Robert J. Malcolm

GABA Systems, , and

Robert J. Malcolm, M.D.

Alterations in the γ-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of and benzodiazepines. Chronic modulation

of the GABAA- receptor complex plays a major role in central nervous system dysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreased

GABAergic inhibitory function and an increase in glutamatergic excitatory function. GABAA recep- tors play a role in both reward and withdrawal phenomena from alcohol and -.

Although less well understood, GABAB receptor complexes appear to play a role in inhibition of moti- vation and diminish potential to reinforcing . Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate ben- zodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substan- tial drawbacks in the treatment of substance useÐrelated disorders that include interactions with alco- hol, rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with benzodiazepines. Selective GABA agents with novel mechanisms of action have , , and reward inhibition profiles that have potential in treating substance use and with-

drawal and enhancing with less liability than benzodiazepines. The GABAB receptor agonist has promise in relapse prevention in a number of substance dependence dis-

orders. The GABAA and GABAB pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative- withdrawal and also possibly a role in relapse prevention. (J Clin 2003;64[suppl 3]:36–40)

lcohol dependence is among the most common psy- the central nervous system (CNS). During continuous Achiatric disorders in the general population. Current exposure to alcohol, neuroadaptive changes occur to prevalence of is fairly stable in the compensate for alcohol’s destabilizing effects.3 When United States at approximately 6% of men and 2% alcohol use is discontinued, the maladaptive nature of of women,1 although 14% of Americans may be alcohol these changes becomes evident. Gamma-aminobutyric dependent at some point during their lives.2 According to acid (GABA)—the main inhibitory neurotransmitter in the DSM-IV, a diagnostic criterion of physiologic alcohol the mammalian CNS—is implicated in multiple aspects dependence is the presence of an alcohol withdrawal syn- of , dependency, and withdrawal. drome during acute reduction in or cessation of drinking GABA systems are sensitive to both the initial and the (Table 1). chronic effects of alcohol exposure. The neuropathology of withdrawal is opposite to that MECHANISMS OF ALCOHOL WITHDRAWAL of intoxication. Alcohol intoxication enhances the func- tion of the GABAergic system, resulting in enhanced The alcohol withdrawal syndrome is the result of the inhibitory neurotransmission and, thus, depression of the brain’s adaptation to the long-term presence of alcohol in CNS. Conversely, withdrawal is marked by increased glu- tamatergic action and reduced GABA activity, resulting in heightened excitatory neurotransmission and brain hyper- excitability. In untreated alcohol withdrawal, the neuronal From the Medical University of South Carolina, Center for and Alcohol Programs, Charleston. firing rate and recruitment of neighboring neurons in- This article is derived from the teleconference “The Role crease while CNS levels of oxidative free radicals, peroxi- of GABA in Neuropsychiatric Disorders: A Review of GABA dases, and intracellular calcium rise.4 Cell damage or cell Agents,” which was held April 3, 2002, and supported by an unrestricted educational grant from Cephalon, Inc. death is possible. Cortical, brain stem, and limbic func- Corresponding author and reprints: Robert J. Malcolm, tion are disrupted. At the clinical level, alcohol with- M.D., Medical University of South Carolina, Institute of Psychiatry, Center for Drug and Alcohol Programs, drawal can cause a host of autonomic and CNS effects, 67 President St., P.O. Box 250861, Charleston, SC 29425. including hypertension, tachycardia, excessive sweating,

36 © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANSJ Clin PsychiatryPOSTGRADUATE 2003;64 PRESS (suppl, INC 3). Benzodiazepines and

Table 1. Diagnostic Criteria for Alcohol Withdrawala Figure 1. Cycle of Alcohol Dependencea Decrease in (or cessation of) prolonged and heavy alcohol use 2 or more of the following symptoms developing within several hours Chronic Alcohol Use/Abuse to a few days of the above Autonomic hyperactivity (eg, elevated pulse rate or diaphoresis) Tremor Repeated Withdrawal Episodes Transient hallucinations or illusions Anxiety Altered Brain Function Nausea or vomiting Seizures Decreased GABAergic Function Increased Glutamatergic Function The above symptoms cause considerable distress or impairment and Alcohol are not better accounted for by another or medical Drinking condition Relapse aAdapted with permission from DSM-IV.2 Kindled Withdrawal Symptoms and Consequences Increased Increased Anxiety Increased Sleep Disturbance hypothermia, tremor and other motor incoordination, Increased Seizure Susceptibility cognitive disruption, dysphoria, anxiety, insomnia, hallu- Increased Excitotoxicity Risk cinations, , seizures, and—in about 1% of inad- equately treated cases—death. Potential Neurologic Damage Potential Cognitive Impairment Chronic alcohol use renders GABAA receptors dys- functional, permanently dampening GABAergic function. Autopsies of histologically normal brains of human al- aAdapted with permission from Becker.3 coholics found benzodiazepine receptor sites, which are located on the GABAA receptor complex, reduced by 30% in the hippocampus and by 25% in the frontal cortex.5 Di- prognosis and relatively high mortality rate.10 Patients with minished inhibition via GABAA receptors may contribute withdrawal-related seizures are more likely to have under- to the worsening of withdrawals over time. Also, repeated gone numerous previous detoxifications than patients withdrawals may increase the number of glutamatergic re- without seizures.6,11,12 ceptors, making the brain more vulnerable to neural excit- ability and excitotoxic damage.3 TREATMENT OF ALCOHOL WITHDRAWAL In a process of , sometimes clinically re- ferred to as neuronal “kindling,” withdrawal symptoms For more than 4 decades, benzodiazepines have been intensify as withdrawal episodes grow in number.6 Prior first-line treatment for patients with alcohol withdrawal. withdrawal experience is associated with more severe and Their anxiolytic and anticonvulsant properties appear to medically complicated later withdrawal episodes. This address both psychological and physiologic symptoms. progression is not solely attributable to a worsening of al- More recently, research suggests that benzodiazepines may coholic drinking over the course of . Rather, have substantial drawbacks in the treatment of alcohol- having a previous withdrawal episode reduces the duration related disorders. Benzodiazepines combined with alcohol and extent of intoxication necessary to provoke subse- in the outpatient setting can lead to death, even with rela- quent withdrawal episodes.3 For example, mice exposed tively low levels of blood alcohol.13 Benzodiazepines also to alcohol for 3 cycles of 16 hours showed more severe interact with alcohol to produce motor impairment that withdrawal symptoms than mice exposed to alcohol for patients may not recognize. Additionally, some patients 48 hours straight.7 Further, chronic intermittent alcohol treated with benzodiazepines experience rebound (a rever- exposure led to hippocampal cell loss in rats, but continu- sal of the medication’s effects and return of symptoms) ous alcohol exposure did not.8,9 In mammals, cycles of upon discontinuation of treatment. Benzodiazepines ame- binge-drinking followed by abstinence initially provoke liorate withdrawal symptoms at any one episode of with- no withdrawal symptoms, then mild withdrawal symp- drawal, but they do not appear to interrupt the kindling toms, then moderate and finally severe withdrawal symp- process.11,14,15 Because benzodiazepines are potentially toms. Through “kindling,” the alcoholic brain ultimately habit-forming, there may be a risk of substituting one de- becomes hyperexcitable (Figure 1). pendence (or abuse) for another when benzodiazepines are Kindling is a term originally used in the study of used chronically to treat patients with alcoholism. epilepsy to describe the augmentation process by which My colleagues and I conducted a series of studies16,17 in low level, intermittent, subconvulsant stimulus eventually which we compared the anticonvulsant carbamazepine— provokes seizure.3 Seizure can be a symptom of severe al- which has a long history of use in the detoxification of cohol withdrawal and as such is associated with poor alcohol-dependent patients in Europe—to the benzodiaze-

J© Clin COPYRIGHT Psychiatry 2003 2003;64 PHYSICIANS (suppl P 3)OSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. 37 Robert J. Malcolm pine lorazepam. One such study16 focused on the pharma- taking a first drink after detoxification, 20% of lorazepam- cologic treatment of psychosocial factors associated with treated patients experienced dizziness or ataxia but did alcohol withdrawal (sleep quality, ability to return to work, not recognize their impairment. Outpatients’ unawareness anxiety, and depression). Psychiatric withdrawal symptoms of their impairment could put benzodiazepine-treated such as sleep disturbance may increase the likelihood patients at risk for automobile or other accidents, includ- of relapse as outpatients seek relief by self-medicating ing overdoses. Although carbamazepine was superior to with alcohol. In this study, 136 outpatients with mild-to- lorazepam in the experimental setting, carbamazepine has moderate withdrawal symptoms were grouped according to several liabilities that limit its clinical utility. It interacts their number of previous treated withdrawals, 0-to-1 or to increase the clearance of many other therapeutic agents. multiple (> 2). Subjects from each group received 600 to In some patients, confusion, decreases in serum sodium, 800 mg carbamazepine on day 1, 600 mg/day in 3 divided and, rarely, hematologic and hepatic damage can occur. doses through day 4, and a single dose of 200 mg on day 5. Or, they received 6 to 8 mg lorazepam on day 1, 6 mg/day Relapse Prevention in 3 divided doses through day 4, and a single dose of 2 mg Benzodiazepines may have other qualities that limit on day 5. (Carbamazepine/lorazepam dosage equivalency their usefulness in the treatment of alcohol dependence. was extrapolated from the literature.) All subjects com- In a study by Deutsch and Walton,19 rats subjected to pleted the Zung Anxiety Scale, the Beck Depression In- forced intragastric intubation of alcohol later showed an ventory, and visual analogue scales describing their sleep increase in free-choice self-administration of alcohol. quality and subjective ability to work. Mood symptoms im- Once dependence was established, rats were acclimatized proved for all patients regardless of detoxification history to a free-choice situation in which they could always or the drug they received.16 choose between flavored water and flavored water con- In examining the effect of kindling on symptom sever- taining alcohol. During these free-choice situations, rats ity, we found that the outpatients with a history of multiple treated with showed no decline in their level withdrawals experienced more severe anxiety than those of alcohol drinking, while untreated rats tapered their with no or 1 previous withdrawal. Oddly enough, anxiety drinking over time. In a second study by Hedlund and symptoms responded better to carbamazepine than to lora- Wahlstrom,20 rats were made psychologically alcohol de- zepam. The multiple withdrawal group also felt less able pendent by a regimen of once-weekly injections of alcohol to return to work and experienced more sleep problems accompanied by once-weekly 24-hour periods in which than the group with no or 1 previous withdrawal. In the alcohol was available for drinking. During the first phase posttreatment period, subjects who had received carba- of the study, dependence was established when the rats mazepine reported better sleep than subjects who had consistently drank until they had self-administered a cer- received lorazepam.16 tain dose of alcohol regardless of the differential alcohol Postdetoxification relapse can be predicted in part by concentration in the solution offered them. After depen- the intensity of alcohol withdrawal symptoms at the end of dence was established, alcohol-dependent rats began a withdrawal treatment.18 The progressive re-intensification 3-week treatment course in which randomly selected rats of symptoms may influence a patient’s motivation to drink were treated with diazepam and offered alcohol only on again. Further, protracted withdrawal symptoms—symp- the first and final days of the treatment. On the first day, toms such as anxiety, irritability, mood lability, and sleep when these rats received both a diazepam injection and the disturbance lasting beyond the 5 to 7 days of detoxifica- choice to drink alcohol, they showed a 56% decrease in tion—present a relapse risk. My colleagues and I17 looked mean intake of alcohol compared with the previous week. at relapse to drinking behaviors. In the immediate 7-day Then alcohol was denied the rats for 3 weeks while diaze- posttreatment period, outpatients with no or 1 previous pam treatment continued. On the final day, the rats were withdrawal who had received carbamazepine drank on av- again offered alcohol to drink, and they showed a 140% erage less than 1 drink per day, while those who had re- increase in mean alcohol intake over their pretreatment ceived lorazepam drank about 3 drinks per day. Outpa- alcohol intake. Increased drinking lasted for 1 week. In yet tients with multiple (> 2) previous detoxifications drank another preclinical study not involving alcohol withdraw- less than 1 drink per day following carbamazepine treat- al, benzodiazepines increased the consumption of alcohol ment but about 5 drinks per day following lorazepam use.21 These data19,20 suggest that a distinct effect of diaze- treatment. Ten percent of the carbamazepine multiple pam on alcohol intake may arise early in treatment and detoxification group (> 2) drank posttreatment; 50% of that diazepam may help prime for alcohol use during the the lorazepam multiple detoxification group drank in the course of withdrawal treatment. Our study, while not de- same 7-day interval. Most outpatients who received lora- finitive, supports this premise in humans.18 zepam treatment experienced rebound withdrawal symp- Baclofen, an agent used to treat spasticity, has also been toms posttreatment. Rebound withdrawal symptoms may studied in the treatment of alcoholic patients and encourage relapse.17 In addition to having a higher risk for dependence. In contrast to benzodiazepines, which influ-

38 © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANSJ Clin PsychiatryPOSTGRADUATE 2003;64 PRESS (suppl, INC 3). Benzodiazepines and Substance Abuse

28 ence neurotransmission via the GABAA receptor complex, measures in reducing cocaine use. Although tiaga- baclofen is an agonist at the less-understood GABAB pre- bine has not been studied for relapse to alcohol use in synaptic receptors. Baclofen blocks motor activation of humans, tiagabine did not increase free-choice alcohol use cocaine and prevents development of cocaine-induced be- in alcohol-dependent rats, whereas diazepam did.29 havioral sensitization.22 Krupitsky and colleagues23 con- Repeated exposure to -like psychostimu- ducted a study of baclofen among 90 alcoholic inpatients lants such as cocaine produces in animals a sensitization with comorbid secondary, subclinical anxiety and depres- of effects similar to kindling.22 The threshold for cocaine sion. Anxiety and depression frequently accompany alco- to produce seizures is lowered in animals exposed repeat- hol dependence, but alcohol-dependent individuals tend edly to cocaine over time.30 drugs inhibit to have poor self-recognition of these disorders. Affective GABAA receptor action and block the reuptake or promote disorders alongside alcohol dependence can increase with- the release of and glutamate, thereby increasing drawal severity and vulnerability to relapse. The study seizure potential. Polysubstance users frequently self- subjects had been abstinent for 3 to 4 weeks, and thus were medicate with benzodiazepines31 and show preference for without symptoms of alcohol withdrawal syndrome. They some types of benzodiazepines over others.32 were randomly divided into 4 groups, and for 3 weeks re- Dopamine plays a role in the rewarding aspects of ceived only 37.5 mg/day baclofen, 15 mg/day diazepam, intoxication, and GABA (via GABAB receptors) inhibits 75 mg/day of the antidepressant amitriptyline, or placebo. dopamine neurons. Baclofen is an agonist at GABAB re- The Zung Anxiety Scale, the Minnesota Multiphasic Per- ceptors and inhibits the release of several neurotransmit- sonality Inventory, and Spielberger’s State-Trait Anxiety ters including dopamine and glutamate. Cocaine-abusing Inventory, as well as blood and plasma measurements humans treated with baclofen experienced reduced crav- of dopamine, serotonin, and GABA and an electroen- ing for cocaine but unattenuated highs.33 In rats, acute pre- cephalogram (EEG) were administered before and after treatment with baclofen has been shown to decrease co- medication trial. The results of the posttreatment rating caine self-administration in a dose-dependent manner.34 scale scores showed a decrease in anxiety and depression Tiagabine also appears to have promise in the treatment of in all 3 treatment groups; these results were confirmed by patients with .28 the electrophysiologic tests. Baclofen provoked no side Gasior and colleagues30 tested several drugs in the effects, while diazepam and amitriptyline caused sedation. treatment of cocaine-induced seizures in mice. Of these Blood and plasma measurements revealed no significant drugs, felbamate, , loreclezole, losigamone, changes. The results indicated that selective ligands of progabide, remacemide, stiripentol, tiagabine, and viga-

GABAB receptors can be as efficacious in treating anxiety/ batrin protected against cocaine-induced seizures. Tiaga- affective disorders as GABAA receptor ligands. A recent bine offered the most potent neuroprotection with seizure case report suggested that baclofen also may be of value in suppression but also produced the most pronounced side treating alcohol withdrawal.24 effects (namely motor impairment). The researchers con- Another agent with potential in the management of al- cluded that many classic antiepileptics are ineffective in cohol withdrawal is tiagabine. Tiagabine is an antiepilep- murine models of cocaine-induced seizures, but drugs that tic GABA pump uptake inhibitor; it increases available enhance GABA-mediated neuronal inhibition in a manner extracellular concentrations of GABA in various brain re- distinct from benzodiazepines offer the best anticonvul- 25 gions in both GABAA and GABAB synapses. In a study sant profile in relation to side effects. by Cleton et al.,26 tiagabine resulted in higher maximal GABA concentrations in the brains of rats kindled to sei- CONCLUSION zures versus the brains of unkindled controls. The re- searchers inferred from EEG results during the study that GABAA and GABAB inhibitory systems play substan- tiagabine-induced enhancement of GABAergic inhibition tial roles in addiction including intoxication, reward was less sensitive to functional adaptation in response to inhibition and motivation, sensitization, and kindling. Dis- epileptic activity than modulation of GABAergic inhibi- turbances in GABA are presumed to lead to clinical mani- tion by midazolam. Another interesting feature of tiaga- festations of withdrawal from alcohol and sedative-hyp- bine is that it does not appear to interact with alcohol. In a notics in humans. Until recently, clinical alterations of study of 20 healthy men and women, Kastberg and col- GABA receptor activity in addiction were limited to the leagues27 found that the pharmacokinetic and pharmaco- use of benzodiazepines, but benzodiazepines have sub- dynamic features of tiagabine were unchanged by alcohol, stantial drawbacks in the treatment of alcohol-related dis- and vice versa. The investigators concluded that individu- orders. These drawbacks include serious interactions with als taking tiagabine could ingest moderate amounts of alcohol, rebound, priming, and the risk of supplanting the alcohol and drive and operate machinery safely. In a small alcohol dependence with benzodiazepine dependence. double-blind trial of relapse prevention of cocaine use, Selective GABAB receptor ligands such as baclofen tiagabine was superior to placebo on several subjective and tiagabine, with GABAA and GABAB activity, show

J© Clin COPYRIGHT Psychiatry 2003 2003;64 PHYSICIANS (suppl P 3)OSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. 39 Robert J. Malcolm promise in the treatment of alcohol-dependent patients. 13. Koski A, Ojanperä I, Vuori E. Alcohol and benzodiazepines in fatal poison- ings. Alcohol Clin Exp Res 2002;26:956Ð959 Medication-assisted detoxification should provide a safe 14. Booth BM, Blow FC. The kindling hypothesis: further evidence from withdrawal from alcohol or other drugs and prepare the a U.S. national survey of alcoholic men. Alcohol Alcohol 1993;28: patient for ongoing rehabilatory treatment. 593Ð598 15. Malcolm R, Roberts JS, Wang W, et al. Multiple previous detoxifications are associated with less responsive treatment and heavier drinking during Drug names: amitriptyline (Endep, Elavil, and others), baclofen (Lior- an index outpatient detoxification. Alcohol 2000;22:59Ð164 esal and others), carbamazepine (Tegretol, Epitol, and others), diazepam 16. Malcolm R, Myrick H, Roberts J, et al. The differential effects of medica- (Valium and others), felbamate (Felbatol), gabapentin (Neurontin), lora- tion of mood, sleep disturbance, and work ability in outpatient alcohol zepam (Ativan and others), midazolam (Versed and others), tiagabine detoxification. Am J Addict 2002;11:141Ð150 (Gabatril). 17. Malcolm R, Myrick H, Roberts J, et al. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an Disclosure of off-label usage: The author of this article has determined outpatient randomized trial. J Gen Intern Med 2002;17:1Ð7 that, to the best of his knowledge, amitriptyline is not approved by the 18. O’Connor PG, Gottlieb LD, Kraus ML, et al. Social and clinical features as U.S. Food and Drug Administration for the treatment of depression; predictors of outcome in outpatient alcohol withdrawal. J Gen Intern Med baclofen is not approved for the treatment of alcohol withdrawal 1991;6:312Ð316 and relapse prevention; carbamazepine, diazepam, lorazepam, and mida- 19. Deutsch JA, Walton NY. Diazepam maintenance of alcohol preference zolam are not approved for the treatment of alcohol withdrawal; fel- during alcohol withdrawal. Science 1977;198:307Ð309 bamate, gabapentin; loreclezole, losigamone, progabide, remacemide, 20. Hedlund L, Wahlstrom G. The effect of diazepam on voluntary ethanol stiripentol, and vigabatrin are not approved for the treatment of cocaine intake in a rat model of alcoholism. Alcohol Alcohol 1998;33:207Ð219 withdrawal seizures; and tiagabine is not approved for treating alcohol 21. Söderpalm AH, Hansen S. Benzodiazepines enhance the consumption and withdrawal and relapse. palatability of alcohol in the rat. Psychopharmacology 1998;137:215Ð222 22. Kalivas PW, Stewart J. 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