Nicotinic acetylcholine receptor function in the mesolimbic dopamine system

描述（由申请人提供）：烟草成瘾是对美国和国外公共健康的严重威胁，开发新的治疗方法是一个主要的优先事项。尼古丁是香烟烟雾中的主要精神活性化合物，可激活和/或脱敏整个大脑中的烟碱乙酰胆碱受体（nAChR）。中脑边缘多巴胺（DA）通路中的nAChR对于啮齿动物模型中尼古丁的奖励和强化特性至关重要，这表明它们可能是尼古丁在人体中作用的关键介质。虽然已知α 4和α 6 nAChR亚基是中脑边缘DA途径nAChR的重要组分，但该途径中对于尼古丁奖赏足够和/或必需的nAChR的精确组成和/或化学计量仍然未知。此外，人们对尼古丁暴露后大脑中引起奖励行为的变化知之甚少。该提议将检验以下假设：中脑边缘DA通路中的α 4 α 6 β 2 *（* 表示nAChR五聚体中可能存在其他亚基）nAChR的激活足以实现尼古丁的奖励效应。证实或反驳这一假设将导致进一步鉴定相关的nAChR亚型， 介导尼古丁的生物物理和/或行为效应的中脑边缘DA通路。使用行为，电生理和生物化学技术的组合，我们将解决我们的假设有三个具体的目标。在具体目标1中，我们将测试α 4 α 6 β 2 * nAChR的激活足以产生尼古丁奖励样行为的想法。使用表达对尼古丁过敏的α 6 * nAChR的小鼠，与对尼古丁具有适度功能选择性的化合物平行， α6α2* nAChR，我们将确定这些受体的选择性激活是否足以产生尼古丁CPP。在具体目标2中，我们将使用膜片钳电生理学来测试以下假设：刺激α 4 α 6 β 2 * nAChRs足以激活腹侧被盖区（VTA）DA神经元并加强对这些细胞的多巴胺能输入。在具体目标3中，我们直接测量了暴露于尼古丁的动物DA神经元中nAChR和多巴胺能受体功能的变化。拟议的研究将加强我们对参与尼古丁成瘾的中脑边缘DA通路中的关键nAChRs的理解。确定足够尼古丁奖励的nAChR应该会导致更理性和集中的努力来开发新的戒烟疗法。

DESCRIPTION (provided by applicant): Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine, the primary psychoactive compound in cigarette smoke, activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in the mesolimbic dopamine (DA) pathway are crucial for the rewarding and reinforcing properties of nicotine in rodent models, suggesting that they may be key mediators of nicotine's action in humans. Although it is known that alpha4 and alpha6 nAChR subunits are important components of mesolimbic DA pathway nAChRs, the precise composition and/or stoichiometry of nAChRs in this pathway that are sufficient and/or necessary for nicotine reward remains unknown. Furthermore, the changes in the brain following nicotine exposure that give rise to reward behavior are poorly understood. This proposal will test the hypothesis that activation of alpha4alpha6beta2* (*denotes that other subunits may be present in the nAChR pentamer) nAChRs in the mesolimbic DA pathway is sufficient for nicotine's rewarding effects. Confirming or refuting this hypothesis will result in further identification of the relevant nAChR subtypes in the mesolimbic DA pathway that mediate nicotine's biophysical and/or behavioral effects. Using a combination of behavioral, electrophysiological, and biochemical techniques, we will address our hypothesis with three specific aims. In Specific Aim 1, we will test the idea that activation o alpha4alpha6beta2* nAChRs is sufficient for nicotine reward-like behavior. Using mice which express alpha6* nAChRs that are hypersensitive to nicotine, in parallel with a compound with modest functional selectivity for α6α2* nAChRs, we will determine whether selective activation of these receptors is sufficient for nicotine CPP. In Specific Aim 2, we will use patch clamp electrophysiology to test the hypothesis that stimulation of alpha4alpha6beta2* nAChRs is sufficient to activate ventral tegmental area (VTA) DA neurons and strengthen glutamatergic input to these cells. In Specific Aim 3, we directly measure changes in nAChR and glutamatergic receptor function in DA neurons from animals exposed to nicotine. The proposed studies will enhance our understanding of the key nAChRs in the mesolimbic DA pathway that are involved in nicotine addiction. Identifying the nAChRs that are sufficient for nicotine reward should lead to a more rational and focused effort to develop new smoking cessation therapeutics.