Sleep regulates drug relapse and addiction

睡眠调节药物复发和成瘾

• 批准号: 10548145
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548145
• 关键词: AMPA Receptors; Acceleration; Acute; Address; Behavior; Behavioral; Binding; Brain; Brain region; Calcium; Chronic; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; Darkness; Drug Addiction; Electroencephalography; Excision; Exhibits; Experimental Designs; Fire - disasters; Fostering; Frequencies; Global Change; Hypothalamic structure; Incubated; 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; brain reward regions; cellular targeting; cocaine craving; cocaine relapse; cocaine seeking; cocaine self-administration; cocaine use; comorbidity; depressive symptoms; drug addiction therapy; drug relapse; drug withdrawal; experience; feeding; hormonal signals; in vivo; in vivo calcium imaging; melanin-concentrating hormone; melanin-concentrating hormone receptor; neural; neuromechanism; non rapid eye movement; novel; novel strategies; optogenetics; 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.

抽象的 长期可卡因吸食者戒断后通常会出现睡眠异常，包括总睡眠质量下降。 据推测，与戒断相关的睡眠问题与睡眠时间和睡眠碎片化增加有关。 然而，睡眠机制是否以及如何调节大脑奖励会促进可卡因的使用和复发 使用大鼠可卡因自我给药模型来抑制电路和影响复发样行为仍然难以捉摸。 回顾戒断后的睡眠缺失和碎片化，黄实验室获得了直接证据 睡眠诱导的可卡因寻求调节：实验性增加 REM（不改变 NREM）睡眠 发作持续时间减少了戒断后对可卡因的寻求，表明快速眼动睡眠相关机制 这种调节的神经机制研究主要集中在伏隔核（NAc），这是一个关键的大脑区域。 富含 GluA1 的钙渗透性 AMPA 受体（CP-）的逐渐积累。 NAc 突触处的 AMPARs）对于戒断后可卡因的寻求强度起到了至关重要的作用。 重要的是，增加快速眼动睡眠持续时间的行为睡眠干预会导致睡眠时间减少 NAc 突触 CP-AMPAR 的积累这些结果不仅表明 NAc CP-AMPAR 是关键的神经元。 表达快速眼动睡眠诱导的抗复发作用的底物，但提出了一个关键问题——快速眼动睡眠如何 睡眠干预途径 NAc CP-AMPAR？ 已发表的初步结果表明黑色素- 下丘脑外侧和未定带（简称 LH）中的集中激素（MCH）神经元可能发挥着 LH MCH 神经元在 REM 睡眠诱导的抗复发作用中发挥重要作用。 快速眼动睡眠限制后行为引起的睡眠反弹，这是我们睡眠所采用的策略。 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) 在 NAc 中高度表达；MCHR 信号传导强烈调节 磷酸化并促进含 GluA1 AMPAR 的突触去除。 表明 LH MCH 神经元在戒除可卡因后表现出膜兴奋性降低，而 在光（睡眠）阶段通过 NAc 内注射 MCH 来模拟 MCH 释放，导致突触减少 NAc 中的 CP-AMPAR 和减少与戒断相关的可卡因寻求共同得出这些结果。 表明 REM 睡眠干预可能会参与 LH MCH 神经活动，从而产生抗复发作用 该应用程序将测试睡眠期间的 MCH 信号传导有助于 REM 的假设。 与目前的做法相反，戒断可卡因后睡眠诱导的抗复发作用。 该提案以非快速眼动睡眠为重点，将确定一种新颖的快速眼动睡眠机制，可产生抗复发作用 此外，该提案强调睡眠期间而不是清醒时的目标操纵。 关于药物戒断和睡眠障碍之间的高共病率，该申请揭示了新的 因此，制定基于睡眠的药物成瘾治疗策略与 NIH 的使命高度相关。