Effects of nicotine and varenicline on ethanol behaviors

说明（由申请人提供）：在烟草制品中发现的酒精和尼古丁是两种最常用的精神活性物质，它们的过度使用仍然是可预防的死亡原因清单的首位。流行病学研究一直发现，烟草和酒精的共同滥用率非常高，但目前尚不清楚尼古丁的作用是如何影响使用乙醇的倾向的，反之亦然。对这两种药物共同滥用的一种解释是，尼古丁乙酰胆碱受体（nAChR）可能代表乙醇和尼古丁的共同作用部位。这些药物的组合可能会增强单独使用任何一种药物所产生的奖励效应。我们的初步和已发表的数据表明，非选择性nAChR拮抗剂甲胺能减弱对乙醇的运动刺激，而尼古丁能增强对乙醇的运动刺激。该领域的研究还表明，尼古丁和乙醇可以相互作用，导致伏隔核（NACC）多巴胺水平的协同增强，表明尼古丁可能增强乙醇的奖励作用，并有助于依赖性的发展。单独使用乙醇对神经系统的长期影响可能与尼古丁加乙醇截然不同。该提案的第一个目标是确定尼古丁是否增强了两种与酒精相关的行为的发展：条件位置偏好（CPP）和行为敏感化（一种神经适应的测量）。此外，我们建议采用放射自显影法测量nAChR结合，RT-PCR检测慢性尼古丁、乙醇和联合药物暴露小鼠烟碱受体基因mRNA表达。我们假设尼古丁会增强乙醇的奖励作用，并在行为和nAChR水平上引起神经适应，从而导致这两种药物的高合并症使用。本提案的第二个目标是确定nAChR的药理学操作是否会改变乙醇的奖励和神经适应性作用。治疗酒精和尼古丁依赖的有效药物数量有限。一个初步但有希望的发现是，fda批准的戒烟药物varenicline (Chantix)，一种部分nAChR激动剂，可以减少啮齿动物和人类的乙醇消耗量。尽管研究表明，伐尼克兰可以减少乙醇消耗，但关于伐尼克兰如何影响用于测量乙醇奖励效应的其他行为的研究有限。伐尼克兰可能通过降低乙醇的奖励效应来影响乙醇的消耗；然而，伐尼克兰也可以增加乙醇的奖励效果，并将剂量反应曲线向左移动，减少达到相同奖励水平所需的酒精量。因此，更严格地评估伐尼克兰对其他乙醇相关行为的影响是很重要的；在这种情况下

DESCRIPTION (provided by applicant): Alcohol and nicotine, found in tobacco products, are two of the most commonly used psychoactive substances and their excessive use remains at the top of the list of preventable causes of death. Epidemiological studies have consistently found tobacco and alcohol to have a very high rate of co-abuse, but it remains unclear precisely how the actions of nicotine affect the propensity to use ethanol and vice versa. One explanation for the co-abuse of these two drugs is that nicotinic acetylcholine receptors (nAChR) may represent a common site of action for ethanol and nicotine. The combination of these drugs may potentiate the rewarding effects produced by either drug alone. Our preliminary and published data have shown that the non-selective nAChR antagonist mecamylamine attenuates, while nicotine enhances, locomotor stimulation to ethanol in mice selectively bred for high locomotor stimulation to ethanol. Research in the field has also demonstrated that nicotine and ethanol can interact to cause synergist enhancement of dopamine levels in the nucleus accumbens (NACC), indicating that nicotine may enhance the rewarding effects of ethanol and contribute to the development of dependence. Long term neural effects of ethanol alone may be profoundly different from those of nicotine plus ethanol. The first goal of this proposal is to determine if nicotine potentiates the development of two ethanol-related behaviors: conditioned place preference (CPP) and behavioral sensitization (a measure of neuroadaptation). In addition, we propose to use autoradiography to measure binding at nAChR and RT-PCR to measure mRNA expression of nicotinic receptor genes in mice treated with chronic nicotine, ethanol and combined drug exposure. We hypothesize that nicotine will enhance the rewarding effects of ethanol and cause neuroadaptations at the level of behavior and nAChR that contribute to the high rate of comorbid use of these two drugs. The second goal of this proposal is to determine if pharmacological manipulation of nAChR alters the rewarding and neuroadaptive effects of ethanol. There are a limited number of effective pharmacological agents to treat alcohol and nicotine dependence. One preliminary but promising finding is that the FDA-approved smoking cessation drug varenicline (Chantix), a partial ¿4¿2 nAChR agonist, decreased ethanol consumption in both rodents and humans. Although research indicates that varenicline reduces ethanol consumption, there is limited research focused on how varenicline affects other behaviors used to measure the rewarding effects of ethanol. Varenicline could influence ethanol consumption by reducing the rewarding effects of ethanol; however, varenicline could also increase the rewarding effects of ethanol and shift the dose response curve to the left, reducing the amount of alcohol needed to achieve the same level of reward. Thus, it is important to more critically evaluate the effects of varenicline on other ethanol- related behaviors; in this case we will examine CPP and behavioral sensitization. This will provide a better understanding of how to use this drug in a clinical setting for the treatment of alcohol dependence. PUBLIC HEALTH RELEVANCE: Alcohol and nicotine are two of the most commonly used psychoactive substances and their excessive use remains at the top of the list of preventable causes of death. The proposed work seeks to examine how nicotine and nAChR affect the development of ethanol-related behaviors that are associated with ethanol reward and neuroadaptation in an effort to understand why these two drugs share a high rate of co-abuse. Ultimately, the goal of this research is to understand the biological factors underlying alcohol and co-morbid nicotine dependence and to further evaluate one putative pharmaceutical treatment option, varenicline.