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.

乙醇成瘾治疗中的一个中心问题是使用乙醇成瘾的复吸率。 在长时间的强迫或自我禁欲之后。在阐明这一现象方面取得了进展。 调节渴望和酒精寻求的神经回路，它提供了对神经生物学基础的洞察 故态复萌。人类脑功能成像和使用c-fos表达作为神经标志物的研究 啮齿动物对药物线索、药物的反应涉及相互连接的皮质和边缘脑区的激活 启动和压力诱导的恢复。该回路的主要组成部分包括内侧前额叶 大脑皮质(MPFC)、杏仁基底外侧核(BLA)、杏仁中央核(CEA)、纹状体床核 终末核(BNST)、腹侧被盖区(VTA)、伏隔核(NAC)、海马、丘脑(THAL)、 和背侧纹状体。下丘脑肌素(Hcrt)系统调节广泛的生理过程，包括 摄食、能量代谢和唤醒，并被包括乙醇在内的滥用药物招募。感兴趣的人 目前的建议，最近的研究已经证明了Hcrt在调节压力和 Hcrt受体(hcrt-r)拮抗剂可能的抗焦虑作用。Hcrt神经元，只位于下丘脑， 投射到神经回路的主要组成部分，该回路介导乙醇寻求并密集地神经支配 丘脑室旁核(PVT)。最近的证据表明，PVT参与了 一般的奖赏功能的调节，特别是药物引导的行为。此外，它一直是 研究表明，PVT是压力调节的一个重要因素，这是一个关键因素，可以导致强烈的 在禁欲的个体中，渴望并引发复发。早先的调查结果表明，有选择地招募了 在寻找乙醇的过程中出现了LH/DMH/PFA-PVT，初步数据表明有乙醇依赖史 使Hcrt/Hcrt-r系统失调。丘脑损伤是乙醇性脑功能障碍的一个重要特征 在酗酒者中，酒精依赖史在多大程度上失调仍有待确定 HCRT和这种功能障碍是否会预测不适应的强迫性寻求酒精(复发)，即 由压力和正常的(觅食)行为引起的。这一提议将检验这样一个假设，即一段历史 乙醇依赖使Hcrt及其与PVT的相互作用失调，并且这种失调将预测 由压力引起的强迫性酒精寻求(复发)。此外，利用局部基因沉默，这一点 该提案将检验这样一个假设，即通过病毒载体永久减少Hcrt的产量将防止 依赖期间PVT中HCRT传递的失调，从而防止对 酒精禁欲期间的压力。这个项目可能会突出以前未被认识到的机制 禁欲中强迫性酒精寻觅的病因学最终导致小说的身份认同 预防ETOH复发的治疗靶点。