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: 10161182
• 负责人: Ryan Michael Drenan
• 金额: $ 8.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161182
• 关键词: Acute; Address; Animal Behavior; Animals; Attenuated; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Biological; Biophysics; Brain; Bupropion; Cell Communication; Cell Nucleus; Cells; Cessation of life; Chronic; Clinical Research; Clinical Trials; Communication; Complement; Complex; Counseling; Coupled; Data; Dependence; Development; Development Plans; Dopamine; Effectiveness; Electrochemistry; Electrophysiology (science); Family Smoking Prevention and Tobacco Control Act; Fiber; Financial compensation; Fostering; Glutamates; Goals; Health; Human; Hypertension; Image; Individual; Individual Differences; Industry; Intervention; Intravenous; Kinetics; Knowledge; Lead; Learning; Location; Malignant neoplasm of lung; Maps; Mediating; Mentors; Methods; Modeling; Neuronal Plasticity; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Output; Pathway interactions; Pharmacology; Pharmacotherapy; Photometry; Physiological; Policies; Population; Positioning Attribute; Procedures; Process; Psychological reinforcement; Public Policy; Pulmonary Emphysema; Rattus; Relapse; Research; Rewards; Rodent; Rodent Model; Science; Self Administration; Site; Slice; Structure; Substance abuse problem; Synapses; Synaptic Transmission; System; Techniques; Tobacco; Tobacco Dependence; Tobacco use; Training; Treatment Efficacy; United States; United States Food and Drug Administration; Ventral Tegmental Area; Volition; Walkers; Work; addiction; adverse outcome; authority; career development; cell type; cholinergic; desensitization; design; experimental study; gamma-Aminobutyric Acid; healing; improved; innovation; mesolimbic system; neurochemistry; neurotransmission; nicotine exposure; nicotine replacement; nicotine seeking behavior; nicotine use; novel; optogenetics; patch clamp; pre-clinical research; preventable death; receptor; receptor expression; receptor function; smoking cessation; tobacco control; tobacco products; tool; transmission process; two photon microscopy; two-photon; varenicline

PROJECT SUMMARY Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer, emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have moderate effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Development of such strategies requires a more detailed understanding of the biological mechanisms leading to nicotine addiction. An essential goal related to mechanistic studies on nAChRs is gaining a better understanding of the location and activity of nAChRs in discrete sites within individual nerve cells. It is also critical that we connect this location/activity information to the various neurochemically-defined (e.g. dopamine, GABA, glutamate) cell types within the brain reward pathways. For these specific cell types in the reward pathway, recent research points to a highly complex input/output relationship. We identified nAChR expression in glutamate-producing neurons in the ventral tegmental area (VTA), and have demonstrated that these receptors enable nicotine- or ACh-mediated alterations in synaptic transmission within the VTA. However, several gaps in knowledge remain, which we will address in this project. First (in Aim 1), we will identify the location within VTA glutamate neurons where nAChRs show the greatest functional activity. This will be done using electrophysiological recordings during 2-photon imaging of neurons in brain slices. This approach will be coupled with studies using a novel photoactivatable nicotine, which we recently introduced. Directly connecting this structural and functional information is critical to fully understanding how nAChRs modulate glutamate transmission in the VTA. In Aim 2, we will answer questions related to nAChR modulation of cell-cell communication within the VTA. Glutamate neurons in this nucleus directly impinge on local DA/GABA neurons, activity which is modulated by nAChR activity on glutamate cells. We will investigate the mechanisms underlying this synaptic communication using optogenetics, photostimulation techniques, and 2-photon microscopy. In Aim 3, we move our queries to the behaving animal to determine which of the components investigated in Aims 1-2 are most important during animal behavior. Using fiber photometry, we will image Ca2+ activity in VTA neurons during acute nicotine exposure and during acquisition/expression of nicotine conditioned reward behavior. To complement these experiments, we will also use chemogenetics to determine whether VTA glutamate neurons are important for nicotine reward-like behavior. By determining how cholinergic mechanisms map onto the complexity (neurochemical and connectivity) of cell types in the VTA, this project will significantly advance our understanding of cholinergic neurotransmission. These studies could also lead to novel treatments for addiction or novel hypotheses about reward system function/activity.

项目摘要 长期暴露于烟草产品中的尼古丁会导致许多健康后果（肺癌， 肺气肿，高血压等），每年死亡超过600万。复发率很高 那些试图戒烟的人以及试图促进吸烟的药物治疗 中等的效力。因此，有很大的未满足需要更有效的策略来治疗尼古丁 依赖。这种策略的制定需要对生物学的更详细的了解 导致尼古丁成瘾的机制。与NACHRS机械研究有关的一个基本目标是 对单个神经内离散部位中NACHR的位置和活动有了更好的了解 细胞。我们将此位置/活动信息连接到各种神经化学定义也很重要 （例如多巴胺，GABA，谷氨酸）大脑奖励途径中的细胞类型。对于这些特定的细胞类型 奖励途径，最近的研究指出了高度复杂的输入/输出关系。我们确定了 NACHR在产生谷氨酸的神经元中的NACHR表达（VTA），并具有 证明这些受体在突触传播中启用了尼古丁或ACH介导的改变 在VTA中。但是，仍然存在一些知识差距，我们将在该项目中解决这些差距。首先（在 AIM 1），我们将确定NACHRS显示最大功能的VTA谷氨酸神经元内的位置 活动。这将在大脑中神经元的2光子成像期间使用电生理记录完成 切片。这种方法将与使用新型光活化尼古丁的研究结合，我们最近 引入。直接连接此结构和功能信息对于充分了解如何 NACHRS调节VTA中的谷氨酸传播。在AIM 2中，我们将回答与NACHR有关的问题 VTA中细胞电池通信的调制。该核中的谷氨酸神经元直接撞击 局部DA/GABA神经元，由NACHR活性在谷氨酸细胞上调节。我们将调查 使用光遗传学，光刺激技术和 2光子显微镜。在AIM 3中，我们将查询移至行为动物，以确定哪个 在AIMS 1-2中研究的组件在动物行为中最为重要。使用纤维光度法，我们 将在急性尼古丁暴露期间以及在获取/表达期间对VTA神经元中的Ca2+活性图像 尼古丁条件奖励行为。为了补充这些实验，我们还将使用化学遗传学 确定VTA谷氨酸神经元是否对尼古丁奖励样行为很重要。通过确定 胆碱能机制如何映射到细胞类型的复杂性（神经化学和连通性）中 VTA，该项目将大大提高我们对胆碱能神经传递的理解。这些研究 还可能导致有关成瘾或有关奖励系统功能/活动的新假设的新治疗方法。