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

最近的临床研究，包括该中心的研究表明，心理应激源会使药物升高 渴望和下丘脑-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。该项目的假设是：戒除滥用药物 应激持续改变HPA轴基因表达水平和大脑应激反应 啮齿动物杏仁延长区和大脑中皮质边缘区域的系统；对持续性 强迫吸毒和复吸毒品。在本资助期内，已找到 A)杏仁内侧核精氨酸加压素(AVP)基因表达在早期被激活 戒断海洛因；和b)选择性AVP V1b受体拮抗剂减弱两种受体的恢复 长期戒毒应激诱导的海洛因寻觅行为和HPA激活。这 提示杏仁核AVP/V1b受体和HPA系统是神经回路的重要组成部分。 药物戒断的不良情绪后果以及负面情绪的影响 关于寻求毒品行为的国家(消极强化机制)。血管紧张素转换酶基因表达增加 杏仁核在急性可卡因戒断中进一步被发现，并通过阿片受体激活而介导。 因此，这个项目的第一个目标是确定AVP/V1b受体系统在复发性高血压中的作用。 寻找和吸食可卡因行为(目标1)。这个项目的其他主要目标是 特定的应激反应基因涉及：(A)长期后的动态和区域特异性改变 在急性和慢性药物再暴露后(目标2)或在急性应激后停止慢性药物暴露 (目标3)；(B)它们与应激引起的焦虑或抑郁行为的相关性(目标3)；(C)它们 与应激诱导的寻药或吸毒行为的相关性(目标1)；和(D)潜在的表观遗传 基因表达改变的潜在机制(目标4)。本论文的研究重点是研究急性 以及长期停药后的慢性药物再暴露。这一结果将阐明 应激和阿片系统在类药物成瘾状态调节中的作用，这可能导致识别 潜在的新治疗靶点。

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.