Neuropeptides, Social Stress and Drugs of Abuse

项目摘要 目前具体目标的理论基础是一致的流行病学调查结果， 压力对成瘾周期的所有阶段，从开始到升级再到复发，都起着至关重要的作用。的 社会压力和毒品使用之间的密切联系是基于急诊室的报告， 刑事司法系统关于吸毒者暴力犯罪的统计数据以及 流行病学证据和神经生物学数据。拟议的方案所要回答的首要问题是， 研究是：社会压力和可卡因自我给药升级之间的机械联系是什么？我们 特别强调的是促肾上腺皮质激素释放因子（CRF，通常称为CRH）如何调节 中脑皮质边缘多巴胺（DA）系统。通用报告格式制度继续受到关注，不仅是因为它 对内分泌应激反应的启动至关重要，但其下丘脑外的定位和作用， 在应激障碍中具有重要意义，并代表了治疗干预的潜在靶点。 具体目标一是检验高度厌恶的社会压力会放大强烈奖励的假设 可卡因自我给药通过作用于CRF和多巴胺（DA）在微电路从后腹 被盖区（pVTA）至中缝背核（DRN）。神经解剖束追踪用于识别 突触与DA神经元接触，作为CRF输入的来源。在这些终端的体内微透析 微电路被用来表征动态神经适应，有助于压力引起的 可卡因自我给药的升级（获得、维持、狂欢、复发）。 特定目的二检验了VTA中特定CRF细胞群的激活和抑制的假设， DRN微电路调节可卡因自我给药。体内光遗传学和平行的Gq-或Gi- 在CRF神经元中特异性表达视紫红质的小鼠（ChR/Crh小鼠）中的DREADD将用于 激活CRF输入VTA或用古视紫红质抑制。显微注射CRFR1、CRFR2和结合 蛋白质拮抗剂和激动剂进入VTA-DRN微电路将确定预防和 逆转社交失败压力或光遗传学激活的影响，使可卡因自我给药升级。 这项工作的一个特点是测试假设，社会压力升级可卡因 自我给药以性别特异性方式缓冲。

Project Summary The rationale for the current specific aims builds on the consistent epidemiological finding that social stress contributes critically to all phases of the addiction cycle, from initiation to escalation to relapse. The close link between social stress and drug use is based on reports from emergency rooms treating victims of violence and statistics from the criminal justice system on violent crimes committed by drug users as well as epidemiological evidence and neurobiological data. The overarching question to be answered by the proposed research is: what is the mechanistic link between social stress and escalated cocaine self-administration? Our special emphasis is on how corticotropin releasing factor (CRF, often referred to as CRH) modulates mesocorticolimbic dopamine (DA) systems. The CRF system is of continued interest, not only because it is critical to the initiation of the endocrine stress response, but its extra-hypothalamic localization and action are of significance in stress disorders and represent potential targets for therapeutic intervention. Specific Aim One tests the hypothesis that highly aversive social stress amplifies intensely rewarding cocaine self-administration by action on CRF and dopamine (DA) in microcircuits from the posterior ventral tegmental area (pVTA) to the dorsal raphe nuclei (DRN). Neuroanatomical tract tracing is employed to identify the synaptic contacts with DA neurons as a source of CRF input. In vivo microdialysis in the terminals of these microcircuits are used to characterize the dynamic neuroadaptions that contribute to the stress-induced escalation of cocaine self-administration (acquisition, maintenance, binge, relapse). Specific Aim Two tests the hypothesis that activation and inhibition of specific CRF cell groups in the VTA- DRN microcircuit modulate cocaine self-administration. In vivo optogenetics and, in parallel, Gq- or Gi- DREADD in mice expressing Channelrhodopsin specifically in CRF neurons (ChR/Crh mice) will be used to activate CRF inputs into the VTA or inhibit with archaerhodopsin. Microinjections CRFR1, CRFR2 and binding protein antagonists and agonists into the VTA-DRN microcircuit will identify targets for preventing and reversing effects of social defeat stress or optogenetic activation that escalate cocaine self-administration. A special feature of the proposed work is the test of the hypothesis that social stress-escalated cocaine self-administration is buffered in a sex-specific manner.