Sleep regulates drug relapse and addiction

睡眠调节药物复发和成瘾

• 批准号: 10092144
• 负责人: Yanhua H Huang
• 金额: $ 35.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092144
• 关键词: AMPA Receptors; Acute; Address; Behavior; Behavioral; Brain; Brain region; Calcium; Chronic; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Drug Addiction; Electroencephalography; Excision; Exhibits; Fire - disasters; Fostering; Frequencies; Global Change; Hypothalamic structure; Infusion procedures; Intervention; Knowledge; Lateral; Lead; Light; Maintenance; Mediating; Membrane; Mission; Modeling; Molecular Target; Neurons; Nucleus Accumbens; Permeability; Pharmaceutical Preparations; Phase; Phosphorylation; Play; Procedures; Publishing; REM Sleep; Rattus; Receptor Signaling; Recovery; Regulation; Relapse; Role; Route; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Synapses; Synaptic Transmission; System; Testing; Time; United States National Institutes of Health; Wakefulness; Withdrawal; addiction; base; brain reward regions; cellular targeting; cocaine relapse; cocaine self-administration; cocaine use; comorbidity; craving; depressive symptoms; design; drug addiction therapy; drug relapse; drug withdrawal; experience; experimental study; feeding; hormonal signals; in vivo; in vivo calcium imaging; melanin-concentrating hormone; melanin-concentrating hormone receptor; neuromechanism; non rapid eye movement; novel; novel strategies; optogenetics; relating to nervous system; response; reward circuitry; reward processing; sleep abnormalities; zona incerta

Abstract Sleep abnormalities commonly occur among chronic cocaine users after withdrawal, including loss of total sleep time and increase in sleep fragmentation. The withdrawal-associated sleep problems are speculated to foster cocaine use and relapse, however, whether and how sleep mechanisms may regulate the brain reward circuitry and impact relapse-like behaviors remain elusive. Using a rat cocaine self-administration model to recapitulate sleep loss and fragmentation after withdrawal, the Huang lab has obtained direct evidence of sleep-induced regulation of cocaine seeking: experimentally increasing REM (without changing NREM) sleep episode durations reduces cocaine seeking after withdrawal, suggesting REM sleep-associated mechanisms in this regulation. Neural mechanism studies have focused on the nucleus accumbens (NAc), a key brain region for reward processing. Progressive accumulation of the GluA1-rich, calcium-permeable, AMPA receptors (CP- AMPARs) at synapses in the NAc critically contributes to the intensified cocaine seeking after withdrawal. Importantly, behavioral sleep interventions that increase REM sleep episode durations lead to decreased accumulation of NAc synaptic CP-AMPARs. These results not only suggest NAc CP-AMPARs as key neuronal substrates that express REM sleep-induced anti-relapse effects, but raise the critical question – how do REM sleep interventions route to NAc CP-AMPARs? Published and preliminary results suggest that the melanin- concentrating hormone (MCH) neurons in the lateral hypothalamus and zona incerta (LH for short) may play an important role in the REM sleep-induced anti-relapse effects. LH MCH neurons predominantly fire during REM sleep. Behaviorally induced sleep rebound after REM sleep restriction, a strategy utilized by our sleep intervention, further enhances the activity of these neurons. Moreover, MCH neurons project to the NAc, where MCH receptors (MCHRs) are highly expressed; MCHR signaling in the NAc strongly regulates the phosphorylation and facilitates synaptic removal of GluA1-containing AMPARs. Preliminary results further show that LH MCH neurons exhibited reduced membrane excitability after withdrawal from cocaine, whereas mimicking MCH release by intra-NAc infusion of MCH during light (sleep) phase led to reduction of synaptic CP-AMPARs in the NAc and decreased withdrawal-associated cocaine seeking. Together, these results suggest that REM sleep interventions may engage LH MCH neural activity to produce anti-relapse effects after withdrawal. This application will test the hypothesis that MCH signaling during sleep contributes to REM sleep-induced anti-relapse effects after withdrawal from cocaine. In contrast to the current practice focusing on NREM sleep, this proposal will identify a novel REM sleep mechanism that produces anti-relapse effects. Moreover, the proposal emphasizes target manipulations during sleep rather than in wakefulness. Concerning the high comorbidity between drug withdrawal and sleep disturbance, this application reveals novel strategies for developing sleep-based therapies for drug addiction, thus is highly relevant to NIH’s mission.

摘要 长期可卡因使用者在戒断后通常会出现睡眠异常，包括总睡眠时间的减少 睡眠时间和睡眠碎片增加。据推测，与戒断相关的睡眠问题 然而，睡眠机制是否以及如何调节大脑的奖赏， 回路和影响复发样行为仍然难以捉摸。使用大鼠可卡因自我给药模型， 概括了戒断后的睡眠丧失和碎片，黄实验室已经获得了直接的证据， 可卡因寻求的睡眠诱导调节：实验性增加REM（不改变NREM）睡眠 发作持续时间减少了戒断后的可卡因寻求，这表明REM睡眠相关机制， 这个规定。神经机制的研究集中在脑桥核（NAc），一个关键的大脑区域 用于奖励处理。富含GluA 1的、可渗透钙的AMPA受体（CP-1）的进行性积累， 在NAc的突触中的AMPAR）对戒断后可卡因寻求的加强起着关键作用。 重要的是，增加快速眼动睡眠持续时间的行为睡眠干预导致减少 NAc突触CP-AMPAR的积累。这些结果不仅表明NAc CP-AMPAR作为关键的神经元 表达REM睡眠诱导的抗复发作用的底物，但提出了关键问题-REM如何 睡眠干预路由到NAc CP-AMPAR？已发表的和初步的结果表明，黑色素- 下丘脑外侧部和不定核（简称LH）内的激素集中（MCH）神经元可能在这一过程中起重要作用。 在REM睡眠诱导的抗复发作用中起重要作用。LH MCH神经元主要在REM期间放电 睡吧快速眼动睡眠限制后行为诱导的睡眠反弹，这是我们的睡眠 干预，进一步增强了这些神经元的活性。此外，MCH神经元投射到NAc， MCH受体（MCHR）高度表达; NAc中的MCHR信号强烈调节MCHR的表达。 磷酸化并促进含GluA 1的AMPAR的突触去除。初步结果进一步 表明LH MCH神经元在可卡因戒断后表现出降低的膜兴奋性，而 通过在光（睡眠）期内注入MCH来模拟MCH释放， NAc中的CP-AMPAR和戒断相关的可卡因寻求减少。这些结果一起 提示REM睡眠干预可能参与LH MCH神经活动，以产生抗复发作用， 戒断这个应用程序将测试的假设，MCH信号在睡眠有助于快速眼动 可卡因戒断后睡眠诱导的抗复吸作用。与现行做法相比， 这项研究的重点是非快速眼动睡眠，它将确定一种新的快速眼动睡眠机制，从而产生抗复发作用 方面的影响.此外，该建议强调在睡眠而不是清醒时的目标操作。 关于药物戒断和睡眠障碍之间的高共病性，该应用揭示了新的 因此，开发基于睡眠的药物成瘾治疗策略与NIH的使命高度相关。