PRECLINICAL CIRCUITRY UNDERLYING METHAPHETAMINE ADDICTION

项目1将评估皮质边缘回路在消退训练和线索中的作用--以及 甲基苯丙胺诱导接受自我给药训练的动物恢复寻药行为 甲基苯丙胺同时使用短期和长期访问治疗方案。它被假设为 甲基苯丙胺成瘾者的认知障碍已经被很好地记录下来，这将体现在 模型大鼠在消退训练中存在缺陷。此外，在动物的灭绝学习上训练得很差 获取甲基苯丙胺方案会产生这样一个事实，即前额叶皮质，这通常是 从事灭绝训练，受到损害，因此不再能够规范恢复 寻找毒品。因此，假设缺少前额叶的参与会加剧恢复。 对先前关联的巴甫洛夫条件线索和非偶然注入的 冰毒。这项关于甲基苯丙胺自我管理、灭绝和 将与项目3合作开发恢复，该项目将使用此协议来检查 甲基苯丙胺自我给药的认知效应。此外，在项目1中生成的电路图将 与项目2中从甲基苯丙胺成瘾者那里获得的神经成像数据相结合，后者将 经历类似的线索诱导的药物兴趣和随后的线索诱导的消失的过程 回应。最后，项目3和4将检验公认的认知增强剂Nacylcysteine， D-环丝氨酸和莫达非尼在甲基苯丙胺消退动物模型中的作用 复职和甲基苯丙胺成瘾者。然后将整合项目3或4中的积极影响 通过目前的项目来确定这些药物在大脑中的哪个部位可能会改善与成瘾有关的问题 行为。基于甲基苯丙胺导致前额叶皮质功能缺陷的假说 功能抑制绝对化学习，加剧复吸毒品，预计 项目3或4中确定的使用认知增强剂的系统治疗的任何效果都将通过以下方式复制 将药物直接注射到前额叶皮质。 通过识别大脑中能够缓解甲基苯丙胺成瘾的药物的作用部位， 未来的蛋白质组学和活体多光子神经成像可以更有效地针对药物部位 大脑内的活动，并为未来药物治疗的改进确定新的细胞靶点 为冰毒瘾君子准备的。

Project 1 will evaluate the role of corticolimbic circuitry in extinction training and cue- and methamphetamine-induced reinstatement of drug-seeking in animals trained to self-administer methamphetamine using both a short and long access treatment protocol. It is hypothesized that the cognitive impairment that has been well documented in methamphetamine addicts will be manifested in this rat model as deficits in extinction training. Further, poor extinction learning in animals trained on a long access methamphetamine protocol will arise from the fact that the prefrontal cortex, which is normally engaged by extinction training, is impaired and therefore no longer able to regulate the reinstatement of drug-seeking. Thus, the lack of prefrontal involvement is hypothesized to exacerbate reinstatement responding to both a previously associated Pavlovian conditioned cue and a noncontingent injection of methamphetamine. This basic protocol for methamphetamine self-administration, extinction and reinstatement will be developed in collaboration with Project 3 that will use this protocol to examine cognitive effects of methamphetamine self-administration. Also, circuitry maps generated in Project 1 will be integrated with neuroimaging data obtained from methamphetamine addicts in Project 2 who will undergo analogous procedure of cue-induced drug interest and subsequent extinction of the cue-induced response. Finally, Projects 3 and 4 will examine the effects of putative cognitive enhancers, Nacetylcysteine, D-cycloserine and modafinil in both the animal model of methamphetamine extinction and reinstatement and in methamphetamine addicts. Positive effects in projects 3 or 4 will then be integrated with the present project to determine where in the brain these drugs may be ameliorating addiction-related behaviors. Based upon the hypothesis that methamphetamine-induced deficits in prefrontal cortical function inhibit extinction learning and exacerbate the reinstatement of drug-seeking, it is anticipated that any effect of systemic treatment with cognitive enhancers identified in Projects 3 or 4 will be replicated by microinjecting the drug directly into the prefrontal cortex. By identifying sites of action in the brain by drugs capable of ameliorating methamphetamine addiction, future proteomic and in vivo multiphoton neuroimaging can be more efficiently targeted to sites of drug action within the brain, and to identify new cellular targets for future improvements in pharmacotherapies for methamphetamine addicts.