydrodeoxycorticosterone were significantly lower during early with- Exterior drawal than in nonalcoholic subjects (Romeo et al. 1996). Consistent with the hypothesis that steroidal GABAA agonists may modulate withdrawal Interior severity, the decrease in neuroactive steroids during alcohol withdrawal Ca++ Ca++ Ca++ was associated with increased levels of anxiety and depression in the alco- Glutamatergic excitatory neurotransmission increases following chronic alcohol holic subjects. administration. In the absence of alcohol (left), the neurotransmitter glutamate allows calcium to enter the neuron via the NMDA receptor-ion channel. Short-term Chronic alcohol exposure also alcohol exposure decreases calcium flow into the neuron through the receptor- significantly increases plasma corti- channel complex. In alcohol dependence, NMDA receptor sensitivity to glutamate costerone levels in WSP mice, with a increases, resulting in excess flow of calcium into neurons. marginal increase in WSR mice. , a C. Voltage-gated density is increased produced by the adrenal glands, plays Normal Acute alcohol Alcohol dependence Ca++ Ca++ Ca++ a role in the body’s response to stress Voltage Voltage Voltage and can increase sensitivity to the development of convulsions in some Exterior genotypes. Handling to induce HIC increases corticosterone in WSP mice compared with WSR mice. The mag- nitude of this increase in corticos- Interior terone is greater between handled WSP and WSR mice than between Ca++ Ca++ unhandled alcohol-exposed WSP and Voltage-sensitive calcium (Ca++) channels increase from chronic alcohol administration WSR mice (Finn et al. 1994). and dependence, increasing neural excitability. These channels admit calcium into Therefore, the increase in plasma the neuron in response to electrical changes in the neuronal membrane. corticosterone and decrease in allo-

VOL. 21, NO. 2, 1997 153 following chronic alco- symptoms of withdrawal are no longer VSCC’s often employ calcium chan- hol exposure in WSP compared with apparent (i.e., after 24 hours). nel antagonists, especially those WSR mice suggests that biological Additional support for the involve- known as dihydropyridines (DHP’s). synthesis of these two steroids may be ment of NMDA receptors in alcohol Because of their effects on the cardio- regulated differently in the selected withdrawal is provided by the demon- vascular system, calcium channel lines. More important, the decrease in stration that alcohol withdrawal can antagonists such as the DHP nifedip- plasma allopregnanolone noted previ- be reduced by administration of MK- ine (e.g., Adalat¨) are commonly ously was observed only in WSP mice 801, whereas withdrawal convulsions prescribed to treat high blood pressure and not in a genetically heterogeneous are exacerbated by doses of NMDA and some chronic heart conditions. stock of rats. This is consistent with that are not convulsant in control Experiments with DHP calcium the hypothesis that genetic differences animals. channel antagonists have provided in alcohol withdrawal severity are Results of studies on withdrawal evidence for the involvement of modulated by both convulsant (i.e., severity in WSP and WSR mice are VSCC’s in withdrawal hyperexcitabil- corticosterone) and anticonvulsant inconclusive. Initially, research sug- ity (reviewed in Little 1991). For (i.e., allopregnanolone) steroids, gested that WSP mice never exposed example, chronic alcohol administra- which have dramatically different to alcohol (i.e., alcohol-naive) had a tion increases the number of DHP mechanisms of action. significantly greater number of MK- binding sites by approximately 50 801 binding sites in the hippocampus percent. This treatment can produce NMDA Receptor Complex compared with alcohol-naive WSR varying degrees of mild withdrawal mice. Chronic alcohol administration without spontaneous convulsions. Of Alterations in excitatory amino acid in a liquid diet for 1 week significant- interest, the number of binding sites receptors have been reported follow- ly increased the number of binding increased after 3 to 4 days of chronic ing chronic exposure to alcohol (see sites in both lines, and the binding reviews by Crews et al. 1996; alcohol exposure and was modulated sites remained significantly higher in by calcium flow into neurons (see Tabakoff and Hoffman 1996). Most the WSP mice. However, further important in this regard is the N- Little 1991). research disclosed that 24 hours of Consistent with these results, ge- methyl-D-aspartate (NMDA) receptor, alcohol vapor inhalation, while pro- netic regulation of neuronal calcium which responds to the excitatory ducing clear signs of withdrawal in amino acid glutamate. The NMDA channels also occurred after chronic WSP mice, had no effect on MK-801 alcohol administration. After exposure receptor, which regulates an ion chan- binding. These differences may result nel permeable to calcium and sodium, to alcohol vapor for 72 hours, the from the different methods of alcohol WSP mice experienced a significantly plays a role in memory, learning, and administration employed. greater compensatory increase in DHP the generation of seizures. The observed alterations in the binding sites in brain and heart muscle Researchers have investigated the number and function of NMDA recep- tissue than did the WSR mice. function of the NMDA receptor-ion tors following chronic alcohol expo- Additional studies found that the channel complex using MK-801, an sure may result from alcohol-induced administration of DHP calcium chan- NMDA antagonist thought to bind changes in the quantity of specific nel antagonists reduced all forms of within the ion channel. Chronic alco- NMDA receptor subunit proteins, hol administration in a liquid diet which have been reported to occur alcohol withdrawal hyperexcitability produced a 16-percent increase in the following chronic alcohol administra- in slices of hippocampus removed number of MK-801 binding sites in tion. Although the exact molecular from experimental animals immedi- the hippocampus, a brain region in- processes involved are not fully un- ately after cessation of chronic alcohol volved in memory processes and derstood, many studies support the administration. In addition, adminis- convulsions. Chronic alcohol adminis- hypothesis that chronic alcohol ad- tration of the DHP’s and tration also increased the number of ministration results in supersensitive reduced spontaneous and glutamate binding sites. Although NMDA receptors. handling-induced alcohol withdrawal these alterations have not been found convulsions at doses that had little consistently, evidence suggests that Voltage-Sensitive Calcium action. Furthermore, adminis- tration of a DHP during chronic alco- chronic alcohol administration may Channels increase the number of NMDA recep- hol consumption prevented the tor complexes in the hippocampus. Calcium ions are essential to many upregulation of DHP binding sites in The time course for the increase in nervous system functions. Voltage- the brain and significantly reduced MK-801 binding sites correlates with sensitive calcium channels (VSCC’s) withdrawal severity as measured by the onset of withdrawal: The increase admit calcium into the neuron in re- tremor and convulsions. This decrease in binding sites occurs at the onset of sponse to changes in the electrical in alcohol withdrawal hyperexcitabili- withdrawal and at peak withdrawal properties of the neuron’s outer mem- ty in animals given nitrendipine plus (i.e., by 8 hours), but dissipates when brane. Scientists investigating alcohol was also demonstrated in

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hippocampal slice preparations. In By understanding the relative impor- DEVAUD, L.L.; PURDY, R.H.; FINN, D.A.; AND conclusion, both behavioral and bio- tance and contribution of these neuro- MORROW, A.L. Sensitization of γ-aminobutyric acidA receptors to neuroactive steroids in rats chemical evidence suggest that in- chemical changes to the alcohol during alcohol withdrawal. Journal of creases in DHP-sensitive binding sites withdrawal syndrome, researchers can Pharmacology and Experimental Therapeutics may underlie some adaptations to develop more effective treatment 278:510Ð517, 1996. alcohol at the neuronal level, which, strategies in humans to minimize FINN, D.A.; ROBERTS, A.J.; KEITH, L.D.; in turn, can produce behavioral adap- increased withdrawal severity in sub- MERRILL, C.; YOUNG, E.; AND CRABBE, J.C. tations and influence withdrawal sequent episodes. ■ Chronic alcohol differentially alters severity. Additional clinical research in withdrawal seizure prone and is needed to confirm this hypothesis. resistant mice. Alcoholism: Clinical and Experimental Research 18:448, 1994. EDITORIAL NOTE FRIEDMAN, H.J. Assessment of physical CONCLUSIONS The reference list accompanying dependence on and withdrawal from alcohol in this article has been shortened. A animals. In: Rigter, H., and Crabbe, J.C., eds. Because chronic alcohol administra- and Dependence. Amster- complete bibliography is available dam: Elsevier/North-Holland Biomedical Press, tion alters various neurochemical on request. 1980. pp. 93Ð121. systems, it is unlikely that one specific mechanism induces physical depen- GLUE, P., AND NUTT, D. Overexcitement and disinhibition: Dynamic neurotransmitter dence. More important, the time REFERENCES interactions in alcohol withdrawal. British course for changes in receptor function Journal of 157:491Ð499, 1990. and sensitivity (Sanna et al. 1993; BALLENGER, J.C., AND POST, R.M. Kindling as a model for alcohol withdrawal syndromes. GOLDSTEIN, D.B. Inherited differences in Watson and Little 1995) indicate that British Journal of Psychiatry 133:1Ð14, 1978. intensity of alcohol withdrawal reactions in the pattern of neuronal changes occur- mice. Nature 245:154Ð156, 1973. ring during alcohol withdrawal is BECKER, H.C., AND HALE, R.L. Repeated episodes of withdrawal potentiate the KAKIHANA, R. and complex. Currently, researchers do not severity of subsequent withdrawal seizures: An withdrawal in inbred strains of mice: Behav- know whether changes in a particular animal model of alcohol withdrawal “kindling.” ioral and endocrine studies. Behavioral and neurochemical system contribute to Alcoholism: Clinical and Experimental Neural Biology 26:97Ð105, 1979. one specific symptom of alcohol with- Research 17:94Ð98, 1993. KOSOBUD, A.E., AND CRABBE, J.C. Genetic drawal or whether alteration in one BUCK, K.J. Molecular genetic analysis of the influences on the development of physical neurochemical system generates a role of GABAergic systems in the behavioral dependence and withdrawal in animals. In: cascade of neurochemical changes that and cellular actions of alcohol. Behavior Begleiter, H., and Kissin, B., eds. The Genetics manifest as the withdrawal syndrome. Genetics 26:313Ð323, 1996. of Alcoholism. Oxford: Oxford University Press, 1995. pp. 221Ð256. Genetic animal models will contin- BUCK, K.J.; METTEN, P.; BELKNAP, J.K.; AND ue to be useful in tracing the pathways CRABBE, J.C. Quantitative trait loci involved in LITTLE, H.J. The role of neuronal calcium from complex drug responses to spe- genetic predisposition to acute alcohol channels in dependence on alcohol and other sedatives/. Pharmacology and cific genes. QTL mapping and new withdrawal in mice. Journal of Neuroscience 17:3946Ð3955, 1997. Therapeutics 50:347Ð365, 1991. molecular biological techniques, cou- pled with the homology between COPELAND, N.G.; JENKINS, N.A.; GILBERT, D.J.; METTEN, P., AND CRABBE, J.C. Dependence and EPPIG, J.T.; MALTAIS, L.J.; MILLER, J.C.; withdrawal. In: Deitrich, R.A., and Erwin, V.G., mouse and human chromosomal eds. Pharmacological Effects of Alcohol on the maps, will facilitate the identification DEITRICH, W.F.; WEAVER, A.; LINCOLN, S.E.; STEEN, R.G.; STEIN, L.D.; NADEAU, J.H.; AND Nervous System. New York: CRC Press, 1996. and study of specific genes relevant to LANDER, E.S. A genetic linkage map of the pp. 269Ð290. the alcohol withdrawal syndrome in mouse: Current applications and future MORROW, A.L. Regulation of GABAA receptor humans. In addition, the QTL findings prospects. Science 262:57Ð66, 1993. function and gene expression in the central nervous system. In: Bradley, R.J., and Harris, in mice can be compared with the CRABBE, J.C.; YOUNG, E.R.; AND KOSOBUD, A. results obtained through the Genetic correlations with alcohol withdrawal R.A., eds. International Review of Neuro- severity. Pharmacology Biochemistry and biology. Vol. 38. New York: Academic Press, Collaborative Study on the Genetics 1995. pp. 1Ð41. of Alcoholism (COGA), which is a Behavior 18(Suppl. 1):541Ð547, 1983. PAUL, S.M., AND PURDY, R.H. Neuroactive large-scale, multidisciplinary research CREWS, F.T.; MORROW, A.L.; CRISWELL, H.; steroids. FASEB Journal 6:2311Ð2322, 1992. program to investigate the genetic AND BREESE, G. Effects of alcohol on ion components of the susceptibility to channels. International Review of Neurobiology ROMEO, E.; BRANCATI, A.; DELORENZO, A.; alcohol abuse and dependence. 39:283Ð367, 1996. FUCCI, P.; FURNARI, C.; POMPILI, E.; SASSO, G.F.; SPALLETTA, G.; TROISI, A.; AND PASINI, A. DEITRICH, R.A., AND SPUHLER, K. Genetics of Overall, physical dependence on Marked decrease of plasma neuroactive steroids alcoholism and alcohol actions. In: Smart, R.G.; alcohol produces abnormalities in a during alcohol withdrawal. Clinical Neuro- number of neurotransmitter systems, Cappell, H.D.; Glaser, F.B.; Israel, Y.; Kalant, pharmacology 19:366Ð369, 1996. resulting in reduced inhibitory func- H.; Popham, R.E.; Schmidt, W.; and Sellers, E.M. Research Advances in Alcohol and Drug SANNA, E.; SERRA, M.; COSSU, A.; COLOMBO, tion and increased activity of excitato- Problems. Vol. 8. Plenum Publishing Corp., G.; FOLLESA, P.; CUCCHEDDU, T.; CONCAS, A.; ry systems during alcohol withdrawal. 1984. pp. 47Ð98. AND BIGGIO, G. Chronic alcohol intoxication

VOL. 21, NO. 2, 1997 155 induces differential effects on GABAA and TABAKOFF, B., AND HOFFMAN, P.L. Alcohol and WATSON, W.P., AND LITTLE, H.J. Identification NMDA receptor function in the rat brain. glutamate receptors. In: Deitrich, R.A., and of distinct components, with different time Alcoholism: Clinical and Experimental Research Erwin, V.G., eds. Pharmacological Effects of courses, of the changes in response to 17:115Ð123, 1993. Alcohol on the Nervous System. New York: convulsive stimuli during alcohol withdrawal. CRC Press, 1996. pp. 73Ð93. SCHUCKIT, M.A.; TIPP, J.E.; REICH, T.; Journal of Pharmacology and Experimental HESSELBROCK, V.M.; AND BUCHOLZ, K.K. The VICTOR, M., AND ADAMS, R.D. The effect of Therapeutics 272:876Ð884, 1995. histories of withdrawal convulsions and alcohol on the nervous system. In: Metabolic and in 1648 alcohol dependent Toxic Diseases of the Nervous System. Baltimore, YOST, D.A. Alcohol withdrawal syndrome. subjects. Addiction 90:1335Ð1347, 1995. MD: Williams & Wilkins, 1953. pp. 526Ð573. American Family Physician 54:657Ð664, 1996. ALCOHOL ALERT

Do patients, based on their characteristics, respond better to one therapy versus another? Which types of interventions most successfully prevent alcohol abuse? How does the body’s metabolism of alcohol affect body weight, hormones, and medication effectiveness?

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¥ Preventing Alcohol Abuse and Related Problems (No. 34) summarizes research on the effectiveness of policy, community, and educational interventions to reduce alcohol abuse and its consequences.

¥ Alcohol Metabolism (No. 35) discusses the process of alcohol metabolism and its impact on body weight, hormones, and medication effectiveness.

¥ Patient Treatment Matching (No. 36) discusses research findings from Project MATCH, an in-depth study designed to determine whether treatment outcome is affected by matching alcoholics to specific treatments.

For a free subscription to Alcohol Alert, write to: National Institute on Alcohol Abuse and Alcoholism, Attn.: Alcohol Alert, Publication Distribution Center, P.O. Box 10686, Rockville, MD 20849Ð0686. Fax: (202) 842Ð0418. Alcohol Alert is available on the World Wide Web at http://www.niaaa.nih.gov

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