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.2005 Jan 18;102(3):915-20.
doi: 10.1073/pnas.0405621102. Epub 2005 Jan 11.

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

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

James K Rowlett et al. Proc Natl Acad Sci U S A..

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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Figures

Fig. 1.
Fig. 1.
Effects of zolpidem (⋄, α1GABAA-preferring agonist), L-838,417 (□, agonist with functional selectivity for α2GABAA, α3GABAA, and α5GABAA receptors), and diazepam (•, nonselective agonist) on behavior maintained by food presentation that was suppressed by presentation of mild electric shock (n = 4 rhesus monkeys). V, vehicle (50% propylene glycol, 50% saline).*,P <0.05 vs. vehicle, Dunnett's tests.
Fig. 2.
Fig. 2.
Ability of zolpidem (⋄), L-838,417 (□), and diazepam (•) to engender muscle relaxation (a) and ataxia (b) in squirrel monkeys (n = 4). Data are the mean cumulative score (±SEM).*,P < 0.05 vs. vehicle, Dunnett's tests.
Fig. 3.
Fig. 3.
Effects of zolpidem (⋄), L-838,417 (□), and diazepam (•) on observable measures related to sedation, including locomotor activity (a) and procumbent posture (sedation,b), in squirrel monkeys (n = 4). Data are expressed as the mean frequency score (±SEM).*,P < 0.05 vs. vehicle, Dunnett's tests.
Fig. 4.
Fig. 4.
Effects of selective and nonselective benzodiazepine agonists in squirrel monkeys (n = 5) trained to discriminate triazolam (0.03 mg/kg) from vehicle. Data are mean (±SEM) percentage of responding on the triazolam-associated lever. ▾, Triazolam; •, diazepam; ⋄, zolpidem; □, L-838,417.
Fig. 5.
Fig. 5.
Antagonism of the effects of triazolam by L-838,417 in squirrel monkeys (n = 4) trained to discriminate triazolam (0.03 mg/kg) from vehicle. Data are mean (±SEM) percentage of responding on the triazolam-associated lever. ▾, Triazolam alone; □, +0.1 L-838,417;▵, +0.3 L-838,417; ⋄, +1.0 L-838,417.
Fig. 6.
Fig. 6.
Self-administration of benzodiazepine agonists by rhesus monkeys trained under a progressive-ratio schedule of i.v. drug delivery. (a) Dose-response functions for the mean number of injections per session (±SEM) maintained by zolpidem and L-838,417 (n = 5 monkeys).*,P < 0.05 compared to saline availability, Dunnett's tests. ⋄, Zolpidem; □, L-838,417. (b) Maximum BP irrespective of dose (BPmax). Data are mean + SEM forn = 5 monkeys. Lines represent reliable differences from L-838,417, Bonferroni tests.
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