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

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Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR

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

Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):915-20. doi: 10.1073/pnas.0405621102. Epub 2005 Jan 11.

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15644443 [ View in PubMed
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Abstract

Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain alpha1-, alpha2-, alpha3-, and alpha5-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 alpha1-subunits (alpha1GABAA receptors); L-838,417, which shows functional selectivity for alpha2GABAA, alpha3GABAA, and alpha5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha2GABAA, alpha3GABAA, and/or alpha5GABAA subtypes. Our results also suggest that the alpha1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.

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