Ethanol effects on GABA-serotonin interactions in the Dorsal Raphe Nucleus

乙醇对中缝背核 GABA-血清素相互作用的影响

• 批准号: 8783666
• 负责人: EMILY Geyer LOWERY-GIONTA
• 金额: $ 5.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-06 至 2016-05-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783666
• 关键词: Acute; Alcohol dependence; Alcohols; Attenuated; Behavioral; Brain; Calcium; Cell Nucleus; Cells; Chronic; Clinical; Coupled; Data; Development; Disease; Dorsal; Electrophysiology (science); Ethanol; Functional disorder; Goals; Health; Lesion; Mediating; Methods; Midbrain structure; Mus; Neurons; Outcome; Pathology; Pharmacotherapy; Population; Pre-Clinical Model; Relapse; Reporter; Role; Serotonin; Slice; Stress; Swimming; Synapses; System; Testing; alcohol effect; alcohol exposure; alcohol use disorder; alcoholism therapy; calcium indicator; chronic alcohol ingestion; dorsal raphe nucleus; drinking; effective therapy; gamma-Aminobutyric Acid; insight; mouse model; neuroadaptation; optogenetics; postsynaptic; public health relevance; receptor; research study; stem; therapeutic development; transmission process; vapor

DESCRIPTION (provided by applicant): Alcohol dependence is a serious disorder for which effective treatments are lacking. Dysregulation of the serotonin system has been widely implicated in alcohol dependence though little is known about chronic ethanol's effects on serotonin neurons themselves or the microcircuit to which they belong. In the dorsal raphe (DR), a midbrain structure from which 50% of the brain's serotonin arises, serotonin neuron activity is modulated by local GABA neurons. The effects of chronic ethanol on GABA neurons of the DR and their modulation of serotonin neuron activity have not been explored to date. Using whole-cell slice electrophysiology, chronic ethanol vapor exposure, behavioral, optogenetic and chemogenetic approaches, the goal of this proposal is to test the hypothesis that chronic ethanol induces adaptations in GABA neuron function within the DR, resulting in altered modulation of serotonin neuron activity. The results of the proposed experiments will provide insight into the role of DR GABA neurons in dysregulated serotonin activity resulting from chronic ethanol exposure and will inform the development of pharmacotherapies targeting the serotonin system for the treatment of alcoholism.

描述（由申请人提供）：酒精依赖是一种严重的疾病，缺乏有效的治疗方法。5-羟色胺系统的失调被广泛地认为与酒精依赖有关，尽管人们对慢性乙醇对5-羟色胺神经元本身或它们所属的微回路的影响知之甚少。在中缝背核（DR）（大脑50%的5-羟色胺产生的中脑结构）中，5-羟色胺神经元活动受到局部GABA神经元的调节。长期乙醇对DR的GABA神经元的影响及其对5-羟色胺神经元活性的调节迄今尚未研究。使用全细胞切片电生理学，慢性乙醇蒸汽暴露，行为，光遗传学和化学遗传学的方法，这个建议的目标是测试的假设，慢性乙醇诱导适应的GABA神经元功能的DR内，导致5-羟色胺神经元活动的调制改变。拟议的实验的结果将提供深入了解DR GABA神经元的作用，在失调的5-羟色胺活性引起的慢性乙醇暴露，并将告知针对5-羟色胺系统治疗酒精中毒的药物疗法的发展。