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

• 批准号: 9249719
• 负责人: Ryan Michael Drenan
• 金额: $ 33.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/9249719
• 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); 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; 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; behavioral study; 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; patch clamp; preference; receptor; receptor function; research study; response; smoking cessation; stoichiometry; tool; varenicline

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.

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一个主要优先事项，尼古丁是香烟烟雾中的主要精神活性化合物，可激活尼古丁和/或使尼古丁脱敏。中脑边缘多巴胺 (DA) 通路中的乙酰胆碱受体 (nAChR) 对于奖励和强化特性至关重要。尽管已知 α4 和 α6 nAChR 亚基是中脑边缘 DA 通路 nAChR 的重要组成部分，但该通路中 nAChR 的精确组成和/或化学计量此外，尼古丁暴露后引起奖励行为的大脑变化也很有限。该提案将检验中脑边缘 DA 通路中 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奖励作用的假设，确认或反驳这一假设将导致进一步的鉴定。相关 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，我们将结合电生理学和生化技术，通过三个具体目标来验证我们的假设，即激活 alpha4alpha6beta2 *。 nAChRs 足以产生尼古丁奖励样行为，同时使用表达对尼古丁过敏的 alpha6* nAChRs 的小鼠，同时使用具有适度的功能选择性 α6α2* nAChR，我们将确定这些受体的选择性激活是否足以激活尼古丁 CPP。在特定目标 2 中，我们将使用膜片钳电生理学来测试刺激 α4α6beta2* nAChR 足以激活腹侧被盖区 (VTA) 的假设。在特定目标 3 中，我们直接测量 nAChR 和 DA 神经元的变化。接触尼古丁的动物的 DA 神经元中谷氨酸能受体的功能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，这应该会导致更合理的研究。并集中精力开发新的戒烟疗法。