Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB-114, La Jolla, CA, 92037, USA.
Department of Biomedical Sciences, University of Cagliari, (CA), I-09042, Monserrato, Italy.
Psychopharmacology (Berl). 2022 Jan;239(1):201-213. doi: 10.1007/s00213-021-06022-3. Epub 2021 Nov 23.
Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABA receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD. Recently, we demonstrated that COR659, a novel GABA PAM, effectively reduced (i) alcohol drinking under the 2-bottle choice regimen, (ii) alcohol self-administration under both fixed and progressive ratio schedules of reinforcement, and (iii) cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats.
The present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents.
COR659 was tested on the "drinking in the dark" (DID) paradigm in C57BL/6J mice and the 4-bottle "alcohol [10%, 20%, 30% (v/v)] versus water" choice regimen with limited and unpredictable access to alcohol in sP rats.
Acute administration of non-sedative doses of COR659 (10, 20, and 40 mg/kg; i.p.) effectively and selectively suppressed the intake of intoxicating amounts of alcohol (> 2 g/kg) consumed by C57BL/6J mice and sP rats exposed to these binge-like drinking experimental procedures.
The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABA PAMs may represent a potentially effective pharmacotherapy for alcohol misuse.
狂饮（BD）是一种广泛存在的饮酒模式，可能导致酒精使用障碍（AUD）的发展。理解其神经生物学基础和确定可能预防 BD 的分子是至关重要的。临床前研究表明，GABA 受体的正变构调节剂（PAMs）有效地减少了，偶尔抑制了，在啮齿动物中，酒精的强化和动机特性，表明它们作为 AUD 的潜在药物治疗的潜在用途，包括 BD。最近，我们证明了 COR659，一种新型 GABA PAM，有效地减少了（i）在 2 瓶选择方案下的饮酒，（ii）在固定和递增比率强化方案下的酒精自我给药，以及（iii）在撒丁岛酒精偏好（sP）大鼠中，线索诱导的酒精寻求行为的复燃。
本研究调查了 COR659 的“抗酒精”特性是否扩展到啮齿动物的 binge-like 饮酒。
在 C57BL/6J 小鼠的“暗饮”（DID）范式和 sP 大鼠的 4 瓶“酒精[10%、20%、30%（v/v）]与水”选择方案中，测试了 COR659 的作用，该方案对酒精的限制和不可预测的获取。
非镇静剂量的 COR659（10、20 和 40mg/kg；ip）的急性给药有效地和选择性地抑制了 C57BL/6J 小鼠和暴露于这些 binge-like 饮酒实验程序的 sP 大鼠摄入的中毒量的酒精（>2g/kg）的摄入。
本研究数据表明 COR659 有能力抑制啮齿动物的 binge-like 饮酒，并加强了 GABA PAMs 可能代表一种有效的酒精滥用药物治疗的假说。
