Sharma Rishi, Sahota Pradeep, Thakkar Mahesh M
Department of Neurology, Harry S. Truman Memorial Veterans Hospital, University of Missouri, Columbia, Missouri.
Alcohol Clin Exp Res. 2014 May;38(5):1315-20. doi: 10.1111/acer.12353. Epub 2014 Feb 11.
Alcohol and nicotine are the most commonly abused drugs. The frequent co-morbidity of alcohol and nicotine addiction has led to the hypothesis that they may act via a common substrate: the nicotinic acetylcholine receptors (nAChRs) especially α4β2 and α7 subtypes, the most prevalent nAChRs in the brain. Compelling evidence suggests that alcohol enhances the function of α4β2 subtype. The FDA approved smoking cessation drug, varenicline ("Chantix"), a partial agonist of α4β2 nAChR subtype, reduces alcohol self-administration and alcohol craving in humans and rodents. The cholinergic basal forebrain (BF) controls various functions including arousal, attention, and cognition, and there is a predominance of α4β2 and α7 subtypes. We have shown that the BF has an important role in mediating the effects of alcohol and local infusion of nicotine in the BF activates nucleus accumbens. Does BF have any role in mediating the effect of nicotine on alcohol consumption? This study was designed to address this question.
Under standard surgical procedure, C57BL/6J mice were stereotaxically implanted with bilateral stainless steel guide cannula above the BF. Following post operative recovery and habituation, the animals were exposed to the "drinking-in-the-dark" paradigm whereby alcohol (20%) was presented for 2 hours daily for 3 days. On the fourth day, nicotine or artificial cerebrospinal fluid (ACSF) was microinjected bilaterally in the BF. After 1 hour, mice were exposed to alcohol and allowed to self-administer for 4 hours. The effect of BF nicotine infusion on sucrose consumption was also examined. On completion, mice were euthanized, brain removed and processed to localize the BF injection sites.
As compared with the ACSF, bilateral nicotine injections into the BF significantly (p < 0.05; n = 5/group) increased alcohol consumption. Sucrose consumption remained unaffected.
Based on our results, we believe that the BF may have an important role in nicotine-alcohol co-use.
酒精和尼古丁是最常被滥用的药物。酒精成瘾和尼古丁成瘾经常合并出现，这引发了一种假说，即它们可能通过共同的底物发挥作用：烟碱型乙酰胆碱受体（nAChRs），尤其是α4β2和α7亚型，它们是大脑中最普遍的nAChRs。有力证据表明，酒精可增强α4β2亚型的功能。美国食品药品监督管理局（FDA）批准的戒烟药物伐尼克兰（“畅沛”），是α4β2 nAChR亚型的部分激动剂，可减少人类和啮齿动物的酒精自我给药及对酒精的渴望。胆碱能基底前脑（BF）控制包括觉醒、注意力和认知在内的各种功能，且α4β2和α7亚型占主导。我们已经表明，BF在介导酒精的作用中起重要作用，并且在BF局部注射尼古丁可激活伏隔核。BF在介导尼古丁对酒精消费的影响中是否起任何作用？本研究旨在解决这个问题。
在标准手术程序下，将C57BL/6J小鼠立体定位植入双侧不锈钢引导套管，置于BF上方。术后恢复和适应后，使动物暴露于“黑暗中饮酒”范式，即每天提供20%的酒精2小时，持续3天。在第四天，将尼古丁或人工脑脊液（ACSF）双侧微量注射到BF中。1小时后，使小鼠接触酒精并允许其自我给药4小时。还检查了BF注射尼古丁对蔗糖消费的影响。实验结束后，对小鼠实施安乐死，取出大脑并进行处理以定位BF注射部位。
与ACSF相比，双侧向BF注射尼古丁显著（p < 0.05；每组n = 5）增加了酒精消费。蔗糖消费未受影响。
基于我们的结果，我们认为BF可能在尼古丁与酒精共同使用中起重要作用。
