Steensland Pia, Simms Jeffrey A, Holgate Joan, Richards Jemma K, Bartlett Selena E
Ernest Gallo Clinic and Research Center, University of California, San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA.
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12518-23. doi: 10.1073/pnas.0705368104. Epub 2007 Jul 11.
Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.
酒精依赖是一种影响全球数百万人的疾病。在针对酒精依赖个体的药物治疗方面已经取得了一些进展；然而，仍然迫切需要开发新的和更多的治疗方法。酒精和尼古丁经常被同时滥用，并且有证据表明神经元烟碱型乙酰胆碱受体（nAChRs）在酒精和尼古丁依赖中都起作用。伐尼克兰是α4β2 nAChRs的部分激动剂，可减少尼古丁摄入量，最近被批准作为戒烟辅助药物。我们使用三种不同的饮酒动物模型研究了伐尼克兰在调节乙醇消耗和觅酒行为中的作用。我们发现，以据报道可减少尼古丁奖赏的剂量急性给予伐尼克兰，使用操作性自我给药饮酒范式可选择性地减少乙醇觅求，但不减少蔗糖觅求，并且在伐尼克兰治疗前长期暴露于乙醇2个月的动物中，也可减少自愿性乙醇消耗，但不减少水的消耗。此外，长期给予伐尼克兰可减少乙醇消耗，在停止给予伐尼克兰后，乙醇摄入量不会出现反弹增加。数据表明，α4β2 nAChRs可能在长期暴露于乙醇的动物的乙醇觅求行为中起作用。伐尼克兰在降低乙醇消耗方面的选择性，以及其在人类中已报道的安全性和轻微副作用表明，伐尼克兰可能被证明是一种治疗酒精依赖的药物。
