Pivotal role of thalamic hypocretin transmission during EtOH seeking and relapse

丘脑下丘脑分泌素传输在乙醇寻找和复发过程中的关键作用

• 批准号: 10200612
• 负责人: Remi Martin-Fardon
• 金额: $ 43.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200612
• 关键词: Abstinence; Acute; Affect; Alcohol consumption; Amygdaloid structure; Animals; Anti-Anxiety Agents; Area; Arousal; Behavior; Brain imaging; Brain region; Cell Nucleus; Chronic; Corpus striatum structure; Cues; Data; Dependence; Development; Dorsal; Energy Metabolism; Ethanol; Ethanol dependence; Etiology; FOS gene; Food; Functional disorder; Gene Expression; Gene Silencing; Goals; Hippocampus (Brain); Human; Hypothalamic structure; Impairment; Individual; Laboratory Finding; Lateral; Measures; Medial; Mediating; Messenger RNA; Milk; Molecular; Nature; Neurobiology; Neurons; Nucleus Accumbens; Palate; Peptides; Pharmaceutical Preparations; Physiological Processes; Prefrontal Cortex; Prevalence; Prevention; Production; RRM1 gene; Rattus; Recording of previous events; Regulation; Relapse; Research; Rewards; Rodent; Role; Signal Transduction; Source; Specific qualifier value; Stress; Structure; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; System; Testing; Thalamic structure; Therapeutic; Time; Ventral Tegmental Area; Viral Vector; alcohol abstinence; alcohol relapse; alcohol seeking behavior; alcoholism prevention; behavior test; biological adaptation to stress; brain dysfunction; craving; disorder later incidence prevention; drug of abuse; experimental study; feeding; hypocretin; improved; insight; interest; knock-down; neural circuit; neurotransmission; new therapeutic target; novel; prepro-orexin; prevent; problem drinker; receptor; recruit; reinforcer; relating to nervous system; response; small hairpin RNA; therapeutic target; transmission process; vector

A central problem in the treatment of ethanol (EtOH) addiction is the prevalence of relapse to EtOH use even after protracted intervals of forced or self-imposed abstinence. Advances have been made in elucidating the neurocircuitry that mediates craving and EtOH seeking, which provides insights into the neurobiological basis of relapse. Functional brain imaging in humans and studies that use c-fos expression as a marker of neural activation in rodents implicate interconnected cortical and limbic brain regions in response to drug cue-, drug priming-, and stress-induced reinstatement. Major components of this circuitry include the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), ventral tegmental area (VTA), nucleus accumbens (NAC), hippocampus, thalamus (THAL), and dorsal striatum. The hypocretin (Hcrt) system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal, and is recruited by drugs of abuse, including EtOH. Of interest for the present proposal, recent studies have demonstrated a critical role of Hcrt in the modulation of stress and a possible anxiolytic effect of Hcrt receptor (Hcrt-r) antagonism. Hcrt neurons, located only in the hypothalamus, project to the major components of the neurocircuitry that mediates EtOH seeking and innervates densely the paraventricular nucleus of the thalamus (PVT). Recent evidence suggests that the PVT participates in the modulation of reward function in general and drug-directed behavior in particular. Furthermore, it has been shown that PVT is an important contributor in the regulation of stress, a critical factor that can induce intense craving and trigger relapse in abstinent individuals. Earlier findings demonstrated selective recruitment of the LH/DMH/PFA-PVT during EtOH seeking, and preliminary data suggest that a history of EtOH dependence dysregulates the Hcrt/Hcrt-r system. Thalamic impairments are a key feature of EtOH-related brain dysfunction in alcoholics, remaining to be determined are the extent to which a history of EtOH dependence dysregulates Hcrt and whether this dysfunction will predict maladaptive compulsive EtOH-seeking (relapse) that is precipitated by stress vs. normal (food-seeking) behavior. This proposal will test the hypothesis that a history of EtOH dependence dysregulates Hcrt and its interaction with the PVT, and that this dysfunction will predict compulsive EtOH seeking (relapse) precipitated by stress. Furthermore, using local gene silencing, this proposal will test the hypothesis that the permanent decrease in Hcrt production via a viral vector will prevent Hcrt transmission dysregulation in the PVT during dependence and therefore prevent exacerbated response to stress during EtOH abstinence. This project is likely to highlight a previously unrecognized mechanism in the etiology of compulsive EtOH seeking during abstinence; ultimately leading to the identification of novel therapeutic targets for the prevention of EtOH relapse.

治疗乙醇（EtOH）成瘾的一个中心问题是，即使在治疗过程中， 经过长时间的强迫或自我禁欲。在阐明 调节渴望和乙醇寻求的神经回路，这提供了对神经生物学基础的见解 复发。人类的脑功能成像和使用c-fos表达作为神经系统疾病标志物的研究 啮齿类动物的激活涉及相互连接的皮质和边缘脑区域对药物提示、药物 启动和压力诱导的恢复。这个回路的主要组成部分包括内侧前额叶 皮质（mPFC）、基底外侧杏仁核（BLA）、杏仁中央核（CeA）、纹状体床核 终末区（BNST）、腹侧被盖区（VTA）、中脑核（NAC）、海马、丘脑（塔尔）， 和背侧纹状体。下丘脑泌素（Hcrt）系统调节广泛的生理过程，包括 进食、能量代谢和唤醒，并被滥用药物（包括乙醇）招募。感兴趣的 最近的研究表明，Hcrt在应激调节中起着关键作用， Hcrt受体（Hcrt-r）拮抗作用的可能的抗焦虑作用。Hcrt神经元，只位于下丘脑 投射到神经回路的主要组成部分，介导EtOH寻求并密集地支配 丘脑室旁核（PVT）。最近的证据表明，PVT参与了 一般而言，对奖赏功能的调节，特别是药物导向的行为。此外，它还 显示PVT是调节压力的重要因素，是可以诱导强烈压力的关键因素， 渴望并引发禁欲者的复发。早期的研究结果表明， LH/DMH/PFA-PVT，初步数据表明，EtOH依赖史 Hcrt/Hcrt-r系统失调。丘脑损伤是EtOH相关脑功能障碍的关键特征 在酗酒者中，乙醇依赖史失调的程度仍有待确定 Hcrt和这种功能障碍是否会预测适应不良的强迫性EtOH寻求（复发）， 由压力与正常（觅食）行为促成。这一提议将检验一个假设，即 乙醇依赖性使Hcrt及其与PVT的相互作用失调，这种功能障碍将预测 强迫性乙醇寻求（复发）由压力促成。此外，使用局部基因沉默， 一项提案将检验这样一种假设，即通过病毒载体永久减少Hcrt的产生将阻止 Hcrt在依赖期间PVT中的传递失调，从而防止对 乙醇戒断期间的应激。该项目可能会突出一个以前未被认识的机制， 禁欲期间强迫性EtOH寻求的病因学;最终导致确定新的 用于预防EtOH复发的治疗靶点。