GABA Systems, Benzodiazepines, and Substance Dependence

Alterations in the γ-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulation of the GABA_A-benzodiazepine 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. GABA_A receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics. Although less well understood, GABA_B receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substantial drawbacks 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 addiction to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with 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 GABA_B receptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders. The GABA_A and GABA_B pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.

J Clin Psychiatry 2003;64(suppl 3):36-40