Modulation of Methamphetamine Actions in the CNS

描述（由申请人提供）：甲基苯丙胺的广泛使用，导致滥用和依赖，是一个重大的医学、精神病学和公共卫生问题。确定管理甲基苯丙胺滥用和依赖的有效药物疗法是一项研究重点。甲基苯丙胺的使用与行为敏感、睡眠和昼夜节律的改变、焦虑、情绪变化和易怒有关，无论是在滥用期间还是在戒断时。本应用的目的是研究选择性褪黑激素受体配体的潜力，以减轻与慢性甲基苯丙胺滥用相关的行为敏化，增加奖励行为和昼夜节律不同步。褪黑激素受体（MTi, MT2）正在成为调节多巴胺介导的信号、扰乱行为昼夜节律和促进睡眠的目标。神经药理学方法将用于研究内源性和外源性褪黑素在前脑区域激活褪黑素受体（MTi, MT2）在通过CREB途径调节甲基苯丙胺诱导的运动致敏、奖励行为和多巴胺能信号传导中的作用。我们还将研究慢性甲基苯丙胺诱导昼夜节律紊乱和产生自由运动节律的机制中CLOCK、NPAS-2基因和褪黑激素受体的参与。最后，我们将建立小鼠模型，以评估褪黑激素和多巴胺配体对甲基苯丙胺诱导的视交叉上核独立自由运行节律的影响。这些研究结果应该为发现和开发新的褪黑素配体提供基础，以减轻与医疗使用和滥用甲基苯丙胺类药物相关的失眠、昼夜节律睡眠障碍和抑郁症状（内源性抑郁症）。

DESCRIPTION (provided by applicant): The wide spread use of methamphetamine, causing abuse and dependence, is a significant medical, psychiatric, and public health concern. Identifying effective pharmacotherapies for the management of methamphetamine abuse and dependence is a research priority. Methamphetamine use is associated with behavioral sensitization, alterations in sleep and circadian rhythmicity, anxiety, mood changes and irritability either during abuse or upon withdrawal. The goal of this application is to investigate the potential of selective melatonin receptor ligands to attenuate the behavioral sensitization, increase reward behavior and circadian rhythm desynchronization associated with chronic methamphetamine abuse. Melatonin receptors (MTi, MT2) are emerging as targets for the modulation of dopamine-mediated signals, entrainment of disrupted behavioral circadian rhythms and sleep promotion. Neuropharmacological approaches will be used to investigate the role of melatonin receptor (MTi, MT2) activation by endogenous and exogenous melatonin in forebrain areas to modulate methamphetamine-induced locomotor sensitization, reward behavior and dopaminergic signaling through the CREB pathway. The involvement of CLOCK and NPAS-2 genes and melatonin receptors on the mechanism(s) by which chronic methamphetamine induce circadian rhythms disorganization and generates free running activity rhythms will also be investigated. Finally, we will develop mouse models to assess the potency of melatonin and dopamine ligands to entrain methamphetamine-induced suprachiasmatic nucleus independent free running rhythms. Results from these studies should provide the basis for the discovery and development of novel melatonin ligands to alleviate insomnia, circadian sleep disorders and depressive symptoms (endogenous depression) associated with the medical use and abuse of methamphetamine-like drugs.