Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
Department of Psychiatry and Human Behavior, Center for Innovation and Discovery in Addictions, University of Mississippi Medical Center, Jackson, MS, USA.
J Psychopharmacol. 2024 Dec;38(12):1157-1169. doi: 10.1177/02698811241286760. Epub 2024 Oct 9.
Benzodiazepines bind to γ-aminobutyric acid type A (GABA) receptor subtypes identified by different α subunits (i.e., α1GABA, α2GABA, α3GABA, and α5GABA). Sedative-motor effects of benzodiazepines are thought to involve α1GABA and α3GABA subtypes.
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 receptors), with varying degrees of selective efficacy at different GABA receptor subtypes. We predicted that the induction of sedative-motor effects would depend on the degree of α1GABA and α3GABA efficacy.
Adult female rhesus monkeys ( = 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 subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABA subtypes), and MP-III-22 (preferential potency and efficacy for α5GABA subtypes).
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 subtypes.
GABAkines with preferential efficacy at α2/α3GABA and/or α5GABA subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABA 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 subtype in this milder form of sedation.
苯二氮䓬类药物与不同 α 亚基（即 α1GABA、α2GABA、α3GABA 和 α5GABA）鉴定的γ-氨基丁酸 A 型（GABA）受体亚型结合。苯二氮䓬类药物的镇静-运动效应被认为涉及 α1GABA 和 α3GABA 亚型。
我们评估了新型 GABAkin（GABA 受体的正变构调节剂）在猴子中的急性给药后的镇静-运动效应的可观察指标和种属典型行为，这些药物在不同 GABA 受体亚型上具有不同程度的选择性疗效。我们预测，诱导镇静-运动效应将取决于 α1GABA 和 α3GABA 疗效的程度。
成年雌性恒河猴（n=4）植入了慢性留置静脉内导管。在给予多种剂量的常规苯二氮䓬类药物阿普唑仑和 GABAkin MP-III-80（对 α2/α3/α5GABA 亚型具有优先疗效）、KRM-II-81、MP-III-24（对 α2/α3GABA 亚型均具有优先疗效）和 MP-III-22（对 α5GABA 亚型具有优先效力和疗效）后，由经过培训的观察者进行定量行为观察。
与阿普唑仑一样，所有 GABAkin 均引起明显程度的轻度镇静（“休息/睡眠姿势”）。阿普唑仑、MP-III-80 和 MP-III-22 引起深度镇静；仅在阿普唑仑、KRM-II-81 和 MP-III-22 中观察到运动效应（可观察到共济失调）。令人惊讶的是，休息/睡眠姿势的效力顺序仅与 α5GABA 亚型的效力显著相关。
具有对 α2/α3GABA 和/或 α5GABA 亚型优先疗效的 GABAkin 在猴子中产生镇静-运动效应，尽管只有具有 α5GABA 活性的化合物才引起深度镇静。此外，在体外电生理学数据和休息/睡眠姿势测量中获得的效力之间的显著关系表明 α5GABA 亚型在这种较轻形式的镇静中起作用。
