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...

基本信息

批准号：
7628370
负责人：
YAN ZHOU
金额：
$ 24.18万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7628370
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

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

展开

项目摘要

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，表明心理压力升高了药物渴望和下丘脑 - 垂体 - 肾上腺（HPA）轴活动，以及应力诱导的HPA轴响应预测随后的药物使用量。该项目的假设是：退出滥用药物并暴露于胁迫持续改变HPA轴的基因表达水平和大脑应力反应啮齿动物扩展的杏仁核和中质膜的系统；批判性贡献持续强迫药物服用和寻求药物的复发。在当前的资金期间，已经发现 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退出海洛因； b）选择性的AVP V1B受体拮抗剂可减弱同时恢复原状的长期海洛因戒断压力引起的寻求海洛因行为和HPA激活。这建议杏仁核AVP/V1B受体和HPA系统是神经回路的关键组成部分戒毒的厌恶情绪后果以及负面情绪的影响是基本的关于寻求毒品行为的国家（负增强机制）。 AVP基因表达的增加在急性可卡因戒断中进一步发现了杏仁核，并通过阿片受体激活介导。因此，该项目的第一个目标是确定AVP/V1B受体系统复发的作用可卡因寻求和采取行为（目标1）。该项目的另一个主要目标是表征相对于：（a）长期后的动态和区域特异性改变急性和慢性药物重新暴露后或急性应激后退出慢性药物暴露（AIM 2）（目标3）; （b）它们与压力引起的焦虑或抑郁症状行为的相关性（AIM 3）；（c）他们的与压力引起的毒品寻求或服用行为的相关性（AIM 1）；（d）潜在的表观遗传基因表达改变的基础机制（AIM 4）。该提案的重点是研究急性长期戒断后的慢性药物再暴露。结果将阐明在药物成瘾状态的调节中，压力和阿片类药物系统可能导致鉴定潜在的新型治疗靶标。