Neuronal nicotine acetylcholine receptors and the response to alcohol

描述（由申请人提供）：酗酒与严重的短期和长期健康问题有关，包括判断力受损，情绪波动和心脏病。经常暴饮暴食的重度酒精使用者对酒精表现出更高的兴奋和奖励反应。因此，了解酒精奖励和狂饮的分子基础，应该会导致识别新的分子靶点，用于减少酒精消耗的治疗。像尼古丁和其他滥用药物一样，酒精会激活腹侧被盖区（VTA）的多巴胺能（DA能）神经元，最终导致丘脑核（NAc）中多巴胺（DA）浓度的增加，这一现象与药物的奖励或强化特性广泛相关。此前，利用A 通过神经元烟碱乙酰胆碱受体（nAChR）小鼠模型、药理学、行为测定和电生理学的组合，我们确定先前发现在引发尼古丁依赖中至关重要的含有α 4亚基的nAChR（表示为“α 4 * nAChR”）也涉及乙醇和狂饮的奖励性质。基于以前的研究，我们将测试的假设，a4 * nAChRs，特别是在腹侧被盖区（VTA）有助于酒精奖励，消费和酒精介导的激活VTA多巴胺能（DA能）神经元。将通过经由病毒介导的基因递送在α 4敲除（KO）小鼠的VTA中特异性地重新表达α 4 nAChR亚基并测量与对照KO小鼠相比的酒精奖赏、狂饮和酒精介导的VTA DA能神经元的活化来测试该假设。此外，对激动剂过敏的α 4亚基将在腹侧被盖区内的不同神经元亚群中选择性表达，以确定腹侧被盖区微回路内的nAChR表达如何影响酒精奖励和急性消耗。在目标2中，我们将使用分子和生物物理学方法来测试的假设，乙醇介导的DA能腹侧被盖区神经元的激活也涉及nAChRs，含有α 6亚基。最后，目标3将使用小鼠遗传学和药理学的组合来确定alpha6* nAChRs如何参与酒精奖励和消费。预计这些实验的结果将对酒精奖励和酗酒的分子基础产生有价值的见解，并确定戒酒治疗的潜在目标。

DESCRIPTION (provided by applicant): Binge drinking is associated with significant short- and long-term health problems including impaired judgment, mood swings, and heart disease. Heavy alcohol users who frequently binge drink exhibit increased stimulant and rewarding responses to alcohol. Thus, understanding the molecular bases of alcohol reward and binge drinking should lead to identification of novel molecular targets for therapeutics designed to decrease alcohol consumption. Like nicotine and other drugs of abuse, alcohol activates dopaminergic (DAergic) neurons in the ventral tegmental area (VTA), which ultimately yields an increase in dopamine (DA) concentrations in the nucleus accumbens (NAc), a phenomenon widely associated with the rewarding or reinforcing properties of the drug. Previously, utilizing a combination of neuronal nicotinic acetylcholine receptor (nAChR) mouse models, pharmacology, behavioral assays, and electrophysiology, we determined that nAChRs containing the alpha4 subunit (denoted "alpha4* nAChRs"), previously found to be paramount in initiating nicotine dependence, are also involved in the rewarding properties of ethanol and binge drinking. Building upon previous studies, we will test the hypothesis that alpha4* nAChRs specifically in the ventral tegmental area (VTA) contribute to alcohol reward, consumption, and alcohol-mediated activation of VTA dopaminergic (DAergic) neurons. This hypothesis will be tested by re-expressing alpha4 nAChR subunits specifically in the VTA of alpha4 knock- out (KO) mice via viral-mediated gene delivery and measuring alcohol reward, binge drinking, and alcohol-mediated activation of VTA DAergic neurons compared to control KO mice. In addition, alpha4 subunits that are hypersensitive to agonist will be expressed selectively in distinct neuronal subpopulations within the VTA to determine how nAChR expression within VTA micro-circuitry affects alcohol reward and acute consumption. In aim 2, we will use molecular and biophysical approaches to test the hypothesis that ethanol-mediated activation of DAergic VTA neurons also involves nAChRs that contain the alpha6 subunit. Finally, aim 3 will determine how alpha6* nAChRs are involved in alcohol reward and consumption using a combination of mouse genetics and pharmacology. It is anticipated that the results from these experiments will yield valuable insight into the molecular underpinnings of alcohol reward and binge drinking, as well as identify potential targets for alcohol cessation therapeutics.