Neuronal nicotinic acetylcholine receptors and the response to alcohol

描述（由申请人提供）：尼古丁和乙醇是世界上最常被滥用的两种药物，据估计，50-90%的酗酒者吸烟，这表明尼古丁（烟草烟雾的主要成瘾成分）和乙醇在参与成瘾的多巴胺能脑区之间存在功能相互作用。神经元尼古丁乙酰胆碱受体（nAChR）是尼古丁的分子靶点，与乙醇的增强特性有关，但是，尽管存在这种关联，介导这些作用的特定nAChR亚型尚不清楚。本提案的目的是利用尼古丁受体小鼠模型、药理学、行为分析和电生理学的组合来验证假设，即先前发现的在启动尼古丁依赖中起重要作用的14* nachr也参与对乙醇的生理和行为反应，以及尼古丁和乙醇的交叉依赖特性。小鼠模型要么不表达高亲和力的14* nachr，要么表达对激动剂敏感50倍的超敏感14*烟碱受体，将被用来验证这些受体的激活对乙醇消耗、偏好和奖励至关重要的假设。此外，我们将通过测量慢性尼古丁治疗后的乙醇消耗、偏好和奖励，来验证14* nachr是尼古丁-乙醇交叉耐受所必需的假设，因为它与酒精自我给药有关。在目标3中，我们将使用生物物理方法来验证乙醇对尼古丁反应和多巴胺能VTA中脑神经元兴奋性的调节依赖于14* nAChR的表达和激活的假设。预计这些实验的结果将对酒精依赖的生物学产生有价值的见解，并确定戒酒治疗的潜在目标。尼古丁和酒精是世界上最广泛滥用的两种药物，这表明尼古丁（烟草烟雾的主要成瘾成分）和乙醇之间存在功能上的相互作用。该项目的目标是了解这两种药物在分子、神经元和行为水平上的潜在功能相互作用。从这个项目中获得的见解应该有助于确定戒酒治疗的分子靶点。

DESCRIPTION (provided by applicant): Nicotine and ethanol are the two most co-abused drugs in the world and it is estimated that 50-90% of alcoholics smoke cigarettes suggesting a functional interaction exists between nicotine, the primary addictive component of tobacco smoke, and ethanol, in dopaminergic brain areas involved in addiction. Neuronal nicotinic acetylcholine receptors (nAChRs), the molecular targets of nicotine, have been implicated in the reinforcing properties of ethanol, but, despite this association, the specific nAChR subtypes mediating these effects are unknown. The goal of this proposal is to utilize a combination of nicotinic receptor mouse models, pharmacology, behavioral assays, and electrophysiology to test the hypothesis that 14* nAChRs, previously found to be paramount in initiating nicotine dependence, are also involved in the physiological and behavioral response to ethanol, and the cross-dependent properties of nicotine and ethanol. Mouse models that either do not express high affinity 14* nAChRs, or that express hypersensitive 14* nicotinic receptors 50-fold more sensitive to agonist, will be utilized to test the hypothesis that activation of these receptors is critical for ethanol consumption, preference, and reward. In addition, we will test the hypothesis that 14* nAChRs are necessary for nicotine-ethanol cross-tolerance as it pertains to alcohol self-administration by measuring ethanol consumption, preference, and reward after chronic nicotine treatment in these mouse lines. In aim 3, we will use a biophysical approach to test the hypothesis that ethanol modulation of nicotinic responses and excitability of dopaminergic VTA midbrain neurons is dependent on 14* nAChR expression and activation. It is anticipated that the results from these experiments will yield valuable insight into the biology of alcohol dependence, as well as identify potential targets for alcohol cessation therapeutics. PUBLIC HEALTH RELEVANCE Nicotine and alcohol are the two most widely co-abused drugs in the world suggesting that there is a functional interaction between nicotine, the primary addictive component of tobacco smoke, and ethanol. The goal of the proposed project is to understand the underlying functional interaction between these two drugs on a molecular, neuronal, and behavioral level. The insights gained from this project should help identify molecular targets for alcohol cessation therapeutics.