Neuropeptides, Social Stress and Drugs of Abuse

神经肽、社会压力和滥用药物

• 批准号: 9238287
• 负责人: KLAUS A MICZEK
• 金额: $ 33.67万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238287
• 关键词: Accident and Emergency department; Agonist; Alcohols; Behavioral; Binding Proteins; Brain; Buffers; CRH gene; Cells; Cocaine; Cocaine Abuse; Corticotropin-Releasing Hormone; Criminal Justice; Data; Dopamine; Dose; Drug usage; Drug user; Endocrine; Epidemiology; Exposure to; Extinction (Psychology); Female; Genetic; Human; Hypothalamic structure; Intervention; Learning; Link; Maintenance; Mediating; Methodology; Methods; Microdialysis; Microinjections; Modeling; Mus; Neurobiology; Neurons; Neuropeptides; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Process; Punishment; Rattus; Relapse; Reporting; Research; Resistance; Resolution; Rewards; Rodent; Self Administration; Source; Stress; Synapses; System; Testing; Therapeutic Intervention; Translating; Ventral Tegmental Area; Violence; Viral Vector; Work; addiction; base; biological adaptation to stress; dopamine system; dopaminergic neuron; dorsal raphe nucleus; drug abuse therapy; drug of abuse; effective therapy; in vivo; interest; male; neuroadaptation; neurochemistry; nonhuman primate; novel; optogenetics; prevent; programs; sex; social; social stress; statistics; stress disorder; targeted treatment; tool; violent crime

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.

项目摘要 当前特定目标的基本原理是基于社会的一致的流行病学发现 从开始到升级再到复发，压力对成瘾周期的所有阶段都有巨大贡献。这 社会压力与吸毒之间的紧密联系是基于急诊室的报告 刑事司法系统的暴力和统计数据对吸毒者犯下的暴力犯罪以及 流行病学证据和神经生物学数据。拟议中要回答的总体问题 研究是：社会压力与可卡因自我管理之间的机械联系是什么？我们的 特别强调皮质激素释放因子（CRF，通常称为CRH）如何调节 中皮质糖多巴胺（DA）系统。 CRF系统引起了人们的持续关注，不仅是因为它是 对于内分泌压力反应的启动至关重要，但其超丘脑本地化和作用是 在应激障碍中的显着性并代表了治疗干预的潜在靶标。 特定的目标检验了以下假设，即高度厌恶的社会压力会增强强烈的回报 可卡因通过对CRF和多巴胺（DA）在后腹侧的CRF和多巴胺（DA）的自我管理 侧面raphe核（DRN）的侧距区域（PVTA）。使用神经解剖学跟踪来识别 与DA神经元作为CRF输入来源的突触接触。这些终端中的体内微透析 微电路用于表征有助于应力诱导的动态神经适应 可卡因自我管理的升级（获取，维护，暴饮暴食，复发）。 具体目的两个检验了以下假设：VTA-中特定CRF细胞基团的激活和抑制 DRN微电路调节可卡因自我给药。体内光遗传学，并同时使用GQ-或GI- 在CRF神经元（CHR/CRH小鼠）中表达通道Rhopopsin的小鼠中的Dreadd将用于 激活CRF输入到VTA中或用古hopopsin抑制。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 社会失败压力或光遗传激活的逆转效果，使可卡因自我管理升级。 拟议工作的一个特征是对社会压力提升可卡因的假设的检验 自我管理以特定的方式缓冲。