Rationale

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_B 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_B receptor modulators also decrease alcohol self-administration without untoward side effects.

Objectives

We assessed the impact of the novel GABA_B-positive allosteric modulator ASP8062 and baclofen on operant alcohol self-administration and their potential non-specific effects.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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GABAB 受体正变构调节剂 ASP8062 减少雄性和雌性 Sprague Dawley 大鼠的操作性酒精自我给药

基本原理

临床前证据表明 GABA 能系统介导酒精的增强作用，并为酒精使用障碍 (AUD) 提供治疗靶点。正构 GABA _B受体激动剂巴氯芬可减少动物的酒精自我管理和人类的酒精使用；然而副作用限制了它的实用性。临床前证据表明，正变构 GABA _B受体调节剂还可以减少酒精自我给药，而不会产生不良副作用。

目标

我们评估了新型 GABA _B阳性变构调节剂 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。

方法

ASP8062 (1 - 10 mg/kg, PO) 和巴氯芬 (0.3 - 3 mg/kg, IP) 的影响在雄性和雌性大鼠杠杆压力下评估酒精 (10%, w/v) 固定比例 2强化时间表。在车辆连续第四天，ASP8062 或巴氯芬给药、活动和非活动杠杆按压、获得的强化物、头部条目和估计的酒精消耗量被分析。给药后在不同的大鼠组中评估运动活动。

结果

ASP8062 和巴氯芬都降低了雄性和雌性大鼠的酒精自我给药和消耗量 (g/kg)。ASP8062 在更大程度上减少了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 不会改变任何性别的运动活动，而巴氯芬 (3.0 mg/kg) 会降低雄性大鼠的活动，但 (1.0 mg/kg) 会增加雌性大鼠的活动。

结论

ASP8062 像巴氯芬一样减少酒精强化，但没有受性别影响的非特异性作用。结果支持进一步开发 ASP8062 作为人类 AUD 的潜在治疗方法。