exploring alcohol withdrawal

VOL. 21, NO. 2, 1997 149

Alcohol withdrawal syndromeconsists of unpleasant physicaland mental symptoms follow-

ing the cessation of alcohol consump-tion. These symptoms may range frommild tremor to hallucinations andconvulsions. Repeated withdrawalepisodes may contribute to the devel-opment of alcohol dependence and tothe negative health consequences ofdrinking. An increased understandingof the genetic and biochemical corre-lates of the syndrome may lead toimproved treatments for withdrawalas well as for other aspects of alcoholdependence.

The symptoms of withdrawal rep-resent a phase in the alcohol-inducedcycle of neuronal inhibition and exci-tation. Research has demonstrated thatshort-term (i.e., acute) administrationof alcohol can alter the release ofchemical messengers (i.e., neurotrans-mitters) from neurons and can disruptthe function of proteins in neuronalmembranes, including receptor pro-

teins, which bind to neurotransmitters,and ion channels through which ions1

(e.g., sodium or calcium) enter thecell. Following repeated administra-tion of alcohol, the brain attempts torestore normal functioning throughadaptations (i.e., tolerance) that re-duce alcohol’s initial perturbing ef-fects (figure 1). Long-term exposureto alcohol can lead to physical depen-dence, in which neuronal adaptationsto alcohol become sufficiently pro-nounced that the brain requires thecontinued presence of alcohol to func-tion normally. When a person termi-nates a prolonged drinking session,the adaptations that developed tooffset alcohol’s initial inhibitory ac-tions are unopposed, resulting in arebound hyperexcitability, or with-drawal syndrome.

This article describes the symp-toms of alcohol withdrawal; the use of

animal models to study the mecha-nisms and genetics of withdrawal; andthe involvement of neurotransmitters,receptors, and ion channels in thesyndrome. For a discussion on the role

Exploring AlcoholWithdrawal Syndrome

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

Alcohol withdrawal syndrome is characterized by hyperactivity of the nervoussystem. This hyperactivity represents the brain’s attempt to function normally despitethe inhibitory effect of chronic alcohol consumption. The syndrome manifests whenalcohol consumption ceases. Experimental, clinical, and genetic research have linkedthe development of withdrawal to alterations in the sensitivity of neuronalcommunication systems. Early treatment of the syndrome is advised, because thesymptom severity may increase with each subsequent episode. KEY WORDS: AODwithdrawal syndrome; chronic AODE (alcohol and other drug effects); symptom; biologicalinhibition; neurotransmission; neurochemistry; neurotransmitters; neurotransmitterreceptors; animal model; animal strains; membrane channel; genetic mapping; biochemicalmechanism; literature review

DEBORAH A. FINN, PH.D., is anassistant professor in the Departmentof Behavioral Neuroscience, OregonHealth Sciences University, and aresearch pharmacologist at the Dept.of Veterans Affairs Medical Center,Portland, Oregon.

JOHN C. CRABBE, PH.D., is a professorin the Department of BehavioralNeuroscience, Oregon HealthSciences University, director of thePortland Alcohol Research Center,and a research career scientist at theDept. of Veterans Affairs MedicalCenter, Portland, Oregon.

Support for this work was provided bygrants from the National Institute onAlcohol Abuse and Alcoholism(AA10760 and AA08621) and theDepartment of Veterans Affairs.

1For a definition of this and other technicalterms used in this article, see central glossary,pp. 177–179.

150 ALCOHOL HEALTH & RESEARCH WORLD

of withdrawal in the development ofaddiction, see the article by Robertsand Koob, pp. 101–106.

SYMPTOMS OF ALCOHOLWITHDRAWAL

Alcohol withdrawal is characterized bysymptoms of hyperactivity of the auto-nomic nervous system, a division ofthe nervous system that helps managethe body’s response to stress (Schuckitet al. 1995; Yost 1996). Alcoholicsoften continue to consume alcohol torelieve or avoid withdrawal symptoms.

The initial symptoms usually arerelatively mild and include anxiety,insomnia, and tremors. These symp-toms may begin within 3 to 6 hoursfollowing cessation of drinking andoften before the blood alcohol concen-tration (BAC) has returned to zero.The symptoms usually abate within 1 to 3 days. Severe convulsions also

may occur within the first 2 days ofabstinence in 5 to 10 percent of pa-tients (Victor and Adams 1953;Schuckit et al. 1995; Yost 1996).

According to clinical studies, ap-proximately 10 percent of alcoholicsmay develop an additional set of with-drawal symptoms. These symptomsrepresent a combination of markedautonomic nervous system hyperactiv-ity, including large increases in bloodpressure, pulse, breathing rate, andheart rate, as well as elevated bodytemperature. Drenching sweats cancause severe dehydration, and tremorcan become sufficiently pronouncedto prevent the patient from performingsuch simple activities as manipulatingan eating utensil. Typically, thesemore severe symptoms peak in inten-sity between the third and fourth daysof abstinence and generally improveby the fifth day (Schuckit et al. 1995)(figure 2).

Severe alcohol withdrawal is fre-quently complicated in its later stagesby the presence of delirium tremens(DT). Patients with DT are agitated,confused, and disoriented, with delu-sions and vivid hallucinations. DT maypersist until 96 hours after cessation ofdrinking (Victor and Adams 1953).

THE KINDLING MODELOF ALCOHOL WITHDRAWALSEVERITY

Several factors are associated withincreased withdrawal severity, includ-ing increased alcohol consumption, agreater number of prior withdrawalepisodes, the occurrence of medicalproblems, and the use of other drugsin addition to alcohol (Schuckit et al.1995). According to one hypothesis(Ballenger and Post 1978), repeatedwithdrawal episodes increase theseverity of subsequent withdrawalsyndromes as a result of “kindling.” In kindling, a convulsion-promotingdrug or electric shock administeredrepeatedly at doses below the effec-tive level for a single administrationeventually elicits a convulsion after asingle administration. Thus, the neu-rochemical changes that occur duringalcohol withdrawal (i.e., reducedfunction of inhibitory neurotransmis-sion and increased activity of excitatoryneurotransmission) not only contributeto the withdrawal syndrome, but alsomay cause long-term changes in brainexcitability by a kindlinglike process(Glue and Nutt 1990). Consistent withthe kindling hypothesis, the severityof withdrawal in mice, measured byhandling-induced convulsions(HIC’s), increases with repeated expo-sure to alcohol vapor and subsequentwithdrawal episodes compared withmice that received an equivalent doseof alcohol vapor in a single adminis-tration (Becker and Hale 1993).Therefore, both animal and humanstudies indicate a greater likelihood ofsevere withdrawal symptoms in pa-tients who have experienced a greaternumber of past withdrawal episodes.These data suggest that early treat-ment for alcohol withdrawal convul-

Figure 1 Alcohol’s effect during exposure and withdrawal. The zero line representsa hypothetical measure of overall brain excitability. For most physiologicalor behavioral measures, acute alcohol administration produces short-termstimulation (i.e., points above the zero line), followed by depression orsedation (i.e., points below the zero line). Continued alcohol adminis-tration causes neuronal adaptations that reduce alcohol’s initial perturbingeffects and result in tolerance. Physical dependence indicates that alcoholis needed to balance the neuronal adaptations and maintain normal brainfunction. Removal of alcohol from the body induces a rebound stimulatoryeffect, resulting in hyperexcitability of the nervous system (i.e., withdrawalsyndrome).

SOURCE: Adapted from Metten and Crabbe 1996.

0

+Drug-free

WithdrawalAcute

Sed

atio

n

Chronic

Tolera

nce

Time

Lastdose

Cen

tral

Ner

vou

s S

yste

m A

ctiv

ity

sions may minimize increased with-drawal severity in subsequentepisodes by preventing this kindling-like process. Research is needed toconfirm this possibility.

ANIMAL MODELS OF ALCOHOLWITHDRAWAL

Researchers have used various meth-ods to induce physical dependence inanimals in order to define and quanti-fy the withdrawal syndrome. Themost common paradigms utilize anutritionally balanced liquid diet con-taining alcohol, inhalation of alcoholvapor, or multiple daily doses of alco-hol administered either by injection orby a tube inserted into the esophagus(i.e., intubation). Although each pro-cedure has both advantages and disad-vantages, each one attempts toachieve relatively stable BAC’s overtime so that alcohol dose and durationof exposure can be determined.

Symptoms of alcohol withdrawalin animals include tremors and othermotor dysfunction as well as auto-nomic overactivity (reviewed inFriedman 1980). One of the mostcommonly studied symptoms is con-vulsions. Depending on the severity ofthe withdrawal, convulsions can bespontaneous or induced by handling.Susceptibility to chemically inducedconvulsions and audiogenic seizures(i.e., seizures elicited by sound stim-uli) is also increased during alcoholwithdrawal. Additional measures ofwithdrawal include decreased bodytemperature (i.e., hypothermia), de-creased locomotor activity, increasedanxiety, and increased change in be-havioral reactivity to stimuli.

Since Goldstein (1973) initiallydemonstrated that genetic factors caninfluence withdrawal severity, severalgenetic animal models—includinginbred strains, recombinant inbredstrains, and selectively bred lines—have been used to study alcohol with-drawal (for reviews, see Deitrich andSpuhler 1984; Kosobud and Crabbe1995; Metten and Crabbe 1996). Thefollowing subsections focus on theusefulness of genetic animal models

and provide an overview of the mainfindings with each animal model.

Inbred Strains

An inbred strain is derived from 20generations of brother-sister matings,resulting in a population of animalsthat is essentially genetically identical.Thus, trait variation within an inbredstrain can be attributed to environ-mental causes, whereas variationbetween inbred strains can be attribut-ed to genetic causes. Studies docu-menting differences in alcoholwithdrawal severity among inbredstrains show clear evidence of geneticinfluence (Kakihana 1979; Crabbe etal. 1983).

One advantage of testing inbredstrains is that genetic correlationsamong alcohol-related traits can beestimated. Using 20 inbred mousestrains, Crabbe and colleagues (1983)correlated ratings of alcohol withdraw-al severity with 13 different measuresof alcohol sensitivity and found nostrong genetic correlations betweenwithdrawal severity and other mea-sures of alcohol sensitivity. Recently,the magnitude of acute withdrawalseverity in inbred animal strains fol-lowing a single injection of alcoholwas found to be similar to that result-ing from an injection of the barbituratepentobarbital. That is, animals withhigh pentobarbital withdrawal alsoexhibited high withdrawal to alcohol.This finding suggests that some genesmay influence withdrawal severityfrom multiple depressant drugs.

Selective Breeding

Another method for testing the role ofgenes in the expression of withdrawalseverity and its relation to other traitsutilizes selective breeding. For thispurpose, researchers often use bidirec-tional selection, in which one line isbred for maximal expression of a giventrait and the other is bred for minimalexpression of that trait. Bidirectionalselection for many generations pro-duces animals that differ dramaticallyin the selection trait and also differwith respect to the genes relevant to the

selection trait. This strategy has beenused to generate lines of mice thatdiffer in withdrawal severity followingchronic alcohol administration. With-drawal seizure-prone (WSP) and -resis-tant (WSR) mice were generated bybreeding for increased and decreasedHIC severity, respectively, after with-drawal from 72 hours of exposure toalcohol vapor. Under these conditions,WSP mice exhibited a 10-fold increasein withdrawal severity compared toWSR mice.

During the past 15 years, the WSPand WSR lines have been tested usingvarious behavioral tasks and withvarious drugs (Kosobud and Crabbe1995; Metten and Crabbe 1996).Alcohol withdrawal tremors, in addi-tion to HIC, are more severe in WSPmice compared with WSR mice.However, the lines do not appear todiffer with respect to other indicatorsof withdrawal severity, such as de-creased activity. Acute withdrawalseverity following a single administra-tion of an anesthetic dose of alcoholwas also significantly greater in WSPmice compared with WSR mice.

Consistent with results using in-bred strains, WSP and WSR mice notpreviously exposed to alcohol did not

VOL. 21, NO. 2, 1997 151

Running HeadsAlcohol Withdrawal Syndrome

Figure 2 The relation of withdrawalsymptoms to cessation of drinking.

SOURCE: Adapted from Victor and Adams 1953.

70

60

50

40

30

20

10

01 2 3 4 5 6 7 14

Convulsions (68 patients)

Transient hallucinations (50 patients)

Tremors (50 patients)

Motor and autonomicoveractivity, confusion, anddisordered sense perception(44 patients)

Days After Cessation of Drinking

Per

cen

tag

e o

f p

atie

nts

differ from each other in sensitivity toseveral other effects of alcohol.

QUANTITATIVE TRAIT LOCUSANALYSIS

An additional strategy for understand-ing mechanisms contributing to genet-ic differences in alcohol withdrawalseverity involves the identification ofthe specific genes that confer sensitivi-ty or resistance to a particular drug-related behavior. Quantitative traits(e.g., withdrawal severity) are continu-ously distributed in a population—thatis, individual people or animals vary inthe degree to which they exhibit suchtraits. A quantitative trait locus (QTL)is a small section of chromosomalDNA that has been demonstrated tocontain a gene or genes that influencea specific trait. Because of the highdegree of similarity between locationsof specific genes on mouse and humanchromosomes (Copeland et al. 1993),when a QTL is mapped in mice, it ishighly likely that the human chromo-somal map site can be specified.

A recent QTL analysis of with-drawal severity from a single injectionof alcohol (i.e., acute withdrawal) hasbeen successfully completed in threedistinct genetic populations (Buck etal. 1997). Among other results, a QTLon chromosome 11 was mapped to alocation near a cluster of genes thataffect the synthesis of a receptor in-volved in alcohol’s effects (i.e., thegamma-aminobutyric acid [GABAA]receptor). Studies are under way tolink the function of specific genes toacute alcohol withdrawal severity(Buck et al. 1997).

NEUROTRANSMITTERS ANDNEUROMODULATORS

The following subsections brieflysummarize the effects of chronicalcohol exposure on neurotransmitterreceptors and ion channels (figure 3).

GABAA Receptor Complex

The amino acid GABA is the princi-pal inhibitory neurotransmitter in the

brain. GABA functions by attachingto a binding site on GABAA receptors,thereby causing a pore in the cellmembrane to open and admit chlorideions.2 The flow of these negativelycharged ions into the neuron renders itless sensitive to further neurotrans-mission. GABAA receptors—withbinding sites for various moleculesand the chloride ion channel—formintegrated complexes of five proteinsubunits (Morrow 1995; Buck 1996).

Various substances that bind toGABA receptors (i.e., GABAergicligands) can reduce alcohol withdraw-al, including benzodiazepine sedatives(e.g., Valium®) and certain steroids.The anticonvulsant effect of thesesubstances is shown by reductions inboth HIC and sensitivity to chemicallyinduced convulsions. Depending on theligand, experiments have demonstratedboth tolerance and sensitization to theanticonvulsant effects of GABAergicligands during withdrawal.

Although alcohol’s initial effectsare inhibitory, chronic alcohol admin-istration decreases the ability ofGABA, benzodiazepines, and barbitu-rates to activate the inhibitory effect ofGABAA receptors in alcohol-dependent animals (i.e., tolerance)(reviewed in Morrow 1995; Buck1996). In addition, chronic alcoholadministration decreases chlorideuptake induced by the GABAA activa-tor (i.e., agonist) muscimol and re-duces the augmenting effect ofbenzodiazepines and barbiturates onmuscimol-stimulated chloride ionuptake. After alcohol withdrawal, thereduced effectiveness of benzodi-azepines on agonist-stimulated chlo-ride uptake is reversed.

Studies in mice, rats, and neuronalcell cultures show that chronic alcoholexposure alters the activity of genesthat direct the synthesis of GABAA

receptor component subunits, increas-ing the levels of some while decreas-ing others. In all studies, chronic alco-hol administration decreased levels ofthe subunit termed α1. This subunitalso was found to be decreased inalcohol-dependent WSP mice, but notin WSR mice, suggesting the possibil-

ity of a genetic link between alcoholwithdrawal severity and decreased α1subunit level. Overall, changes in thelevel of GABAA receptor subunitsfollowing chronic alcohol administra-tion may reflect an alteration in theassembly of GABAA receptors, which,in turn, may underlie some of thecellular and behavioral adaptations inalcohol dependence and withdrawal.

Steroidal GABA Agonists

Allopregnanolone—a product of themetabolism of the hormone proges-terone—is the most potent steroidalmodulator of GABAA receptor activi-ty. Found in the brain and in thebloodstream, allopregnanolone isthought to be synthesized by theadrenal glands and, in females, by theovaries; some synthesis also mayoccur in the brain. Allopregnanolonebinds to GABAA receptors at a sitedistinct from the binding sites forbenzodiazepines, barbiturates, andGABA. As a GABA agonist, allopreg-nanolone’s overall effects are inhibito-ry, and its binding to GABAA recep-tors suppresses the development ofconvulsions. Chronic alcohol adminis-tration produces an increased respon-siveness (i.e., sensitization) to theanticonvulsant effect of allopreg-nanolone. In addition, the allopreg-nanolone-induced augmentation ofGABA-stimulated chloride ion uptakeincreased by 42 percent in alcohol-withdrawing rats compared with ratsnot administered alcohol (Devaud etal. 1996). Similar results were foundwith another potent steroidal GABAAagonist, tetrahydrodeoxycorticos-terone, indicating that the sensitizationof GABAA receptors to neuroactivesteroids during alcohol withdrawal isnot unique to allopregnanolone. Thisenhancement of steroidal agonistaction during alcohol withdrawalcontrasts with the reduced effective-ness of GABA, benzodiazepines, andbarbiturates during withdrawal. Moreimportantly, evidence suggests that


2The GABAB receptor, which is anotherGABA receptor subtype, has a different modeof action and is therefore not discussed here.

the sites of action of benzodiazepines,barbiturates, and neuroactive steroidsare differentially modulated by thedevelopment of alcohol dependence.

Since allopregnanolone is a potentmodulator of GABAA receptors, andbecause its levels in brain and plasmacan reach physiologically active con-centrations (see review by Paul andPurdy 1992), the possibility exists thatalterations in the sensitivity or synthe-sis of this steroid with anticonvulsantproperties might modulate alcoholwithdrawal severity. For example,following 24 hours of alcohol vaporinhalation, plasma allopregnanolonedecreased significantly (approximate-ly 40 percent) in WSP mice but not inWSR mice (Finn et al. 1994).Separate studies did not find anychange in plasma allopregnanolone inalcohol-dependent male rats followingan alcohol-containing liquid diet(Devaud et al. 1996). However, in agroup of nine alcohol-dependent humansubjects, plasma allopregnanolone andtetrahydrodeoxycorticosterone weresignificantly lower during early with-drawal than in nonalcoholic subjects(Romeo et al. 1996). Consistent withthe hypothesis that steroidal GABAA

agonists may modulate withdrawalseverity, the decrease in neuroactivesteroids during alcohol withdrawalwas associated with increased levelsof anxiety and depression in the alco-holic subjects.

Chronic alcohol exposure alsosignificantly increases plasma corti-costerone levels in WSP mice, with amarginal increase in WSR mice.Corticosterone, a steroid hormoneproduced by the adrenal glands, playsa role in the body’s response to stressand can increase sensitivity to thedevelopment of convulsions in somegenotypes. Handling to induce HICincreases corticosterone in WSP micecompared with WSR mice. The mag-nitude of this increase in corticos-terone is greater between handledWSP and WSR mice than betweenunhandled alcohol-exposed WSP andWSR mice (Finn et al. 1994).Therefore, the increase in plasmacorticosterone and decrease in allo-

VOL. 21, NO. 2, 1997 153


A. GABAA receptor sensitivity is reduced

B. NMDA receptor sensitivity is enhanced

NormalCl-

GABA

Acute alcoholCl-

GABA & alcohol

Alcohol dependenceCl-

GABA & alcohol

Exterior

Interior

Figure 3 Ion channel adaptations revealed by alcohol withdrawal. Changes in ion channel sensitivity or number during alcohol withdrawal results in decreasedinhibitory and increased excitatory receptor function.

GABAergic inhibitory neurotransmission is reduced following chronic alcoholadministration. In the absence of alcohol (left), the neurotransmitter GABA opensGABAA receptor-chloride (Cl-) channels, inhibiting neurotransmission. Alcoholincreases GABA’s effect (middle), allowing more chloride to enter the neuron andincreasing inhibition. In alcohol dependence (right), both GABA and alcohol havesmaller effects on GABAA receptors. Less chloride enters the neuron, increasing theactivation of neurons previously inhibited by GABAergic neurotransmission.

Cl- Cl- Cl-

NormalCa++NMDA

Acute alcoholCa++

NMDA & alcohol

Alcohol dependenceCa++

NMDA & alcohol

Ca++ Ca++ Ca++

Glutamatergic excitatory neurotransmission increases following chronic alcoholadministration. In the absence of alcohol (left), the neurotransmitter glutamateallows calcium to enter the neuron via the NMDA receptor-ion channel. Short-termalcohol exposure decreases calcium flow into the neuron through the receptor-channel complex. In alcohol dependence, NMDA receptor sensitivity to glutamateincreases, resulting in excess flow of calcium into neurons.

C. Voltage-gated calcium channel density is increased

Exterior

Interior

NormalCa++

Voltage

Acute alcoholCa++

Voltage

Alcohol dependenceCa++

Voltage

Voltage-sensitive calcium (Ca++) channels increase from chronic alcohol administrationand dependence, increasing neural excitability. These channels admit calcium intothe neuron in response to electrical changes in the neuronal membrane.

Ca++ Ca++

Exterior

Interior

pregnanolone following chronic alco-hol exposure in WSP compared withWSR mice suggests that biologicalsynthesis of these two steroids may beregulated differently in the selectedlines. More important, the decrease inplasma allopregnanolone noted previ-ously was observed only in WSP miceand not in a genetically heterogeneousstock of rats. This is consistent withthe hypothesis that genetic differencesin alcohol withdrawal severity aremodulated by both convulsant (i.e.,corticosterone) and anticonvulsant(i.e., allopregnanolone) steroids,which have dramatically differentmechanisms of action.

NMDA Receptor Complex

Alterations in excitatory amino acidreceptors have been reported follow-ing chronic exposure to alcohol (seereviews by Crews et al. 1996;Tabakoff and Hoffman 1996). Mostimportant in this regard is the N-methyl-D-aspartate (NMDA) receptor,which responds to the excitatoryamino acid glutamate. The NMDAreceptor, which regulates an ion chan-nel permeable to calcium and sodium,plays a role in memory, learning, andthe generation of seizures.

Researchers have investigated thefunction of the NMDA receptor-ionchannel complex using MK-801, anNMDA antagonist thought to bindwithin the ion channel. Chronic alco-hol administration in a liquid dietproduced a 16-percent increase in thenumber of MK-801 binding sites inthe hippocampus, a brain region in-volved in memory processes andconvulsions. Chronic alcohol adminis-tration also increased the number ofglutamate binding sites. Althoughthese alterations have not been foundconsistently, evidence suggests thatchronic alcohol administration mayincrease the number of NMDA recep-tor complexes in the hippocampus.

The time course for the increase inMK-801 binding sites correlates withthe onset of withdrawal: The increasein binding sites occurs at the onset ofwithdrawal and at peak withdrawal(i.e., by 8 hours), but dissipates when

symptoms of withdrawal are no longerapparent (i.e., after 24 hours).Additional support for the involve-ment of NMDA receptors in alcoholwithdrawal is provided by the demon-stration that alcohol withdrawal canbe reduced by administration of MK-801, whereas withdrawal convulsionsare exacerbated by doses of NMDAthat are not convulsant in controlanimals.

Results of studies on withdrawalseverity in WSP and WSR mice areinconclusive. Initially, research sug-gested that WSP mice never exposedto alcohol (i.e., alcohol-naive) had asignificantly greater number of MK-801 binding sites in the hippocampuscompared with alcohol-naive WSRmice. Chronic alcohol administrationin a liquid diet for 1 week significant-ly increased the number of bindingsites in both lines, and the bindingsites remained significantly higher inthe WSP mice. However, furtherresearch disclosed that 24 hours ofalcohol vapor inhalation, while pro-ducing clear signs of withdrawal inWSP mice, had no effect on MK-801binding. These differences may resultfrom the different methods of alcoholadministration employed.

The observed alterations in thenumber and function of NMDA recep-tors following chronic alcohol expo-sure may result from alcohol-inducedchanges in the quantity of specificNMDA receptor subunit proteins,which have been reported to occurfollowing chronic alcohol administra-tion. Although the exact molecularprocesses involved are not fully un-derstood, many studies support thehypothesis that chronic alcohol ad-ministration results in supersensitiveNMDA receptors.

Voltage-Sensitive CalciumChannels

Calcium ions are essential to manynervous system functions. Voltage-sensitive calcium channels (VSCC’s)admit calcium into the neuron in re-sponse to changes in the electricalproperties of the neuron’s outer mem-brane. Scientists investigating

VSCC’s often employ calcium chan-nel antagonists, especially thoseknown as dihydropyridines (DHP’s).Because of their effects on the cardio-vascular system, calcium channelantagonists such as the DHP nifedip-ine (e.g., Adalat®) are commonlyprescribed to treat high blood pressureand some chronic heart conditions.

Experiments with DHP calciumchannel antagonists have providedevidence for the involvement ofVSCC’s in withdrawal hyperexcitabil-ity (reviewed in Little 1991). Forexample, chronic alcohol administra-tion increases the number of DHPbinding sites by approximately 50percent. This treatment can producevarying degrees of mild withdrawalwithout spontaneous convulsions. Ofinterest, the number of binding sitesincreased after 3 to 4 days of chronicalcohol exposure and was modulatedby calcium flow into neurons (seeLittle 1991).

Consistent with these results, ge-netic regulation of neuronal calciumchannels also occurred after chronicalcohol administration. After exposureto alcohol vapor for 72 hours, theWSP mice experienced a significantlygreater compensatory increase in DHPbinding sites in brain and heart muscletissue than did the WSR mice.

Additional studies found that theadministration of DHP calcium chan-nel antagonists reduced all forms ofalcohol withdrawal hyperexcitabilityin slices of hippocampus removedfrom experimental animals immedi-ately after cessation of chronic alcoholadministration. In addition, adminis-tration of the DHP’s nitrendipine andnimodipine reduced spontaneous andhandling-induced alcohol withdrawalconvulsions at doses that had littlesedative action. Furthermore, adminis-tration of a DHP during chronic alco-hol consumption prevented theupregulation of DHP binding sites inthe brain and significantly reducedwithdrawal severity as measured bytremor and convulsions. This decreasein alcohol withdrawal hyperexcitabili-ty in animals given nitrendipine plusalcohol was also demonstrated in


hippocampal slice preparations. Inconclusion, both behavioral and bio-chemical evidence suggest that in-creases in DHP-sensitive binding sitesmay underlie some adaptations toalcohol at the neuronal level, which,in turn, can produce behavioral adap-tations and influence withdrawalseverity. Additional clinical researchis needed to confirm this hypothesis.

CONCLUSIONS

Because chronic alcohol administra-tion alters various neurochemicalsystems, it is unlikely that one specificmechanism induces physical depen-dence. More important, the timecourse for changes in receptor functionand sensitivity (Sanna et al. 1993;Watson and Little 1995) indicate thatthe pattern of neuronal changes occur-ring during alcohol withdrawal iscomplex. Currently, researchers do notknow whether changes in a particularneurochemical system contribute toone specific symptom of alcohol with-drawal or whether alteration in oneneurochemical system generates acascade of neurochemical changes thatmanifest as the withdrawal syndrome.

Genetic animal models will contin-ue to be useful in tracing the pathwaysfrom complex drug responses to spe-cific genes. QTL mapping and newmolecular biological techniques, cou-pled with the homology betweenmouse and human chromosomalmaps, will facilitate the identificationand study of specific genes relevant tothe alcohol withdrawal syndrome inhumans. In addition, the QTL findingsin mice can be compared with theresults obtained through theCollaborative Study on the Geneticsof Alcoholism (COGA), which is alarge-scale, multidisciplinary researchprogram to investigate the geneticcomponents of the susceptibility toalcohol abuse and dependence.

Overall, physical dependence onalcohol produces abnormalities in anumber of neurotransmitter systems,resulting in reduced inhibitory func-tion and increased activity of excitato-ry systems during alcohol withdrawal.

By understanding the relative impor-tance and contribution of these neuro-chemical changes to the alcoholwithdrawal syndrome, researchers candevelop more effective treatmentstrategies in humans to minimizeincreased withdrawal severity in sub-sequent episodes. ■

EDITORIAL NOTE

The reference list accompanying this article has been shortened. Acomplete bibliography is available on request.

REFERENCES

BALLENGER, J.C., AND POST, R.M. Kindling as amodel for alcohol withdrawal syndromes.British Journal of Psychiatry 133:1–14, 1978.

BECKER, H.C., AND HALE, R.L. Repeatedepisodes of ethanol withdrawal potentiate theseverity of subsequent withdrawal seizures: Ananimal model of alcohol withdrawal “kindling.”Alcoholism: Clinical and ExperimentalResearch 17:94–98, 1993.

BUCK, K.J. Molecular genetic analysis of therole of GABAergic systems in the behavioraland cellular actions of alcohol. BehaviorGenetics 26:313–323, 1996.

BUCK, K.J.; METTEN, P.; BELKNAP, J.K.; AND

CRABBE, J.C. Quantitative trait loci involved ingenetic predisposition to acute alcoholwithdrawal in mice. Journal of Neuroscience17:3946–3955, 1997.

COPELAND, N.G.; JENKINS, N.A.; GILBERT, D.J.;EPPIG, J.T.; MALTAIS, L.J.; MILLER, J.C.;DEITRICH, W.F.; WEAVER, A.; LINCOLN, S.E.;STEEN, R.G.; STEIN, L.D.; NADEAU, J.H.; AND

LANDER, E.S. A genetic linkage map of themouse: Current applications and futureprospects. Science 262:57–66, 1993.

CRABBE, J.C.; YOUNG, E.R.; AND KOSOBUD, A.Genetic correlations with alcohol withdrawalseverity. Pharmacology Biochemistry andBehavior 18(Suppl. 1):541–547, 1983.

CREWS, F.T.; MORROW, A.L.; CRISWELL, H.;AND BREESE, G. Effects of alcohol on ionchannels. International Review of Neurobiology39:283–367, 1996.

DEITRICH, R.A., AND SPUHLER, K. Genetics ofalcoholism and alcohol actions. In: Smart, R.G.;Cappell, H.D.; Glaser, F.B.; Israel, Y.; Kalant,H.; Popham, R.E.; Schmidt, W.; and Sellers,E.M. Research Advances in Alcohol and DrugProblems. Vol. 8. Plenum Publishing Corp.,1984. pp. 47–98.

DEVAUD, L.L.; PURDY, R.H.; FINN, D.A.; AND

MORROW, A.L. Sensitization of γ-aminobutyricacidA receptors to neuroactive steroids in ratsduring alcohol withdrawal. Journal ofPharmacology and Experimental Therapeutics278:510–517, 1996.

FINN, D.A.; ROBERTS, A.J.; KEITH, L.D.;MERRILL, C.; YOUNG, E.; AND CRABBE, J.C.Chronic alcohol differentially altersneurosteroids in withdrawal seizure prone andresistant mice. Alcoholism: Clinical andExperimental Research 18:448, 1994.

FRIEDMAN, H.J. Assessment of physicaldependence on and withdrawal from alcohol inanimals. In: Rigter, H., and Crabbe, J.C., eds.Alcohol Tolerance and Dependence. Amster-dam: Elsevier/North-Holland Biomedical Press,1980. pp. 93–121.

GLUE, P., AND NUTT, D. Overexcitement anddisinhibition: Dynamic neurotransmitterinteractions in alcohol withdrawal. BritishJournal of Psychiatry 157:491–499, 1990.

GOLDSTEIN, D.B. Inherited differences inintensity of alcohol withdrawal reactions inmice. Nature 245:154–156, 1973.

KAKIHANA, R. Alcohol intoxication andwithdrawal in inbred strains of mice: Behav-ioral and endocrine studies. Behavioral andNeural Biology 26:97–105, 1979.

KOSOBUD, A.E., AND CRABBE, J.C. Geneticinfluences on the development of physicaldependence and withdrawal in animals. In:Begleiter, H., and Kissin, B., eds. The Geneticsof Alcoholism. Oxford: Oxford UniversityPress, 1995. pp. 221–256.

LITTLE, H.J. The role of neuronal calciumchannels in dependence on alcohol and othersedatives/hypnotics. Pharmacology andTherapeutics 50:347–365, 1991.

METTEN, P., AND CRABBE, J.C. Dependence andwithdrawal. In: Deitrich, R.A., and Erwin, V.G.,eds. Pharmacological Effects of Alcohol on theNervous System. New York: CRC Press, 1996.pp. 269–290.

MORROW, A.L. Regulation of GABAA receptorfunction and gene expression in the centralnervous system. In: Bradley, R.J., and Harris,R.A., eds. International Review of Neuro-biology. Vol. 38. New York: Academic Press,1995. pp. 1–41.

PAUL, S.M., AND PURDY, R.H. Neuroactivesteroids. FASEB Journal 6:2311–2322, 1992.

ROMEO, E.; BRANCATI, A.; DELORENZO, A.;FUCCI, P.; FURNARI, C.; POMPILI, E.; SASSO,G.F.; SPALLETTA, G.; TROISI, A.; AND PASINI, A.Marked decrease of plasma neuroactive steroidsduring alcohol withdrawal. Clinical Neuro-pharmacology 19:366–369, 1996.

SANNA, E.; SERRA, M.; COSSU, A.; COLOMBO,G.; FOLLESA, P.; CUCCHEDDU, T.; CONCAS, A.;AND BIGGIO, G. Chronic alcohol intoxication

VOL. 21, NO. 2, 1997 155



induces differential effects on GABAA andNMDA receptor function in the rat brain.Alcoholism: Clinical and Experimental Research17:115–123, 1993.

SCHUCKIT, M.A.; TIPP, J.E.; REICH, T.;HESSELBROCK, V.M.; AND BUCHOLZ, K.K. Thehistories of withdrawal convulsions anddelirium tremens in 1648 alcohol dependentsubjects. Addiction 90:1335–1347, 1995.

TABAKOFF, B., AND HOFFMAN, P.L. Alcohol andglutamate receptors. In: Deitrich, R.A., andErwin, V.G., eds. Pharmacological Effects ofAlcohol on the Nervous System. New York:CRC Press, 1996. pp. 73–93.

VICTOR, M., AND ADAMS, R.D. The effect ofalcohol on the nervous system. In: Metabolic andToxic Diseases of the Nervous System. Baltimore,MD: Williams & Wilkins, 1953. pp. 526–573.

WATSON, W.P., AND LITTLE, H.J. Identificationof distinct components, with different timecourses, of the changes in response toconvulsive stimuli during alcohol withdrawal.Journal of Pharmacology and ExperimentalTherapeutics 272:876–884, 1995.

YOST, D.A. Alcohol withdrawal syndrome.American Family Physician 54:657–664, 1996.

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?

T he answers to these and other quest ions can be found in Alcohol Alert ,the quarter ly bul le t in publ ished by the Nat ional Inst i tute on AlcoholAbuse and Alcohol ism. Alcohol Alert provides t imely information on

alcohol research and t reatment . Each issue addresses a specif ic topic inalcohol research and summarizes cr i t ical f indings in a br ief , four-page, easy-to-read format .

• Preventing Alcohol Abuse and Related Problems (No. 34) summarizesresearch on the effectiveness of policy, community, and educationalinterventions to reduce alcohol abuse and its consequences.

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

• Patient Treatment Matching (No. 36) discusses research findings fromProject MATCH, an in-depth study designed to determine whether treatmentoutcome 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 20849–0686. Fax: (202) 842–0418.

Alcohol Alert is available on the World Wide Web at http://www.niaaa.nih.gov

ALCOHOL ALERT

exploring alcohol withdrawal

Documents