EFFECTS OF DRUGS OF ABUSE ON STRESS RESPONSIVE BRAIN SYSTEMS AND HYPOTHALAMIC...

滥用药物对应激反应大脑系统和下丘脑的影响......

• 批准号: 7318811
• 负责人: YAN ZHOU
• 金额: $ 22.41万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318811
• 关键词: Acute; Adrenal Glands; Adrenal hormone preparation; Amygdaloid structure; Animals; Anxiety; Arginine; Argipressin; Attenuated; Behavior; Brain; Chronic; Chronic stress; Clinical Research; Cocaine; Daily; Disruption; Dose; Drug Addiction; Drug Exposure; Drug Regulations; Drug abuse; Drug usage; Dynorphins; Emotional; Engineering; Epigenetic Process; Exposure to; Funding; Gene Expression; Gene Expression Alteration; Gene Expression Regulation; Genes; Goals; Heroin; Histones; Human; Hypothalamic structure; Knockout Mice; Knowledge; Lead; Major Depressive Disorder; Measures; Medial; Mediating; Mental Depression; Messenger RNA; Modeling; Modification; Neurons; Nucleus Accumbens; Opioid; Opioid Receptor; Oxytocin; POMC gene; Pattern; Pharmaceutical Preparations; Pituitary Gland; Pituitary-Adrenal System; Play; Prefrontal Cortex; Pro-Opiomelanocortin; Promoter Regions; Proteins; Rattus; Receptor Activation; Regulation; Relapse; Research Personnel; Rewards; Rodent; Role; Self Administration; Staging; Stress; Swimming; System; Testing; Transgenic Mice; V1b vasopressin receptor; Vasopressins; Week; Withdrawal; Withdrawal Symptom; acute stress; beta-Endorphin; drug craving; drug of abuse; drug relapse; drug seeking behavior; drug withdrawal; endogenous opioids; human study; hypothalamic-pituitary-adrenal axis; kappa opioid receptors; negative emotional state; neural circuit; nociceptin; novel therapeutics; parvocellular; prevent; psychological stressor; receptor; receptor binding; relating to nervous system; response; therapeutic target

Recent clinical studies, including those of the Center, have shown that psychological stressors elevate drug craving and hypothalamic-pituitary-adrenal (HPA) axis activity, and that stress-induced HPA axis responses predict amounts of subsequent drug use. The hypothesis of this Project is: withdrawal from drugs of abuse and exposure to stress persistently alter gene expression levels of HPA axis and brain stress responsive systems in rodent extended amygdalar and mesocorticolimbic regions; critically contributing to persistent compulsive drug taking and relapse of drug seeking. During the current funding period, it has been found that a) arginine vasopressin (AVP) gene expression in the medial amygdala is activated during early withdrawal from heroin; and b) a selective AVP V1b receptor antagonist attenuates both reinstatement of heroin-seeking behaviors and HPA activation induced by stress in long-term heroin withdrawal. This suggests that amygdalar AVP/V1b receptor and HPA systems are critical components of the neural circuitry underlying the aversive emotional consequences of drug withdrawal, and the effect of negative emotional states on drug seeking behavior (negative reinforcing mechanism). Increases in AVP gene expression in the amygdala are further found in acute cocaine withdrawal, and are mediated via opioid receptor activation. Therefore, the first goal of this project is to determine the role of the AVP/V1b receptor systems in relapse to cocaine seeking and taking behaviors (Aim 1). The other main goals of this project are to characterize specific stress responsive genes with respect to: (a) dynamic and region-specific alterations after long-term withdrawal from chronic drug exposure after acute and chronic drug re-exposure (Aim 2) or after acute stress (Aim 3); (b) their correlations with stress-induced anxiety- or depression-like behaviors (Aim 3); (c) their correlations with stress-induced drug seeking or taking behaviors (Aim 1); and (d) potential epigenetic mechanisms underlying alterations of gene expression (Aim 4). The focus of this proposol is to study acute and chronic drug re-exposure after long-term withdrawal. The results will elucidate essential mechanisms for stress and opioid systems in the regulation of drug addictive-like states, which may lead to the identification of potentially novel therapeutic targets.

最近的临床研究（包括该中心的研究）表明，心理压力源会提高药物 渴望和下丘脑-垂体-肾上腺 (HPA) 轴活动，以及压力诱导的 HPA 轴反应 预测随后的药物使用量。该项目的假设是：戒除滥用药物 暴露于压力会持续改变 HPA 轴和大脑应激反应的基因表达水平 啮齿动物扩展杏仁核和中皮质边缘区域的系统；关键有助于持久 强迫性吸毒和吸毒复发。在本次资助期间，发现 a) 内侧杏仁核中的精氨酸加压素 (AVP) 基因表达在早期被激活 戒除海洛因； b) 选择性 AVP V1b 受体拮抗剂可减弱 AVP V1b 受体的恢复 长期海洛因戒断中压力引起的海洛因寻求行为和 HPA 激活。这 表明杏仁核 AVP/V1b 受体和 HPA 系统是神经回路的关键组成部分 戒毒所带来的厌恶情绪后果以及消极情绪的影响 关于药物寻求行为的状态（负强化机制）。 AVP 基因表达增加 杏仁核还存在于急性可卡因戒断中，并通过阿片受体激活介导。 因此，该项目的首要目标是确定 AVP/V1b 受体系统在复发中的作用 可卡因寻求和吸食行为（目标 1）。该项目的其他主要目标是表征 特定应激反应基因涉及：（a）长期后的动态和区域特异性改变 急性和慢性药物再暴露（目标 2）或急性应激后退出慢性药物暴露 （目标 3）； (b) 它们与压力引起的焦虑或抑郁样行为的相关性（目标 3）； (c) 他们的 与压力诱发的药物寻求或服用行为的相关性（目标 1）； (d) 潜在的表观遗传 基因表达改变的机制（目标 4）。该提案的重点是研究急性 以及长期戒断后的慢性药物再暴露。结果将阐明基本机制 压力和阿片类药物系统在药物成瘾样状态的调节中，这可能导致识别 潜在的新治疗靶点。