Modulation of Methamphetamine Actions in the CNS

描述(申请人提供)：甲基苯丙胺的广泛使用，导致滥用和依赖，是一个重大的医疗、精神和公共卫生问题。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化、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。这项应用的目的是研究选择性褪黑素受体配体在减弱与慢性甲基苯丙胺滥用相关的行为敏感化、增加奖赏行为和昼夜节律去同步化方面的潜力。褪黑素受体(MTI、MT2)是多巴胺介导的信号调节、行为昼夜节律紊乱和促进睡眠的靶标。神经药理学方法将被用来研究内源性和外源性褪黑素激活前脑区褪黑素受体(MTI，MT2)，通过CREB途径调节甲基苯丙胺诱导的运动敏化、奖赏行为和多巴胺能信号的作用。时钟和NPAs-2基因以及褪黑素受体在慢性甲基苯丙胺引起昼夜节律紊乱和产生自由奔跑活动节律的机制(S)中的参与也将被研究。最后，我们将建立小鼠模型来评估褪黑素和多巴胺配体携带甲基苯丙胺诱导的视交叉上核独立自由奔跑节律的效力。这些研究的结果应该为发现和开发新型褪黑素配体提供基础，以缓解与医疗使用和滥用甲基苯丙胺类药物相关的失眠、昼夜睡眠障碍和抑郁症状(内源性抑郁)。

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.