Neuropeptides, Social Stress and Drugs of Abuse

神经肽、社会压力和滥用药物

• 批准号: 8426709
• 负责人: KLAUS A MICZEK
• 金额: $ 4.3万
• 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/8426709
• 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是基于急诊室的报告，该报告对吸毒者犯下的暴力犯罪以及流行病学证据和神经生物学数据的刑事司法系统的受害者和统计。某些特定类型的社会压力可以促进药物滥用并引发复发，而其他则没有激活离散神经生物学机制。本应用的重点是神经肽CRF，特别是受体亚型1（CRF-r1），基于日益增长的证据和我们自己的初步数据，这将这种系统暗示了社会压力机制，从而导致药物摄入升级。特定目标检验了一个假设，即离散多巴胺能神经元的CRF-R1调节是压力降低行为的关键机制，重点是可卡因自我管理的不同阶段（获取，维持，维持，暴饮暴食，狂热，复发）。拟议的研究采用离散的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外交液，高性能液相色谱，用于分析这些样品以确定多巴胺和其他胺和行为指标作为神经适应性变化的指数。具体目的两个检验表明，VTA中CRF-R1阻断的假设减轻了应力推动的可卡因自我给药，而CRF-R2的拮抗作用加剧了可卡因自我给药。具体目的三个测试表明，VTA中CRF-R1的拮抗剂不仅可以保护（AIM 1），而且更重要的是，通过调节活性VTA DA细胞来逆转社会压力引起的行为敏化和压力提升的可卡因自我给药。特定目的四个测试表明，有条件的CRF-R1基因敲除小鼠将无法表现出应力引起的心理运动和神经敏化，以应对可卡因挑战。我们假设前脑结构中CRF 1受体表达的遗传预防会改变行为，生理和神经化学对社会压力的反应。拟议的对腹侧侧距区域中CRF-R1的研究有望确定社会压力神经循环的一个关键目标，以进行治疗干预，尤其是在强烈的“暴饮暴食”类似可卡因的摄入量中。