CNS circuitry and receptors mediating the effects of MDMA

描述（由申请人提供）：使用安非他明MDMA（摇头丸，3,4 -亚甲基二氧基甲基苯丙胺）可导致危及生命的医学并发症，包括致命的高热和心律失常。这些并发症的部分原因是交感神经系统、下丘脑-垂体-肾上腺轴（HPA）和躯体运动系统同时激活。主要研究者的长期目标是确定MDMA激活这些系统的关键大脑区域和机制。本应用程序的目的是确定MDMA激活下丘脑背内侧（DMH）神经元的机制（DMH是参与MDMA引起的反应的一个部位），并随后确定这种激活如何刺激涉及交感神经、躯体运动和神经内分泌反应的其他大脑区域。在DMH中，神经元活动似乎取决于来自两个关键大脑区域的抑制性和兴奋性输入之间的平衡：来自内侧视前区（mPOA）的抑制性（gaba能）投射和来自外侧/背外侧导水管周围灰质（l/dlPAG）的兴奋性（谷氨酸能）投射。一旦被激活，DMH中的神经元就会将兴奋性信号发送到参与激活HPA轴（室旁核，PVN）和交感心血管和温度反应（白斑中段髓质，rPa）的大脑区域。这些区域内的神经元（DMH、mPOA、l/dlPAG、PVN和rPa）的活动似乎受谷氨酸能和gaba能神经传递的控制。这项拨款的具体目的是确定这些大脑区域在mdma诱导的反应中所起的作用。这些研究将在自由活动的有意识大鼠中进行，使用以下三种互补的实验技术：(1)免疫组织化学技术，以确定在mdma诱发反应中参与DMH投射和从DMH投射的假定的gaba能和谷氨酸能神经元；(2)显微注射技术，以确定抑制或刺激感兴趣的区域对mdma诱发反应的影响；(3)微透析技术，以确定抑制或刺激感兴趣的区域如何影响DMH中的gaba能和谷氨酸能神经传递。这项研究具有重要意义，因为了解与使用替代苯丙胺相关的毒性的主要途径和机制为合理的治疗和预防策略提供了必要的框架。此外，这些结果可能会导致医疗条件的治疗，如MDMA，涉及交感神经、躯体运动和神经内分泌系统的病理生理激活：血清素综合征；可卡因毒性、抗精神病药恶性综合征；脑损伤引起的自主神经障碍，以及中暑。

DESCRIPTION (provided by applicant): Use of the amphetamine MDMA (ecstasy, 3, 4-methylenedioxymethamphetamine) can result in life- threatening medical complications including fatal hyperthermia and cardiac arrhythmias. These complications result in part from simultaneous activation of the sympathetic nervous system, the hypothalamic-pituitary- adrenal axis (HPA) and somatic motor systems. It is the long-term objective of the principal investigator to identify the key brain regions and mechanisms through which MDMA activates these systems. The objective of this application is to determine the mechanism by which MDMA activates neurons in the dorsomedial hypothalamus (DMH) - a site involved in the responses evoked by MDMA - and to subsequently determine how this activation stimulates other brain regions involved in sympathetic, somatic motor and neuroendocrine responses. In the DMH, neuronal activity appears to depend on the balance between inhibitory and excitatory inputs from two key brain regions: inhibitory (GABAergic) projections from the medial preoptic area (mPOA) and excitatory (glutamatergic) projections from the lateral/dorsolateral periaqueductal gray (l/dlPAG). Once activated, neurons in the DMH then send excitatory signals to brain regions involved in activating the HPA axis (paraventricular nucleus, PVN) and sympathetic cardiovascular and temperature responses (medullary raphe pallidus, rPa). The activity of neurons within these areas (the DMH, mPOA, l/dlPAG, PVN and rPa) appears to be governed by glutamatergic and GABAergic neurotransmission. The specific aims of this grant will define the roles that these brain regions play in MDMA-induced responses. These studies will be performed in freely moving conscious rats using the following three complimentary experimental techniques: (1) immunohistochemical techniques to identify the putative GABAergic and glutamatergic neurons projecting to and from the DMH that are involved in MDMA-evoked responses; (2) microinjection techniques to determine the effects of inhibiting or exciting the regions of interest on MDMA-evoked responses; and (3) microdialysis techniques to determine how inhibiting or exciting the regions of interest affect GABAergic and glutamatergic neurotransmission in the DMH. The proposed research is significant because understanding the central pathways and mechanisms responsible for toxicity associated with the use of substituted amphetamines provides the necessary framework for rational treatment and prevention strategies. In addition these results may lead to treatments for medical conditions that, like MDMA, involve pathophysiologic activation of sympathetic, somatic motor and neuroendocrine systems: serotonin syndrome; cocaine toxicity, neuroleptic malignant syndrome; dysautonomia from brain injury, and heat stroke. PUBLIC HEALTH RELEVANCE: Abuse of the amphetamine 3,4-methylenedoxymethamphetamine (ecstasy, MDMA) can result in life-threatening medical complication including heart attacks, heart failure, muscle breakdown and severe elevations in body temperature. By identifying the brain areas and chemical receptors responsible for causing MDMA's toxicity, our research may lead to new and innovative treatments.