Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
Addict Biol. 2021 Mar;26(2):e12908. doi: 10.1111/adb.12908. Epub 2020 Apr 24.
The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist and desensitizer, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating this region in mediating the effects of sazetidine-A. Furthermore, the sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pretreated with sazetidine-A, alcohol induced Fos transcript in Th-, but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A enhances the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.
在过去的 30 年中，美国酗酒障碍（AUD）的患病率稳步上升。酒精作用于多个受体系统，包括尼古丁乙酰胆碱受体（nAChR），已知其介导酒精消费和奖励。我们之前报道过，临床前药物 sazetidine-A 是一种 nAChR 激动剂和脱敏剂，可减少酒精消耗，而不影响 C57BL/6J 小鼠对尼古丁的消耗。在这里，我们发现 sazetidine-A 增强了对酒精的厌恶表达，而不影响 C57BL/6J 小鼠条件性酒精奖励的表达或获得。将 sazetidine-A 注射到腹侧中脑靶向腹侧被盖区（VTA）减少了 binge 酒精消耗，表明该区域介导了 sazetidine-A 的作用。此外，sazetidine-A 诱导的酒精消耗减少是由非-α4 包含的 nAChR 介导的，因为 sazetidine-A 减少了α4 敲除和野生型小鼠的 binge 酒精消耗。最后，我们发现，在预先用 sazetidine-A 处理的小鼠中，与 Gad2 表达神经元相比，酒精诱导了 VTA 中 Th-表达神经元中的 Fos 转录，如通过增加 Fos 转录表达来测量。总之，我们发现 sazetidine-A 增强了对酒精的厌恶表达，这可能是 sazetidine-A 诱导酒精消耗减少的基础。阐明在酒精厌恶机制中非-α4 nAChR 的身份将更好地理解 nAChR 在酒精成瘾中的复杂作用，并可能揭示治疗 AUD 的新药物靶点。
