Ecstasy and the Dorsomedial Hypothalamus

狂喜与下丘脑背内侧

• 批准号: 7596466
• 负责人: DANIEL E RUSYNIAK
• 金额: $ 18.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596466
• 关键词: Accident and Emergency department; Acute; Address; Adrenal Glands; Agonist; Anatomy; Animals; Area; Autonomic nervous system; Behavioral; Bicuculline; Body Temperature; Brain; Brain region; Cardiovascular system; Catecholamines; Cessation of life; Chemical Stimulation; Conscious; Corticotropin; Coupled; Cutaneous; Data; Development; Dopamine; Environment; Fever; Future; GABA Antagonists; Goals; Grant; Heart Rate; High Pressure Liquid Chromatography; Hypertension; Hypothalamic structure; Immunohistochemistry; Ingestion; Injection of therapeutic agent; Kidney Failure; Knowledge; Lead; Link; Literature; Mediating; Mentors; Microdialysis; Microinjections; Motor Activity; Muscimol; Neurons; Neurosecretory Systems; Norepinephrine; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physiologic Monitoring; Physiologic Thermoregulation; Physiological; Pituitary Gland; Plasma; Radioimmunoassay; Rattus; Reporting; Research; Research Personnel; Research Training; Role; Saline; Serum; Shivering; Site; Stream; Stress; Sympathetic Nervous System; System; Tachycardia; Techniques; Teenagers; Temperature; Thermogenesis; Thyroid Gland; Toxic effect; Training Programs; Training and Education; Visit; Work; abuse victim; base; club drug; drug of abuse; ecstasy; expectation; extracellular; improved; in vivo; inhibitor/antagonist; innovation; medical complication; neurotransmitter antagonist; paraventricular nucleus; pituitary thyroid axis; pressure; programs; receptor; research study; response; treatment strategy; vasoconstriction; young adult

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.

MDMA（摇头丸，3，4-亚甲二氧基甲基苯丙胺）是一种流行的滥用药物，使用量不断增加， 再加上医疗并发症和急诊室就诊的报告越来越多。MDMA滥用 与体温过高、心血管衰竭、肾衰竭和死亡有关。先前的研究 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期间 它似乎依赖于背内侧区神经元的激活 下丘脑（DMH）。MDMA的许多生理效应可以通过化学刺激复制。 DMH区域的神经元。这些影响包括心率（HR）、平均动脉压（MAP） (MAP)、体温、血浆ACTH和自发活动。沿着生理相似性，DMH是一种 解剖区域富含去甲肾上腺素和多巴胺，两者在介导MDMA的作用中不可或缺。基于 根据这些发现，我们的中心假设是MDMA导致去甲肾上腺素急性增加， DMH中的多巴胺释放激活参与HPTA轴刺激的关键效应位点， 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：该基金的具体目标将：（1）描述DMH中神经元的作用， 介导MDMA激活正常和正常人的神经内分泌和交感神经系统， 升高的环境温度，（2）识别MDMA介导激活的关键脑区 （3）表征DMH中由于给予 摇头丸这些研究将在自由活动的清醒大鼠中使用显微注射技术进行， 生物遥测生理监测，神经内分泌激活标志物的放射免疫测定，HPLC 血清和脑组织中的儿茶酚胺、微透析和C-fos免疫组织化学分析。 相关性：本申请中提出的研究意义重大，因为通过了解 负责MDMA毒性作用的中心途径，我们将更接近于 改进对滥用二亚甲基双氧苯丙胺和其他兴奋剂者的治疗战略。 目标：通过全面的培训计划，包括教学课程和指导研究 培训这是建议的目标，为申请人提供必要的培训和教育， 发展成为独立调查员。