Ecstasy and the Dorsomedial Hypothalamus

描述(由申请人提供)： 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，随着使用量的增加，医疗并发症和急诊科就诊的报告也越来越多。滥用MDMA与体温过高、心血管衰竭、肾功能衰竭和死亡有关。先前的研究表明，MDMA的毒性作用依赖于下丘脑-垂体-甲状腺肾上腺轴和交感神经系统的激活。这些系统的激活同样发生在应激过程中，它似乎依赖于下丘脑背内侧(DMH)区域神经元的激活。化学刺激DMH区神经元可以复制MDMA的许多生理效应。这些影响包括心率(HR)、平均动脉压(MAP)、体温、血浆ACTH和运动活动的增加。除了生理上的相似之处，DMH是一个富含去甲肾上腺素和多巴胺的解剖区域，这两个区域都是介导MDMA作用的组成部分。基于这些发现，我们的中心假设是，MDMA导致DMH中去甲肾上腺素和多巴胺释放急剧增加，激活与刺激HPTA轴和交感神经系统有关的关键效应部位。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会被放大。具体目标：这笔赠款的具体目标将：(1)表征DMH中的神经元在常温和高温下介导MDMA激活神经内分泌和交感神经系统的作用；(2)确定MDMA通过DMH激活的关键大脑区域；(3)表征由于服用MDMA而导致DMH中儿茶酚胺的变化。这些研究将在自由活动的清醒大鼠上进行，技术包括：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、血清和脑儿茶酚胺的高效液相分析、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，因为通过了解造成MDMA毒性影响的中心途径，我们将更接近于制定针对滥用MDMA和其他兴奋剂的人的改进治疗策略。目标：通过一个全面的培训计划，包括教学课程工作和指导性研究培训，该提案的目标是为申请者作为独立调查人员的发展提供必要的培训和教育。

DESCRIPTION (provided by applicant): 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-thyroidadrenal 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.