Nicotinic acetylcholine receptor function in the mesolimbic dopamine system

描述(由申请人提供)：烟草成瘾在美国和国外是对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，它激活和/或减敏整个大脑的烟碱型乙酰胆碱受体(NAChRs)。在啮齿动物模型中，中脑边缘多巴胺(DA)通路中的nAChRs对于尼古丁的奖赏和增强特性至关重要，这表明它们可能是尼古丁在人类中作用的关键介质。虽然已知α4和α6 nAChR亚基是中脑边缘DA途径nAChRs的重要组成部分，但这一通路中对尼古丁奖赏充分和/或必要的nAChRs的确切组成和/或化学计量仍不清楚。此外，尼古丁暴露后大脑中引起奖励行为的变化还知之甚少。这一提议将检验这样的假设，即在中脑边缘DA途径中激活α4alpha6beta2*(*表示nAChR五聚体中可能存在其他亚单位)nAChRs足以产生尼古丁的奖赏效应。证实或驳斥这一假说将导致进一步确定相关的nAChR亚型 中脑边缘DA通路，介导尼古丁的生物物理和/或行为效应。综合运用行为学、电生理学和生物化学技术，我们将以三个具体目标来阐述我们的假设。在特定的目标1中，我们将测试激活α4alpha6beta2*nAChRs足以产生尼古丁奖赏样行为的想法。使用表达对尼古丁超敏感的α6*nAChR的小鼠，同时使用一种对尼古丁具有适度功能选择性的化合物 α6α2*nAChRs，我们将确定这些受体的选择性激活是否足以引起尼古丁CPP。在具体目标2中，我们将使用膜片钳电生理学来验证刺激α4α6β2*nAChRs足以激活腹侧被盖区(VTA)DA神经元并加强对这些细胞的谷氨酸能输入的假设。在特定目标3中，我们直接测量了尼古丁暴露动物DA神经元中nAChR和谷氨酸受体功能的变化。建议的研究将加强我们对中脑边缘DA通路中与尼古丁成瘾有关的关键nAChRs的理解。确定足以产生尼古丁奖赏的nAChRs应该会导致开发新的戒烟疗法的更合理和更有针对性的努力。

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.