CNS circuitry and receptors mediating the effects of MDMA

中枢神经系统回路和受体介导 MDMA 的作用

• 批准号: 8655527
• 负责人: DANIEL E RUSYNIAK
• 金额: $ 33.61万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655527
• 关键词: Affect; Amphetamine Abuse; Amphetamines; Anxiety; Area; Arrhythmia; Attenuated; Body Temperature; Brain; Brain Injuries; Brain region; Cardiovascular system; Chemicals; Cocaine; Conscious; Data; Dysautonomias; Equilibrium; FOS gene; Generations; Glutamate Receptor; Glutamates; Goals; Grant; Heart failure; Heat Stroke; Hypertension; Hyperthermia; Hypothalamic structure; Lateral; Lead; Life; Medial; Mediating; Medical; Microdialysis; Microinjections; Middle Hypothalamus; Motor; Muscle; Myocardial Infarction; Neuroleptic Malignant Syndrome; Neurons; Neurosecretory Systems; Pathway interactions; Play; Preoptic Areas; Prevention strategy; Principal Investigator; Rattus; Research; Rhabdomyolysis; Role; Serotonin Syndrome; Signal Transduction; Site; Source; Sympathetic Nervous System; System; Techniques; Temperature; Testing; Toxic effect; Work; design; ecstasy; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; innovation; insight; interest; medical complication; midbrain central gray substance; neural circuit; neurochemistry; neuroregulation; neurotransmission; novel; paraventricular nucleus; public health relevance; receptor; relating to nervous system; response; treatment strategy

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.

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疗并发症，包括致命的体温过高和心律失常。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。首席研究人员的长期目标是确定MDMA激活这些系统的关键大脑区域和机制。这项应用的目的是确定MDMA激活下丘脑背内侧(DMH)神经元的机制，并随后确定这种激活如何刺激参与交感、躯体运动和神经内分泌反应的其他大脑区域。在DMH，神经元的活动似乎依赖于来自两个关键脑区的抑制性和兴奋性输入之间的平衡：来自内侧视前区的抑制性(GABA能)投射和来自外侧/背外侧中脑导水管周围灰质(L/dlPAG)的兴奋性(谷氨酸)投射。一旦被激活，DMH中的神经元就会向参与激活HPA轴(室旁核，PVN)和交感心血管反应和温度反应(延髓中缝苍白核，RPA)的大脑区域发送兴奋信号。这些区域(DMH、mPOA、L/dlPAG、PVN和RPA)内神经元的活动似乎受谷氨酸和GABA能神经传递的支配。这笔赠款的具体目标将定义这些大脑区域在MDMA诱导的反应中所扮演的角色。这些研究将在自由活动的清醒大鼠上进行，使用下列三种免费的实验技术：(1)免疫组织化学技术确定投射到和离开DMH的可能的GABA能和谷氨酸能神经元参与MDMA诱发的反应；(2)显微注射技术确定抑制或兴奋感兴趣区对MDMA诱发反应的影响；以及(3)微透析技术确定抑制或兴奋感兴趣区如何影响DMH的GABA能和谷氨酸能神经传递。拟议的研究具有重要意义，因为了解与使用替代苯丙胺有关的毒性的中心途径和机制为合理的治疗和预防战略提供了必要的框架。此外，这些结果可能导致对医疗条件的治疗，如MDMA，涉及交感、躯体运动和神经内分泌系统的病理生理激活：5-羟色胺综合征；可卡因中毒，抗精神病药物恶性综合征；脑损伤导致的自主神经障碍，以及中暑。

项目成果

The Ergogenic Effect of Amphetamine.

安非他明的强效作用。

• DOI: 10.4161/23328940.2014.987564
• 发表时间: 2014
• 期刊: Temperature (Austin, Tex.)
• 作者: Zaretsky,DmitryV;Brown,MaryBeth;Zaretskaia,MariaV;Durant,PamelaJ;Rusyniak,DanielE
• 通讯作者: Rusyniak,DanielE

The orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress.

orexin-1 受体拮抗剂 SB-334867 可降低对中等剂量甲基苯丙胺和压力的交感神经反应。

• DOI: 10.1016/j.physbeh.2012.02.010
• 发表时间: 2012
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Rusyniak,DanielE;Zaretsky,DmitryV;Zaretskaia,MariaV;Durant,PamelaJ;DiMicco,JosephA
• 通讯作者: DiMicco,JosephA

Neurologic manifestations of chronic methamphetamine abuse.

• DOI: 10.1016/j.ncl.2011.05.004
• 发表时间: 2011-08
• 期刊: NEUROLOGIC CLINICS
• 影响因子: 2.4
• 作者: Rusyniak, Daniel E.

Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment.

• DOI: 10.1002/prp2.31
• 发表时间: 2014-04-01
• 期刊: PHARMACOLOGY RESEARCH & PERSPECTIVES
• 影响因子: 2.6
• 作者: Zaretsky, Dmitry V;Zaretskaia, Maria V;Durant, Pamela J;Rusyniak, Daniel E
• 通讯作者: Rusyniak, Daniel E

The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area.

• DOI: 10.1016/j.neulet.2011.05.006
• 发表时间: 2011-07-08
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Rusyniak DE;Zaretsky DV;Zaretskaia MV;DiMicco JA
• 通讯作者: DiMicco JA