Neuropeptides, Social Stress and Drugs of Abuse

说明(申请人提供)：社会压力和吸毒之间的密切联系基于治疗暴力受害者的急诊室的报告、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。一些特定类型的社会压力可以促进药物滥用并引发复发，而其他类型的社会压力则不会，每种应激源都会激活不同的神经生物学机制。目前的应用主要集中在神经肽CRF，特别是受体亚型1(CRF-R1)，基于越来越多的证据和我们自己的初步数据，表明该系统与社会压力导致药物摄取增加的机制有关。具体目的一验证CRF-R1对离散的多巴胺能神经元的调节是应激升级行为的关键机制的假说，重点关注可卡因自我给药的不同阶段(获得、维持、暴饮暴食、复发)。该研究采用脑内不连续微量注射刺激和阻断离散神经区的CRF-R1，体内微透析采集神经元外液，高效液相色谱法检测这些样品以确定多巴胺和其他胺，并将行为测量作为神经适应性变化的指标。特定目的二验证这样的假设，即阻断VTA内的CRF-R1可减弱应激性递增的可卡因自我给药，而拮抗CRF-R2则加强可卡因的自我给药。特定目标三验证了这样的假设，即VTA中CRF-R1的拮抗剂不仅可以保护(目标1)，更重要的是通过调节VTA DA细胞的活动来逆转社会应激诱导的行为敏化和应激升级的可卡因自我给药。具体目标四测试条件CRF-R1基因敲除小鼠将不会表现出应激诱导的精神运动和神经敏化的假说，以回应可卡因的挑战。我们假设，前脑结构中CRF-1受体表达的遗传预防改变了对社会应激的行为、生理和神经化学反应。这项关于腹侧被盖区CRF-R1的拟议研究有望确定社会应激神经回路中的一个关键靶点，用于治疗干预，特别是在摄入大量类似可卡因的情况下。 与公共卫生相关：在缺乏有效的药物滥用治疗方法的情况下，确定治疗目标仍然是一项迫切需要。社会压力会促进类似“狂欢”的强烈可卡因滥用，大脑中一种关键应激肽的机制与可卡因滥用相互作用。这项拟议的研究重点是神经肽CRF，并试图了解如何利用药理学、神经化学和遗传工具来靶向这种多肽。

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. PUBLIC HEALTH RELEVANCE: In the absence of effective therapies for drug abuse, identifying treatment targets remains an urgent need. Social stress can promote intense, "binge"-like cocaine abuse, and the mechanisms for one of the key stress peptides in the brain interact with those of cocaine abuse. The proposed research focuses on the neuropeptide CRF and seeks to understand how this peptide can be targeted with pharmacological, neurochemical and genetic tools.