Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys.

Abstract

Background: Benzodiazepines bind to γ-aminobutyric acid type A (GABA_A) receptor subtypes identified by different α subunits (i.e., α1GABA_A, α2GABA_A, α3GABA_A, and α5GABA_A). Sedative-motor effects of benzodiazepines are thought to involve α1GABA_A and α3GABA_A subtypes.

Aims: We evaluated observable measures of sedative-motor effects and species-typical behaviors in monkeys following acute administration of novel GABAkines (positive allosteric modulators of GABA_A receptors), with varying degrees of selective efficacy at different GABA_A receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABA_A and α3GABA_A efficacy.

Methods: Adult female rhesus monkeys (N = 4) were implanted with chronic indwelling i.v. catheters. Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABA_A subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABA_A subtypes), and MP-III-22 (preferential potency and efficacy for α5GABA_A subtypes).

Results: As with alprazolam, all GABAkines induced significant levels of mild sedation ("rest/sleep posture"). Deep sedation was observed with alprazolam, MP-III-80, and MP-III-22; motoric effects (observable ataxia) were obtained with alprazolam, KRM-II-81, and MP-III-22 only. Surprisingly, the order of potency for rest/sleep posture was significantly associated only with potency at α5GABA_A subtypes.

Conclusions: GABAkines with preferential efficacy at α2/α3GABA_A and/or α5GABA_A subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABA_A activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABA_A subtype in this milder form of sedation.