Neuropeptides, Social Stress and Drugs of Abuse

神经肽、社会压力和滥用药物

• 批准号: 8469849
• 负责人: KLAUS A MICZEK
• 金额: $ 33.34万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469849
• 关键词: Accident and Emergency department; Aggressive behavior; Alcohol or Other Drugs use; Amines; Amygdaloid structure; Area; Attenuated; Behavior; Behavioral; Biological Assay; Brain; Cells; Cocaine; Cocaine Abuse; Commit; Complement; Crime; Criminal Justice; Data; Dimensions; Dopamine; Drug Modulation; Drug abuse; Drug usage; Drug user; Epidemiology; Extinction (Psychology); Genetic; Glutamates; High Pressure Liquid Chromatography; Hippocampus (Brain); Individual; Infusion procedures; Injection of therapeutic agent; Intake; Investigation; Knockout Mice; Link; Liquid substance; Maintenance; Mediating; Microdialysis; Microinjections; Neurobiology; Neurons; Neuropeptides; Nucleus Accumbens; Opioid Peptide; Oxytocin; Peptides; Performance; Pharmaceutical Preparations; Phase; Physiological; Prevention; Prosencephalon; Psychological reinforcement; Relapse; Reporting; Research; Resistance; Role; Sampling; Schedule; Self Administration; Site; Social Values; Stress; Structure; System; Testing; Therapeutic Intervention; United States Substance Abuse and Mental Health Services Administration; Ventral Tegmental Area; Violence; Work; base; behavior measurement; behavioral sensitization; dopaminergic neuron; drug of abuse; drug withdrawal; effective therapy; experience; genetic manipulation; in vivo; indexing; neurobiological mechanism; neurochemistry; prevent; receptor; receptor expression; relating to nervous system; release factor; response; social; social stress; statistics; stressor; tool

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.

描述（由申请人提供）：社会压力与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。某些特定类型的社会压力会促进药物滥用并引发复发，而另一些则不会，每种压力源都会激活不同的神经生物学机制。本申请重点关注神经肽 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，表明该系统与导致药物摄入量增加的社会压力机制有关。具体目标一测试了这样的假设：CRF-R1 对离散多巴胺能神经元的调节是压力升级行为的关键机制，重点关注可卡因自我给药的不同阶段（获取、维持、暴食、复发）。拟议的研究采用离散脑内显微注射来刺激和阻断离散神经区域中的 CRF-R1，体内微透析用于采样神经元外液体，高效液相色谱用于分析这些样本以确定多巴胺和其他胺，以及行为测量作为神经适应性变化的指标。具体目标二检验了这样的假设：阻断 VTA 中的 CRF-R1 会减弱应激升级的可卡因自我给药，而拮抗 CRF-R2 则会强化可卡因自我给药。具体目标三测试了这样的假设：VTA 中的 CRF-R1 拮抗剂不仅可以保护（目标 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。具体目标四测试了这样的假设：条件性 CRF-R1 基因敲除小鼠在应对可卡因挑战时将无法表现出压力诱导的精神运动和神经敏化。我们假设前脑结构中 CRF 1 受体表达的基因预防会改变对社会压力的行为、生理和神经化学反应。拟议的对腹侧被盖区 CRF-R1 的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“狂饮”式可卡因摄入的情况下。