Department of Psychology & TIMES, University of Houston, 4849 Calhoun Rd, Houston, TX, 77204-6022, USA.
Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, USA.
Psychopharmacology (Berl). 2021 Sep;238(9):2587-2600. doi: 10.1007/s00213-021-05881-0. Epub 2021 Jul 6.
Pre-clinical evidence implicates the GABAergic system in mediating the reinforcing effects of alcohol and offers a therapeutic target for alcohol use disorder (AUD). The orthosteric GABA receptor agonist baclofen decreases alcohol self-administration in animals and alcohol use in humans; however side effects limit its utility. Pre-clinical evidence shows positive allosteric GABA receptor modulators also decrease alcohol self-administration without untoward side effects.
We assessed the impact of the novel GABA-positive allosteric modulator ASP8062 and baclofen on operant alcohol self-administration and their potential non-specific effects.
The effects of ASP8062 (1 - 10 mg/kg, PO) and baclofen (0.3 - 3 mg/kg, IP) were evaluated in male and female rats lever pressing for alcohol (10%, w/v) under a fixed ratio 2 schedule of reinforcement. On the fourth consecutive day of vehicle, ASP8062 or baclofen administration, active and inactive lever presses, reinforcers earned, head entries, and estimated alcohol consumed were analyzed. Locomotor activity was assessed in separate groups of rats following dosing.
Both ASP8062 and baclofen decreased alcohol self-administration and amount consumed (g/kg) in male and female rats. ASP8062 decreased operant alcohol self-administration to a greater extent in male rats, whereas baclofen was more efficacious in female rats. ASP8062 did not alter locomotor activity in either sex, whereas baclofen (3.0 mg/kg) decreased activity in male rats yet (1.0 mg/kg) increased activity in female rats.
ASP8062 decreases alcohol reinforcement like baclofen but without non-specific effects which are influenced by sex. Results support further development of ASP8062 as a potential treatment for AUD in humans.
临床前证据表明 GABA 能系统在介导酒精的强化作用中起作用，并为酒精使用障碍（AUD）提供了一个治疗靶点。 正位 GABA 受体激动剂巴氯芬可减少动物的酒精自我给药和人类的酒精使用；然而，副作用限制了其应用。 临床前证据表明，正位变构 GABA 受体调节剂也可减少酒精自我给药，而不会产生不良副作用。
我们评估了新型 GABA 正位变构调节剂 ASP8062 和巴氯芬对操作性酒精自我给药的影响及其潜在的非特异性作用。
在雄性和雌性大鼠中，评估了 ASP8062（1-10mg/kg，PO）和巴氯芬（0.3-3mg/kg，IP）对酒精（10%，w/v）进行按压的影响，操作条件为固定比率 2 强化方案。在连续第四天给予载体、ASP8062 或巴氯芬后，分析主动和被动按压杆、获得的强化物、头部进入和估计的酒精消耗量。在单独的大鼠组中评估了运动活动。
ASP8062 和巴氯芬均减少了雄性和雌性大鼠的酒精自我给药和消耗量（g/kg）。ASP8062 更能减少雄性大鼠的操作性酒精自我给药，而巴氯芬对雌性大鼠更有效。ASP8062 没有改变雄性和雌性大鼠的运动活动，而巴氯芬（3.0mg/kg）降低了雄性大鼠的活动，而（1.0mg/kg）增加了雌性大鼠的活动。
ASP8062 像巴氯芬一样减少酒精强化作用，但没有性别影响的非特异性作用。结果支持进一步开发 ASP8062 作为治疗人类 AUD 的潜在药物。
