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，表明心理压力因素会提高药物治疗的效果。 渴求和下丘脑-垂体-肾上腺（HPA）轴活动，以及应激诱导的HPA轴反应 预测随后的药物使用量。本项目的假设是：戒毒 暴露于应激持续改变HPA轴和脑应激反应的基因表达水平 系统在啮齿动物扩展杏仁核和中皮质边缘区;关键有助于持久性 强迫性吸毒和毒瘾复发。在目前的资助期间， 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， 海洛因戒断;和B）选择性AVP V1 B受体拮抗剂减弱 长期海洛因戒断者觅药行为与应激诱导下丘脑-垂体-肾上腺皮质激活这 表明杏仁核AVP/V1b受体和HPA系统是神经回路的重要组成部分 潜在的令人厌恶的情绪后果的药物戒断，和负面情绪的影响， 药物寻求行为（负强化机制）。AVP基因表达增加， 杏仁核还在急性可卡因戒断中被发现，并通过阿片受体激活介导。 因此，本项目的第一个目标是确定AVP/V1b受体系统在复发中的作用。 可卡因寻求和服用行为（目标1）。该项目的其他主要目标是 特异性应激反应基因：（a）长期胁迫后的动态和区域特异性改变 在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 (Aim 3）;（B）他们与压力引起的焦虑或抑郁样行为的相关性（目的3）;（c）他们的 与压力诱导的药物寻求或服用行为的相关性（目的1）;以及（d）潜在的表观遗传 基因表达改变的潜在机制（目的4）。本课题的重点是研究急性 以及长期停药后的慢性药物再暴露。这些结果将阐明 压力和阿片系统在调节药物成瘾样状态，这可能会导致识别 潜在的新型治疗靶点。