Different GABA_A receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates

摘要

Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain α_1- α_2-, α_3-, and α_5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABA_A receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABA_A receptors containing α_1-subunits (α_1GABA_A receptors); L-838,417, which shows functional selectivity for α_2GABA_A, α_3GABA_A, and α_5GABA_A receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that α_1GABA_A receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve α_2GABA_A, α_3GABA_A, and/or α_5GABA_A subtypes. Our results also suggest that the α_1GABA_A receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of α_1GABA_A receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.