Dysregulation of thalamic hypocretin transmission following ethanol dependence

乙醇依赖后丘脑下丘脑分泌素传输失调

• 批准号: 9110011
• 负责人: Remi Martin-Fardon
• 金额: $ 22.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110011
• 关键词: Abstinence; Alcohol dependence; Animals; Arousal; Behavior; Brain; Chronic; Code; Communication; Corpus striatum structure; Data; Development; Dorsal; Dose; Down-Regulation; Drug Addiction; Energy Metabolism; Ethanol dependence; Etiology; Future; Gene Silencing; Goals; Hypothalamic structure; Laboratories; Lateral; Mediating; Messenger RNA; Molecular; Nature; Neurobiology; Neurons; Peptides; Pharmaceutical Preparations; Phenotype; Physiological Processes; Production; Property; RRM1 gene; Rattus; Recording of previous events; Regulation; Relapse; Rewards; Role; Signal Transduction; Stress; Structure; Structure of paraventricular nucleus of thalamus; System; Testing; Thalamic structure; Therapeutic; Up-Regulation; Work; alcohol seeking behavior; alcoholism prevention; base; design; disorder later incidence prevention; drug of abuse; feeding; hypocretin; improved; insight; knock-down; neurotransmission; novel; orexin A receptor; prevent; problem drinker; public health relevance; relating to nervous system; research study; response; small hairpin RNA; therapeutic target; transmission process; vector

 DESCRIPTION (provided by applicant): The hypocretin (Hcrt) system has long been known to regulate a wide range of physiological processes, including feeding, energy metabolism, and arousal. More recently, concordant observations have demonstrated an important role for Hcrt in the reinforcing properties of most drugs of abuse. Accordingly, Hcrt neurons, which predominantly arise from the lateral hypothalamus (LH), project to brain structures implicated in the regulation of arousal, stress, and reward. Although Hcrt neurons have been shown to massively project to the paraventricular nucleus of the thalamus (PVT), recent evidence suggests that the PVT may be a key relay of Hcrt-coded reward-related communication between the LH and both the ventral and dorsal striatum. While this thalamic region was not thought to be part of "drug addiction circuitry," an increasing amount of evidence indicates that the PVT-particularly Hcrt transmission in the PVT-is implicated in the modulation of reward function in general and several aspects of drug-directed behaviors in particular. Importantly, findings from our laboratory demonstrated selective activation of the PVT during ethanol seeking, and our preliminary data suggest that a history of ethanol dependence produces a downregulation of Hcrt in the LH and upregulation of Hcrtr1 (encoding Hcrt receptor 1) in the PVT. This proposal is designed to study the neurobiological basis of chronic vulnerability to relapse by focusing on Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the compulsive nature of ethanol seeking. Specifically, this proposal will (i) establish the role of Hcrt transmission in the PVT in ethanol-seeking behavior and (ii) test the hypothesis that knocking down Hcrt using local gene silencing in the LH in nondependent rats will mimic the phenotype of postdependent rats. Overall, the planned experiments will provide novel insights into the specific involvement of LH→PVT Hcrt transmission in alcohol-seeking behavior and will likely highlight a previously unrecognized neurotransmission system in the etiology of compulsive alcohol seeking during abstinence and justify targeting the hyprocretin system for alcoholism and relapse prevention.