Nicotinic acetylcholine receptor function in the mesolimbic dopamine system

中脑边缘多巴胺系统中烟碱乙酰胆碱受体的功能

基本信息

批准号：
8696030
负责人：
Ryan Michael Drenan
金额：
$ 33.79万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696030
关键词：
AMPA Receptors Address Alleles Animals Attenuated Behavior Behavioral Biochemical Biochemistry Brain Cell surface Cells Communities Complement Data Development Dopamine Drosophila acetylcholine receptor alpha-subunit Drug Targeting Electrophysiology (science)FDA approved Future Genetic Glutamates Goals Health Human Injection of therapeutic agent Lead Ligands Measures Mediating Mediator of activation protein Molecular Molecular Probes Mus Neurons Neurotransmitter Receptor Nicotine Nicotine Dependence Nicotinic Receptors Pathway interactions Pharmacology Plastics Property Psychological reinforcement Psychotropic Drugs Public Health Publishing Receptor Activation Rewards Rodent Model Role Signal Pathway Signal Transduction Slice Surface System Techniques Testing Therapeutic Tobacco Dependence Tobacco use United States Ventral Tegmental Area calmodulin-dependent protein kinase II cigarette smoking conditioning design dopaminergic neuron improved in vivo innovation insight loss of function mesolimbic system novel strategies novel therapeutic intervention novel therapeutics patch clamp preference public health relevance receptor receptor function research study response smoking cessation stoichiometry tool varenicline

项目摘要

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 ?6?2* 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.

描述（由申请人提供）：烟草成瘾对美国和国外的公共健康构成严重威胁，开发新的治疗方法是当务之急。尼古丁是香烟烟雾中的主要精神活性化合物，可激活整个大脑的烟碱乙酰胆碱受体（nAChR）和/或使其脱敏。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。尽管已知 α4 和 α6 nAChR 亚基是中脑边缘 DA 途径 nAChR 的重要组成部分，但该途径中对于尼古丁奖励足够和/或必需的 nAChR 的精确组成和/或化学计量仍然未知。此外，人们对接触尼古丁后大脑发生的、引起奖赏行为的变化知之甚少。该提案将检验这样的假设：中脑边缘 DA 通路中的 alpha4alpha6beta2*（*表示 nAChR 五聚体中可能存在其他亚基）nAChR 的激活足以产生尼古丁的奖励作用。证实或反驳这一假设将导致进一步鉴定相关 nAChR 亚型介导尼古丁生物物理和/或行为效应的中脑边缘 DA 通路。结合行为、电生理学和生化技术，我们将通过三个具体目标来实现我们的假设。在具体目标 1 中，我们将测试激活 alpha4alpha6beta2* nAChRs 足以实现尼古丁奖励样行为的想法。使用表达对尼古丁过敏的 α6* nAChR 的小鼠，与对 6?2* nAChR 具有适度功能选择性的化合物平行，我们将确定这些受体的选择性激活是否足以尼古丁 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 alpha4alpha6beta2* nAChR 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。在具体目标 3 中，我们直接测量接触尼古丁的动物 DA 神经元中 nAChR 和谷氨酸受体功能的变化。拟议的研究将增强我们对中脑边缘 DA 通路中与尼古丁成瘾有关的关键 nAChR 的理解。确定足以产生尼古丁奖励的 nAChR 应该会导致更加合理和集中的努力来开发新的戒烟疗法。