Neuropeptides, Social Stress and Drugs of Abuse

描述（由申请人提供）：社会压力和吸毒之间的密切联系是基于急诊室治疗暴力受害者的报告和刑事司法系统关于吸毒者所犯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。某些特定类型的社会压力会促进药物滥用并引发复发，而其他类型则不会，每种压力源都会激活离散的神经生物学机制。基于越来越多的证据和我们自己的初步数据，目前的应用主要集中在神经肽CRF，特别是受体亚型1 (CRF- R1)，暗示该系统在社会压力导致药物摄入升级的机制中。一项研究测试了离散多巴胺能神经元的CRF-R1调节是压力升级行为的关键机制的假设，重点研究了可卡因自我给药的不同阶段（获取、维持、暴食、复发）。本研究采用离散脑内微注射刺激和阻断离散神经区域的CRF-R1，体内微透析取样神经元外液，高效液相色谱分析这些样品以测定多巴胺和其他胺，以及行为测量作为神经适应性变化的指标。特异性目的2验证了VTA中CRF-R1的阻断会减弱应激升级的可卡因自我给药，而CRF-R2的拮抗会增强可卡因自我给药的假设。特异性目的3验证了VTA中CRF-R1拮抗剂不仅可以保护（目的1），而且更重要的是通过调节VTA DA细胞的活性来逆转社会压力诱导的行为敏感化和压力升级的可卡因自我给药。特异性目的四测试了条件CRF-R1基因敲除小鼠在可卡因刺激下不会表现出应激诱导的精神运动和神经致敏的假设。我们假设基因预防CRF - 1受体在前脑结构中的表达会改变对社会压力的行为、生理和神经化学反应。对腹侧被盖区CRF-R1的研究有望在社会压力神经回路中确定一个关键目标，用于治疗干预，特别是在强烈的“狂欢”（如可卡因摄入）的情况下。

DESCRIPTION (provided by applicant): 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. Some specific types of social stress can promote drug abuse and trigger relapse, whereas others do not, each stressor activating discrete neurobiological mechanisms. The present application focuses on the neuropeptide CRF, particularly receptor subtype 1 (CRF- R1), based on the growing evidence and our own preliminary data that implicate this system in the mechanisms of social stress leading to escalated drug intake. Specific Aim One tests the hypothesis that CRF-R1 modulation of discrete dopaminergic neurons is a critical mechanism for stress-escalated behavior, with a focus on different phases of cocaine self-administration (acquisition, maintenance, binge, relapse). The proposed research employs discrete intracerebral microinjections to stimulate and block CRF-R1 in discrete neural regions, in vivo microdialysis for sampling extraneuronal fluid, high performance liquid chromatography for assaying these samples to determine dopamine and other amines and behavioral measures as indices of neuroadaptive changes. Specific Aim Two tests the hypothesis that blockade of CRF-R1 in the VTA attenuates stress-escalated cocaine self-administration, whereas antagonism of CRF-R2 intensifies cocaine self-administration. Specific Aim Three tests the hypothesis that antagonists of CRF-R1 in the VTA will not only protect (Aim 1), but more importantly reverse social stress-induced behavioral sensitization and stress-escalated cocaine self- administration by modulating the activity VTA DA cells. Specific Aim Four tests the hypothesis that conditional CRF-R1 knockout mice will fail to show stress- induced psychomotor and neural sensitization in response to a cocaine challenge. We hypothesize that genetic prevention of CRF 1 receptor expression in forebrain structures alters behavioral, physiological and neurochemical responses to social stress. The proposed research on CRF-R1 in the ventral tegmental area promises to identify one critical target in the neurocircuitry of social stress for therapeutic intervention, especially in cases of intense "binge"-like cocaine intake.