Neuropeptides, Social Stress and Drugs of Abuse

社会压力和吸毒之间的密切联系是基于治疗暴力受害者的急诊室的报告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。一些特定类型的社会压力可以促进药物滥用并引发复吸，而其他人则不会，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，本申请集中于神经肽CRF，特别是受体亚型1（CRF-R1），所述证据和我们自己的初步数据表明该系统与导致药物摄入量增加的社会压力机制有关.具体目的一测试的假设，CRF-R1调制离散多巴胺能神经元是一个重要的机制，压力升级的行为，重点是不同阶段的可卡因自我管理（收购，维护，狂欢，复发）。拟议的研究采用离散的脑内微注射刺激和阻断CRF-R1在离散的神经区域，在体内微透析采样神经元液，高效液相色谱分析这些样品，以确定多巴胺和其他胺和行为的措施作为指标的神经适应性变化。具体目的二测试的假设，CRF-R1在腹侧被盖区的封锁减弱的压力升级可卡因自我管理，而拮抗CRF-R2加强可卡因自我管理。具体目的三检验了以下假设：VTA中CRF-R1的拮抗剂不仅保护（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化和压力升级的可卡因自我施用。具体目的四测试条件性CRF-R1敲除小鼠在响应可卡因攻击时将不能显示应激诱导的精神错乱和神经敏化的假设。我们推测，遗传预防CRF 1受体表达的前脑结构改变行为，生理和神经化学反应的社会压力。对腹侧被盖区CRF-R1的拟议研究有望确定社会压力神经回路中的一个关键目标，以进行治疗干预，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.