Modulation of Methamphetamine Actions in the CNS

甲基苯丙胺在中枢神经系统中的作用的调节

基本信息

批准号：
7587365
负责人：
Margarita L Dubocovich
金额：
$ 31.07万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587365
关键词：
Acute Anxiety Area Attenuated Basal Ganglia Behavior Biological Clocks Brain CREB1 gene Chronic Circadian Rhythms Clock protein Cocaine Corpus striatum structure Crying Data Dependence Development Dimerization Dopamine Dopamine Antagonists Dopamine D2 Receptor Dopamine Receptor Dose Endogenous depression Exposure to Gene Deletion Gene Expression Genes Genetic Genetic Transcription Goals Haloperidol Hypothalamic structure In Vitro Lesion Ligands Light Link Mammals Mediating Medical Melatonin Melatonin Receptors Messenger RNA Methamphetamine Moods Motor Activity Mus Mutant Strains Mice Neurons Parietal Lobe Pathway interactions Periodicity Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Phase response curves Phosphorylation Play Prosencephalon Public Health Receptor Activation Receptor, Melatonin, MT1 Receptor, Melatonin, MT2 Research Research Priority Rewards Risperidone Rodent Role Running Signal Transduction Signaling Molecule Site Sleep Sleep Disorders Sleeplessness Slice System Tissues Withdrawal base behavioral sensitization circadian behavioral rhythms circadian pacemaker conditioning depressive symptoms dopaminergic neuron in vivo methamphetamine abuse mouse model novel paralogous gene psychostimulant response suprachiasmatic nucleus transcription factor transmission process treatment duration treatment strategy

项目摘要

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.

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。确定有效的药物疗法来管理甲基苯丙胺滥用和依赖是研究的重点。甲基苯丙胺的使用与滥用期间或戒断后的行为过敏、睡眠和昼夜节律改变、焦虑、情绪变化和烦躁有关。本申请的目的是研究选择性褪黑激素受体配体减弱与慢性甲基苯丙胺滥用相关的行为敏感性、增加奖赏行为和昼夜节律不同步的潜力。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靶标。神经药理学方法将用于研究前脑区域内源性和外源性褪黑激素激活褪黑激素受体（MTi、MT2）的作用，以通过 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传导。还将研究 CLOCK 和 NPAS-2 基因以及褪黑激素受体对慢性甲基苯丙胺诱导昼夜节律紊乱并产生自由运行活动节律的机制的参与。最后，我们将开发小鼠模型来评估褪黑激素和多巴胺配体诱导甲基苯丙胺诱导的视交叉上核独立自由运行节律的效力。这些研究的结果应该为发现和开发新型褪黑激素配体提供基础，以缓解与医疗使用和滥用甲基苯丙胺类药物相关的失眠、昼夜节律睡眠障碍和抑郁症状（内源性抑郁）。