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 戒断后，慢性可卡因使用者通常发生睡眠异常，包括总损失 睡眠时间和睡眠碎片增加。据推测，戒断相关的睡眠问题是 但是，促进可卡因的使用和继电器，但是，睡眠机制是否以及如何调节大脑奖励 电路和影响样的行为仍然难以捉摸。使用大鼠可卡因自我管理模型 戒断后概括睡眠损失和破碎，黄实验室已获得直接证据 睡眠引起的可卡因寻求调节：实验增加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，这表明在 这个法规。神经机制研究集中于伏隔核（NAC），这是一个关键的大脑区域 用于奖励处理。富含钙的钙，可渗透的AMPA接收器的逐步积累（CP-） NAC中的突触中的AMPARS）严重促进了被启发的可卡因在撤离后寻求。 重要的是，增加REM睡眠发作持续时间的行为睡眠干预措施导致下降 NAC突触CP-Ampar的积累。这些结果不仅将NAC CP-Ampars作为关键神经元 表达REM睡眠引起的抗释放作用的底物，但提出了一个关键的问题 - REM如何 睡眠干预措施通往NAC CP-Ampars？发表和初步结果表明，黑色素 - 下丘脑和Zona Incerta（简称LH）中的浓缩马（MCH）神经元可能会发挥作用 在REM睡眠引起的抗释放作用中的重要作用。 LH MCH神经元主要在REM期间发射 睡觉。 REM睡眠限制后行为引起的睡眠反弹，这是我们睡眠所使用的策略 干预，进一步增强了这些神经元的活性。此外，MCH神经元向NAC项目项目 MCH受体（MCHR）高度表达； NAC中的MCHR信号强烈调节 磷酸化和促进含GLUA1的AMPAR的突触去除。进一步的结果 证明LH MCH神经元从可卡因提取后暴露于降低的膜兴奋性，而 在光（睡眠）期间通过NAC输注MCH的MCH释放，导致突触减少 NAC中的CP-Ampars并改善了与可卡因相关的寻求可卡因。在一起，这些结果 建议REM睡眠干预措施可能引起LH MCH神经活动，以产生抗释放作用 提取。该应用将检验以下假设，即睡眠期间的MCH信号有助于REM 从可卡因退出后睡眠引起的抗释放作用。与当前的做法相反 该提案专注于NREM睡眠，将确定一种新型的REM睡眠机制，可产生抗流逝 效果。此外，该提案强调睡眠期间的目标操作，而不是清醒。 关于药物戒断和睡眠障碍之间的合并症高，该应用显示出新颖的 开发基于睡眠的吸毒疗法的策略，因此与NIH的使命高度相关。