Effects of nicotine and varenicline on ethanol behaviors

描述（由申请人提供）：烟草产品中发现的酒精和尼古丁是两种最常用的精神活性物质，其过度使用仍然是可预防的死亡原因之首。流行病学研究一直发现烟草和酒精的共同滥用率非常高，但仍然不清楚尼古丁的作用如何影响使用乙醇的倾向，反之亦然。这两种药物共同滥用的一种解释是，烟碱乙酰胆碱受体（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加强任何一种药物单独产生的奖励作用。我们的初步和已发表的数据表明，非选择性nAChR拮抗剂美加明减弱，而尼古丁增强，在小鼠中选择性繁殖的高运动刺激乙醇的运动刺激。该领域的研究还表明，尼古丁和乙醇可以相互作用，导致丘脑神经核（NACC）中多巴胺水平的显著提高，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。单独使用乙醇的长期神经效应可能与尼古丁加乙醇的长期神经效应截然不同。该提案的第一个目标是确定尼古丁是否会增强两种乙醇相关行为的发展：条件性位置偏好（CPP）和行为敏感化（神经适应的一种措施）。此外，我们建议使用放射自显影法来测量结合在nAChR和RT-PCR来测量尼古丁受体基因的mRNA表达与慢性尼古丁，乙醇和联合药物暴露治疗的小鼠。我们假设尼古丁将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共病率。该建议的第二个目标是确定是否药理学操纵nAChR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<$4 <$2 nAChR激动剂，减少了啮齿动物和人类的乙醇消耗。虽然研究表明伐尼克兰减少了乙醇的消耗，但关于伐尼克兰如何影响其他用于衡量乙醇奖励效果的行为的研究有限。伐尼克兰可以通过减少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应，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，重要的是更严格地评估伐尼克兰对其他乙醇相关行为的影响;在这种情况下，我们 将检查CPP和行为敏感性。这将使人们更好地了解如何在临床环境中使用这种药物治疗酒精依赖。 公共卫生相关性：酒精和尼古丁是两种最常用的精神活性物质，其过度使用仍然是可预防的死亡原因之首。这项拟议的工作旨在研究尼古丁和nAChR如何影响与乙醇奖励和神经适应相关的乙醇相关行为的发展，以了解为什么这两种药物的共同滥用率很高。最终，本研究的目标是了解酒精和共病尼古丁依赖的生物学因素，并进一步评估一种公认的药物治疗选择，伐尼克兰。

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.