Neuropeptides, Social Stress and Drugs of Abuse

神经肽、社会压力和滥用药物

基本信息

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
项目类别：
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

项目摘要

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.

项目概要当前具体目标的基本原理建立在一致的流行病学发现之上，即社会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。这社会压力和吸毒之间的密切联系是基于治疗吸毒受害者的急诊室的报告暴力行为和刑事司法系统关于吸毒者实施的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。拟议方案要回答的首要问题研究的主题是：社会压力与可卡因自我服用升级之间的机制联系是什么？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）如何调节中皮质边缘多巴胺（DA）系统。 CRF 系统一直受到人们的关注，不仅因为它对于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是在应激障碍中具有重要意义，并且代表了治疗干预的潜在目标。具体目标一检验了以下假设：高度厌恶的社会压力会放大强烈的回报可卡因通过作用于后腹侧微电路中的 CRF 和多巴胺 (DA) 进行自我给药被盖区（pVTA）到中缝背核（DRN）。神经解剖学管道追踪用于识别与 DA 神经元的突触接触作为 CRF 输入的来源。在这些终端的体内微透析微电路用于表征有助于应激诱导的动态神经适应可卡因自我使用的升级（获取、维持、暴饮、复发）。具体目标二检验以下假设：VTA 中特定 CRF 细胞群的激活和抑制 DRN 微电路调节可卡因自我给药。体内光遗传学以及并行的 Gq- 或 Gi- 特异性在 CRF 神经元中表达视紫红质通道蛋白的小鼠（ChR/Crh 小鼠）中的 DREADD 将用于激活 CRF 输入到 VTA 或用古视紫红质抑制。显微注射 CRFR1、CRFR2 和结合将蛋白质拮抗剂和激动剂注入 VTA-DRN 微电路将确定预防和治疗的靶点扭转社会失败压力或光遗传学激活的影响，从而升级可卡因的自我给药。拟议工作的一个特点是检验社会压力加剧可卡因的假设自我给药以特定性别的方式缓冲。