Sleep regulates drug relapse and addiction

摘要 长期吸食可卡因的人在戒断后通常会出现睡眠异常，包括睡眠总量的减少 睡眠时间和睡眠碎片化程度增加。与戒断相关的睡眠问题被推测为 然而，促进可卡因的使用和复发，睡眠机制是否以及如何调节大脑奖励 电路和冲击波复发的行为仍然难以捉摸。使用大鼠可卡因自我给药模型 综上所述，戒断后的睡眠丢失和碎片，黄实验室已经获得了直接的证据 睡眠诱导的可卡因寻找调节：实验性增加REM(不改变NREM)睡眠 发作持续时间减少戒断后的可卡因寻求，提示REM睡眠相关机制 这项规定。神经机制的研究主要集中在伏隔核(NAC)，这是大脑的一个关键区域 用于奖励处理。富含GluA1的、钙离子通透性的AMPA受体(CP- NAC内突触的AMPAR)对戒断后寻求可卡因的增强起关键作用。 重要的是，增加REM睡眠持续时间的行为睡眠干预会导致减少 NAC突触CP-AMPAR的积聚。这些结果不仅表明NAC CP-AMPAR是关键神经元 表达快速眼动睡眠诱导的抗复发作用的底物，但提出了关键问题-快速眼动如何 睡眠干预导致NAC CP-AMPAR？已发表的和初步的结果表明，黑色素- 下丘脑外侧区和未定带(简称黄体)的集中激素(MCH)神经元可能起作用。 在快速眼动睡眠诱导的抗复发作用中具有重要作用。LHMCH神经元在快速眼动过程中主要放电 睡吧。在快速眼动睡眠限制后，行为诱导的睡眠反弹，这是我们的睡眠所使用的一种策略 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，在那里 MCH受体(MCHRs)高表达；NAC中的MCHR信号强烈调节 磷酸化并促进含有GluA1的AMPAR的突触移除。初步结果进一步 结果显示，戒断可卡因后，LHMCH神经元的膜兴奋性降低，而 轻(睡眠)相NAC内注入MCH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。总而言之，这些结果 提示快速眼动睡眠干预可能使促黄体生成激素神经活动在下列情况下产生抗复发作用 戒烟。这个应用程序将检验睡眠期间的MCH信号对REM有贡献这一假设 可卡因戒断后睡眠诱导的抗复发作用。与目前的做法形成对比的是 聚焦于非快速眼动睡眠，这项提议将确定一种新的快速眼动睡眠机制，以产生抗复发 效果。此外，该提案强调睡眠时的目标操作，而不是清醒时的操作。 考虑到药物戒断和睡眠障碍的高共患率，这一应用揭示了新的 因此，开发以睡眠为基础的药物成瘾疗法的战略与NIH的使命高度相关。

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.