Effects of nicotine and varenicline on ethanol behaviors

说明(申请人提供)：在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，过度使用它们仍然是可预防的死因清单的首位。流行病学研究一直发现，烟草和酒精的共同滥用比率非常高，但目前尚不清楚尼古丁的行为如何影响使用乙醇的倾向，反之亦然。对这两种药物共同滥用的一种解释是烟碱型乙酰胆碱受体(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其中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Mecamylamine减弱了对乙醇的运动刺激，而尼古丁则增强了对乙醇的运动刺激，这些小鼠是为对乙醇的高运动刺激而选择性繁殖的。该领域的研究还表明，尼古丁和乙醇可以相互作用，导致伏核(NACC)中多巴胺水平的协同增强，表明尼古丁可能增强了乙醇的奖赏效应，有助于依赖的发展。酒精单独的长期神经效应可能与尼古丁加乙醇的神经效应有很大的不同。这项建议的第一个目标是确定尼古丁是否促进了两种与酒精相关的行为的发展：条件性位置偏爱(CPP)和行为敏化(神经适应的一种衡量标准)。此外，我们建议使用放射自显影术来测量nAChR的结合，并使用RT-PCR来测量慢性尼古丁、乙醇和联合药物暴露的小鼠的尼古丁受体基因的mRNA表达。我们假设尼古丁将增强乙醇的奖赏效应，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混合使用率。这项建议的第二个目标是确定nAChR的药理操作是否改变了乙醇的奖赏和神经适应效应。治疗酒精和尼古丁依赖的有效药理药物数量有限。一个初步但有希望的发现是，FDA批准的戒烟药物varenicline(Chantix)是一种部分nAChR激动剂，可以减少啮齿动物和人类的乙醇消耗。尽管研究表明，varenicline减少了乙醇的消耗，但关于varenicline如何影响用于衡量乙醇的回报效应的其他行为的研究有限。Varenicline可以通过减少乙醇的奖赏效应来影响乙醇的消耗；然而，varenicline也可以增加乙醇的奖赏效应，并将剂量反应曲线左移，从而减少达到相同水平的奖赏所需的酒精量。因此，更严格地评估varenicline对其他酒精相关行为的影响是很重要的；在这种情况下，我们 将检查CPP和行为敏感化。这将使人们更好地了解如何在临床环境中使用这种药物来治疗酒精依赖。

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.