Work

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

Year: 2024

Type: article

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.

Source: Journal of Psychopharmacology

DOI: 10.1177/02698811241286760