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GABA Systems, Benzodiazepines, and Substance Dependence

Robert J. Malcolm, MD

Published: March 1, 2003

Article Abstract

Alterations in the γ-aminobutyric acid (GABA) receptor complex and GABA neurotransmissioninfluence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulationof the GABAA-benzodiazepine receptor complex plays a major role in central nervous systemdysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreasedGABAergic inhibitory function and an increase in glutamatergic excitatory function. GABAA receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics.Although less well understood, GABAB receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcoholuse and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepinebinding sites, and in preclinical models lead to cell death. Benzodiazepines have substantialdrawbacks in the treatment of substance use-related disorders that include interactions with alcohol,rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with addictionto both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicatewith benzodiazepines. Selective GABA agents with novel mechanisms of action have anxiolytic,anticonvulsant, and reward inhibition profiles that have potential in treating substance use and withdrawal and enhancing relapse prevention with less liability than benzodiazepines. The GABABreceptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders.The GABAA and GABAB pump reuptake inhibitor tiagabine has potential for managingalcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.

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