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

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National Academy of Sciences

RESUMO

Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain α1-, α2-, α3-, and α5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABAA 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 GABAA receptors containing α1-subunits (α1GABAA receptors); L-838,417, which shows functional selectivity for α2GABAA, α3GABAA, and α5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that α1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve α2GABAA, α3GABAA, and/or α5GABAA subtypes. Our results also suggest that the α1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of α1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.

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