REM Sleep in Cocaine Relapse

摘要 长期吸食可卡因的人在戒毒后很长一段时间都会出现睡眠异常。撤回- 据推测，相关的睡眠问题，包括睡眠不足和睡眠质量下降，可能会导致 可卡因的使用和复发。然而，是否以及如何与睡眠相关的机制尚不清楚 可能调节大脑奖赏回路，影响复发行为。在戒断可卡因的大鼠中， 给药后，总睡眠时间持续减少，睡眠碎片增加，类似于 人类的变化。有趣的是，在实验中增加REM(不改变NREM)睡眠后 戒断减少了对可卡因的渴望，这表明在这一调节中与REM睡眠相关的机制。在 伏隔核(NAC)是大脑中进行奖赏处理的关键区域， 在长期戒断可卡因后，富含GluA1、钙离子通透性的AMPA受体(CP-AMPAR)。 这些受体在长期戒断后对线索诱导的可卡因渴求的加剧起到了关键作用。 重要的是，增加REM睡眠时间/持续时间的睡眠干预会导致脑内CP-AMPAR减少 NAC，伴随着戒断后对可卡因的渴望减少。这些结果不仅表明NAC CP-AMPAR作为表达睡眠调节可卡因渴求和睡眠的关键神经底物 复发，但提出了一个重要的问题-REM睡眠相关机制如何传递到NAC CP- AMPAR？越来越多的证据表明，大脑中的黑色素浓缩激素(MCH)神经元 下丘脑外侧核可能在快速眼动睡眠调节效应中起重要作用。促黄体生成素-甲胎激素的活性 睡眠中的神经元驱动快速眼动睡眠的启动和/或维持。此外，MCH神经元计划 对于高表达MCH受体的NAC，NAC中的MCH受体信号强烈调节 含GluA1的AMPAR的磷酸化和突触移除。初步结果进一步表明， 在戒断可卡因很长一段时间后，LHMCH神经元的膜兴奋性降低，而 光照下NAC内注射MCH模拟NAC长期停药后的MCH释放 (睡眠)阶段导致NAC中CP-AMPAR的减少，并在随后的阶段减少对可卡因的渴望 暗(活跃)阶段。综上所述，这些结果表明，MCH神经元活性的增加可能是 对恢复快速眼动睡眠和减少戒断后对可卡因的渴求都至关重要。此应用程序旨在 检验睡眠中增强LHMCH神经元活性将增加快速眼动的假设 睡眠时间/持续时间，减少戒断后对可卡因的渴求。拟议方案的预期结果 研究将确定一种假定的与REM睡眠相关的机制，该机制调节脑内突触传递 大脑奖赏回路，调节戒断后对可卡因的渴望。鉴于两者之间的密切联系 睡眠障碍和包括吸毒和抑郁在内的共病精神疾病，这 申请与美国国立卫生研究院的任务高度相关。

Abstract Sleep abnormalities commonly occur among chronic cocaine users long after withdrawal. The withdrawal- associated sleep problems, including loss of sleep and worsened sleep quality, have been speculated to foster cocaine use and relapse. However, it is not well understood whether and how sleep-associated mechanisms may regulate the brain reward circuitry and impact relapse-like behaviors. In rats withdrawn from cocaine self- administration, there is persistent reduction in total sleep time and increased sleep fragmentation, resembling the changes in humans. Interestingly, experimentally increasing REM (without changing NREM) sleep after withdrawal reduces cocaine craving, suggesting REM sleep-associated mechanisms in this regulation. In the nucleus accumbens (NAc), a key brain region for reward processing, there is progressive accumulation of the GluA1-rich, calcium-permeable, AMPA receptors (CP-AMPARs) after long-term withdrawal from cocaine. These receptors critically contribute to the intensified cue-induced cocaine craving after long-term withdrawal. Importantly, sleep intervention that increases REM sleep time/duration leads to decreased CP-AMPARs in the NAc, which is accompanied by reduced cocaine craving after withdrawal. These results not only suggest NAc CP-AMPARs as key neuronal substrates that express sleep-mediated regulation of cocaine craving and relapse, but raise the important question – how does REM sleep-associated mechanisms route to NAc CP- AMPARs? Accumulating evidence suggests that the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) may critically contribute to the REM sleep-mediated effects. Activity of LH MCH neurons during sleep drives the initiation and/or maintenance of REM sleep. Moreover, MCH neurons project to the NAc, where MCH receptors are highly expressed; MCH receptor signaling in the NAc strongly regulates the phosphorylation and synaptic removal of GluA1-containing AMPARs. Preliminary results further show that LH MCH neurons exhibited reduced membrane excitability long after withdrawal from cocaine, whereas mimicking MCH release in the NAc after long-term withdrawal by intra-NAc infusion of MCH during the light (sleep) phase led to reductions of CP-AMPARs in the NAc and reduced cocaine craving during the subsequent dark (active) phase. Together, these results suggest that an increase in the activity of MCH neurons may be critical for both normalizing REM sleep and reducing cocaine craving after withdrawal. This application aims to test the hypothesis that enhancing the activity of LH MCH neurons during sleep will increase REM sleep time/duration and reduce cocaine craving after withdrawal. Expected results of the proposed research will identify a putative REM sleep-associated mechanism that modulates synaptic transmission within the brain reward circuitry and regulates cocaine craving after withdrawal. Given the close association between sleep disturbance and the co-morbid psychiatric diseases including drug addiction and depression, this application is highly relevant to the mission of the NIH.