Neuronal nicotinic acetylcholine receptors and the response to alcohol

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 酗酒者吸烟表明尼古丁、主要成分尼古丁之间存在功能性相互作用 烟草烟雾的成瘾成分，以及酒精，在参与成瘾的多巴胺能脑区。 尼古丁的分子靶标神经元烟碱乙酰胆碱受体(NAChRs)已经被认为是 与乙醇的增强特性有关，但尽管存在这种联系，特定的nAChR 调节这些影响的亚型尚不清楚。该提案的目标是利用以下各项的组合 尼古丁受体小鼠模型，药理学，行为分析和电生理学，以测试 假设之前发现的4*nAChRs在引发尼古丁依赖方面起着至关重要的作用 还参与了对酒精的生理和行为反应，并交叉依赖 尼古丁和乙醇的性质。不表达高亲和力的4*nAChRs的小鼠模型， 或者表达对激动剂敏感度高50倍的尼古丁受体，将被用于 验证以下假设：这些受体的激活对酒精的消费、偏好和 奖励。此外，我们还将检验4*nAChRs对尼古丁-乙醇是必需的假设 交叉耐受性，因为它与酒精自我给药有关，通过测量乙醇消耗， 这些小鼠在长期尼古丁治疗后的喜好和奖励。在目标3中，我们将使用 用生物物理方法检验酒精对尼古丁反应和 多巴胺能VTA中脑神经元的兴奋性依赖于4*nAChR的表达和 激活。预计这些实验的结果将对 酒精依赖的生物学研究，以及确定酒精戒断疗法的潜在靶点。

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 ¿4* 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 ¿4* nAChRs, or that express hypersensitive ¿4* 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 ¿4* 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 ¿4* 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.