Neuropeptides, Social Stress and Drugs of Abuse

项目摘要 当前特定目标的理由是建立在一致的流行病学发现基础上的，即 压力在成瘾周期的所有阶段都起着至关重要的作用，从开始到升级再到复发。这个 社会压力和药物使用之间的密切联系是基于急诊室治疗受害者的报告 暴力和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。将由拟议的 研究是：社会压力和不断升级的可卡因自我管理之间的机械联系是什么？我们的 特别强调促肾上腺皮质激素释放因子(CRF，通常称为CRH)是如何调节的 皮质边缘多巴胺(DA)系统。CRF系统继续受到关注，不仅是因为它 对内分泌应激反应的启动至关重要，但其在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。 具体目标一检验这样的假设，即高度厌恶的社会压力会放大极大的回报 可卡因通过作用于CRF和后腹侧微回路中的多巴胺(DA)实现自身给药 被盖区(PVTA)至中缝背核(DRN)。神经解剖束追踪被用来识别 作为CRF输入的来源，突触与DA神经元接触。在体微渗析在这些终末 微电路被用来表征导致应激诱导的动态神经适应 可卡因自我管理的升级(获得、维持、酗酒、复发)。 特定目的二检验VTA中特定CRF细胞群的激活和抑制的假设 DRN微电路调节可卡因的自我给药。活体光遗传学，同时，GQ-或GI- 在CRF神经元中特异性表达通道视紫红质的小鼠(CHR/CRH小鼠)的DREADD将用于 激活CRF传入VTA或用古紫红质抑制。微量注射CRFR1、CRFR2及其结合 进入VTA-DRN微电路的蛋白质拮抗剂和激动剂将识别预防和 逆转社会挫败、压力或光基因激活使可卡因自我给药升级的效果。 这项拟议工作的一个特点是对一种假设的检验，即社会压力加剧的可卡因 自我管理是以特定性别的方式缓冲的。

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.