Ecstasy and the Dorsomedial Hypothalamus

摇头丸(摇头丸，3，4-亚甲基二氧基甲基苯丙胺)是一种受欢迎的滥用药物，其使用率不断上升 再加上不断增加的医疗并发症和急诊科就诊报告。滥用MDMA 与体温过高、心血管衰竭、肾功能衰竭和死亡有关。之前的研究已经 表明MDMA的毒性作用依赖于下丘脑-垂体-甲状腺的激活- 肾上腺轴和交感神经系统。这些系统的激活同样发生在应激过程中 其中，它似乎依赖于背内侧区域神经元的激活 下丘脑(DMH)。MDMA的许多生理效应可以通过化学刺激 DMH区的神经元。这些影响包括心率(HR)、平均动脉压 平均动脉压(MAP)、体温、血浆ACTH和运动活动。除了生理上的相似之处，DMH是一种 解剖区域富含去甲肾上腺素和多巴胺，两者都是介导MDMA作用的组成部分。基于 这些发现是我们的中心假设，即MDMA会导致去甲肾上腺素和 多巴胺在DMH激活的关键效应部位的释放参与HPTA轴的刺激和 交感神经系统。最终，这些系统的激活会导致体温过高，心动过速， 高血压和皮肤血管收缩，这些效应在温暖的环境中被放大。 具体目标：这笔赠款的具体目标将(1)表征DMH中神经元在 亚甲基四氢叶酸对正常和交感神经系统的激活 环境温度升高，(2)确定由MDMA介导激活的关键大脑区域 通过DMH(3)表征DMH中儿茶酚胺的变化 摇头丸。这些研究将在自由活动的清醒大鼠中进行，使用以下技术：微量注射， 生物电测生理监测、神经内分泌激活标志物的放射免疫分析 血清和脑儿茶酚胺分析、微透析和C-fos免疫组织化学。 相关性：本申请中提出的研究具有重要意义，因为通过对 负责MDMA毒副作用的主要途径我们将更接近于 改进了对滥用摇头丸和其他兴奋剂的人的治疗战略。 目标：通过全面的培训计划，包括授课工作和指导性研究 培训该提案的目标是为申请人提供必要的培训和教育 发展成为一名独立的调查员。

MDMA (ecstasy, 3, 4-methylenedioxymethamphetamine) is a popular drug of abuse with rising use being coupled with increasing reports of medical complications and emergency department visits. MDMA abuse has been linked with hyperthermia, cardiovascular collapse, renal failure and death. Previous studies have shown that MDMA's toxic effects are dependent on the activation of the hypothalamic-pituitary-thyroid- adrenal axis and the sympathetic nervous system. Activation of these systems likewise occurs during stress where it appears to be dependent on the activation of neurons in the region of the dorsomedial hypothalamus (DMH). Many of the physiologic effects of MDMA can be replicated by chemical stimulation of neurons in the area of the DMH. These effects include increases in heart rate (HR), mean arterial pressure (MAP), temperature, plasma ACTH and locomotor activity. Along with physiologic similarities, the DMH is an anatomic area rich in norepinephrine and dopamine, both integral in mediating MDMA's effects. Based on these findings, it is our central hypothesis that MDMA causes acute increases in norepinephrine and dopamine release in the DMH activating key effector sites involved in the stimulation of the HPTA axis and the sympathetic nervous system. Ultimately activation of these systems causes hyperthermia, tachycardia, hypertension, and cutaneous vasoconstriction, effects which are amplified in a warm environment. Specific Aims: The specific aims of this grant will (1) Characterize the role of neurons in the DMH in mediating MDMA's activation of neuroendocrine and sympathetic nervous systems in both normal and elevated ambient temperatures, (2) Identify key brain regions whose activation by MDMA is mediated through the DMH (3) Characterize changes in catecholamines in the DMH resulting from administration of MDMA. These studies will be performed in freely moving conscious rats using techniques of; microinjection, biotelemetric physiologic monitoring, radioimmunoassay for the markers of neuroendocrine activation, HPLC analysis of serum and brain catecholamines, microdialysis and C-fos immunohistochemistry. Relevance: The research proposed in this application is significant because through the understanding of the central pathways responsible for MDMA's toxic effects we will come closer to the development of improved treatment strategies for persons abusing MDMA as well as others stimulants. Goals: Through a comprehensive training program including didactic course work and mentored research training it is the goal of the proposal to provide the necessary training and education for the applicant's development as an independent investigator.