COCAINE-INDUCED SYNAPTIC PLASTICITY IN LIMBIC BRAIN REGIONS

毒瘾是世界范围内的一个主要健康问题，也是洛克菲勒NIDA中心的中心焦点 大学。所有成瘾物质均增强腹侧中脑边缘奖赏环路中的多巴胺 被盖区(VTA)至伏核外壳(ACB-SH)，这是一个边缘脑区域，包括 杏仁中央核(CEA)和终纹床核(BNST) 延长的杏仁核。这些区域也是许多兴奋性输入的靶点，它们的生理 这种作用很大程度上归因于谷氨酸(NMDA和AMPA)受体的激活。谷氨酸能 作用于DL受体的多巴胺和促肾上腺皮质激素释放因子有效地调节了信号的传递 (CRF)活性于CRF-1(CRF1)受体的多肽，广泛存在于中枢延伸和 基底外侧(BLA)杏仁核。更像皮质的BLA与VTA有双向联系--以及 其他边缘结构与情绪行为和药物/奖赏关联的学习有关。谷氨酸 受体的可塑性以及与多巴胺和/或CRF系统的联系有助于持久的药物寻求 受压力影响很大的行为。受体分布的亚细胞变化 发生在神经元中，这些已识别的递质表型在单个大脑区域主要是 未知。为了开始解决这些关键问题，续签申请中的项目3将结合 利用电子显微镜免疫标记和时空缺失(敲除)的研究策略 边缘脑区中对药物寻找行为至关重要的NR1NMDA受体亚单位。长距离的 目的是检验以下假设：(1)边缘NMDA受体具有有利于 与多巴胺和CRF系统的区域选择性关联，以及(2)VTA中NR1基因的表达 和/或BLA对于突触靶向和可卡因诱导的AMP A和BLA的运输是必不可少的 多巴胺DL受体，以及应激影响的可卡因条件性位置偏爱(CPP)。这些研究 将在野生型和NR1(两侧为loxP)小鼠身上进行，其中一些小鼠将收到急性或 慢性(14天)可卡因以一种类似于人类吸毒者的不断升级的“狂欢”模式服用。 项目3反映了NIDA中心现有项目中调查人员的合作努力，并是 完全依赖于核心资源和设施。从项目3获得的结果，以及 在其他项目的续签申请中，将提供重要的新信息，这对于 认识和治疗药物成瘾。

Drug addiction is a major health issue worldwide, and the central focus of the NIDA Center at Rockefeller University. All addictive substances enhance dopamine in the mesolimbic reward circuit from the ventral tegmental area (VTA) to the nucleus accumbens shell (Acb-SH), a limbic brain region included with the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) as components of the extended amygdala. These regions are also targeted by many excitatory inputs, whose physiological actions are largely ascribed to activation of glutamate (NMDA and AMP A) receptors. Glutamatergic transmission is potently modulated by dopamine acting at Dl receptors and corticotrophin releasing factor (CRF) peptides active at CRF type-1 (CRF1) receptors that are prevalent in both the central extended and basolateral (BLA) amygdala. The more cortical-like BLA has bidirectional connections with the VTA-and other limbic structures implicated in emotional behavior and learning of drug/reward associations. Glutamate receptor plasticity and associations with the dopamine and/or CRF systems contribute to persistent drugseeking behaviors that are powerfully influenced by stress. The subcellular changes in receptor distributions occurring in neurons with these identified transmitter phenotypes in individual brain regions are largely unknown. To begin addressing these key questions, Project 3 in the renewal application will combine research strategies using electron microscopic immunolabeling and spatial-temporal deletion (knock-out) of the NR1 NMDA receptor subunit in limbic brain regions critical for drug seeking behaviors. The long-range goal is to test the hypotheses that (1) limbic NMDA receptors have subcellular distributions conducive to regionally selective associations with dopamine and CRF systems, and (2) NR1 gene expression in the VTA and/or BLA is essential for the synaptic targeting and cocaine-induced trafficking of both AMP A and dopamine Dl receptors, and for cocaine conditioned place preference (CPP) influenced by stress. The studies will be conducted in wild-type and NR1 "floxed" (flanked by loxP) mice, some of which will receive acute or chronic (14 day) cocaine given in an escalating "binge" pattern mimicking that seen in human addicts. Project 3 reflects a collaborative effort by investigators in existing projects within the NIDA Center and is totally dependent on the core resources and facilities. The results obtained from Project 3, together with those in other projects in the renewal application, will provide important new information that is essential for understanding and treating drug addiction.