Sleep Disturbances During Cocaine Abstinence, Dopamine Adaptations, and Motivation for Cocaine

项目概要/摘要 可卡因使用障碍是一种慢性疾病，目前还没有批准的药物治疗。 治疗可卡因使用障碍的最大挑战之一是预防吸毒复吸。在 大鼠，可卡因使用后的禁欲期加剧了对药物的寻求和动机，这一直是 与复发倾向增加有关。尽管大量证据表明， 多巴胺影响可卡因强化，多巴胺参与睡眠调节已收到 相对较少的关注。我们最近证明了多巴胺转运蛋白控制昼夜节律， 多巴胺的摄取波动， 在睡眠/觉醒周期中，这会影响可卡因抑制多巴胺转运蛋白的效果。 此外，我们的初步和最近发表的数据表明，睡眠障碍发生在 戒断促进可卡因寻求和核内多巴胺转运体功能改变 维生素B6可能有助于这些影响。总之，这些发现提高了多巴胺 延髓核中的神经传递可能作为一个节点， 睡眠/唤醒过程。在这项研究中，我们假设可卡因相关的睡眠中断， 禁欲有助于多巴胺转运体适应，促进可卡因寻求的潜伏期， 增加多巴胺转运体对可卡因的敏感性。此外，我们建议恢复快速眼动 在禁欲期间睡眠和/或多巴胺转运蛋白功能正常化将减弱 可卡因寻求和降低多巴胺转运蛋白对可卡因的敏感性。完成建议 实验将为睡眠中断和可卡因寻求之间的联系提供新的见解， 以及这在多大程度上涉及到丘脑核中多巴胺神经传递的改变。 因此，预期结果应能为现场提供重要信息，并有助于确定未来的治疗方案 可卡因使用障碍的治疗策略

Project Summary/Abstract Cocaine use disorder is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Among the greatest challenges in the treatment of cocaine use disorder is prevention of relapse to drug use. In rats, periods of abstinence following cocaine use intensifies seeking and motivation for drug, which has been associated with increased propensity for relapse. Although extensive evidence indicates that mesolimbic dopamine influences cocaine reinforcement, the involvement of dopamine in the regulation of sleep has received comparatively less attention. We recently demonstrated that the dopamine transporter governs diurnal fluctuations in extracellular dopamine tone in the nucleus accumbens and that dopamine uptake fluctuates across the sleep/wake cycle, which impacts the effects of cocaine at inhibiting the dopamine transporter. Moreover, our preliminary and recently published data suggest that sleep disturbances that occur during abstinence promote cocaine seeking and that alterations in dopamine transporter function in the nucleus accumbens may contribute to these effects. Together, these findings raise the possibility that dopamine neurotransmission in the nucleus accumbens may function as a node that integrates both motivational and sleep/wake processes. In the proposed studies, we hypothesize that cocaine-related sleep disruptions during abstinence contribute to dopamine transporter adaptations that promote incubation of cocaine seeking and increase dopamine transporter sensitivity to cocaine. Further, we propose that restoration of rapid-eye movement sleep and/or normalization of dopamine transporter function during abstinence will attenuate incubation of cocaine seeking and reduce dopamine transporter sensitivity to cocaine. Completion of the proposed experiments will offer new insights into the link between sleep disruptions and development of cocaine seeking, and the extent to which this involves alterations in dopamine neurotransmission in the nucleus accumbens. Consequently, expected results should significantly inform the field and help to identify future treatment strategies for cocaine use disorder.