Neurochemistry and Neurophysiology of MDMA (ecstasy)

MDMA（摇头丸）的神经化学和神经生理学

• 批准号: 7314483
• 负责人: BARRY Dale WATERHOUSE
• 金额: $ 18.75万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314483
• 关键词: Acute; Affect; Afferent Neurons; Animals; Attention; Behavior; Behavioral Assay; Biochemical; Biological Assay; Brain; Cell physiology; Cells; Chronic; Computers; Condition; Data; Dose; Drug user; Electrodes; Esthesia; Future; Goals; Health; Human; Ingestion; Knowledge; Measurable; Methods; Modeling; Motivation; Nervous system structure; Neurons; Neurotransmitters; Operative Surgical Procedures; Oral; Oral Administration; Outcome; Pathway interactions; Perception; Pharmaceutical Preparations; Phase; Physiological; Plasma; Prefrontal Cortex; Procedures; Process; Property; Protocols documentation; Purpose; Range; Rattus; Recreational Drugs; Reporting; Research; Risk; Rodent; Self Administration; Sensory; Synapses; System; Tactile; Techniques; Testing; Thalamic structure; Time; Training; Training Activity; Treatment Protocols; Trigeminal System; Vibrissae; Work; addiction; base; chemical standard; computerized data processing; craving; ecstasy; experience; extracellular; in vivo; intraperitoneal; monoamine; neural circuit; neurochemistry; neurophysiology; neurotoxic; neurotoxicity; relating to nervous system; research study; response; sensory discrimination; somatosensory; subcutaneous

DESCRIPTION (provided by applicant): 3,4-methylenedioxymethamphetamine (MDMA/ 'ecstasy') is a popular "recreational" drug with considerable abuse liability including potential neurotoxicities directed toward the central serotonergic system. Although much attention has focused on MDMA's neurotoxic effects and its' ability to promote release of monoamine transmitters, little is known about how the drug affects the operation of neural circuits and brain function either at high neurotoxic doses or doses considered to be in the "recreational" range. For example, MDMA users report that one of the major pleasurable outcomes of ecstasy self-administration is enhanced tactile sensation, but there is no explanation for how the drug produces this desirable and much sought after sensory experience. Because of the potential for long term damage to the nervous system after MDMA ingestion, there is a pressing need to understand the neural substrates underlying the motivation for human self-administration of this agent. The long-term goal of the proposed research is to better understand the neurophysiology underlying ecstasy's effects. The immediate goal of the present proposal is to develop and validate procedures for evaluating the impact of MDMA on sensory signal processing in the VPM thalamus of intact rats. The project employs plasma level analysis of drug concentrations, and electrophysiological determination of VPM cellular function in intact anesthetized or waking rats. Multi-channel, multi-neuron extracellular recording, systemic drug administration, activation of afferent trigeminal somatosensory pathways, and computer based analysis of spike train data are used to assess the impact of MDMA on sensory signal processing. A significant feature of this multi-dimensional approach is that drug effects will be determined at acute and chronic doses that: 1) approximate human self-administration regimens, 2) produce known plasma levels of the drug, and 3) elicit measurable changes in monoamine efflux within sensory circuits of the brain. Understanding the relationship between MDMA administration, monoamine transmitter efflux, and the operation of the somatosensory system will provide a basis for understanding the neurophysiological mechanisms underlying the drugs' effects on tactile sensory perception, in particular; and neural circuit functions, in general. A detailed knowledge of MDMA's effects on cellular and neural circuit function including its effects on sensory neurophysiology is essential in order to provide the public with accurate information regarding the risks associated with recreational use of this popular compound and its derivatives. Furthermore, once established, these methods will be used in future studies to characterize MDMA actions in other brain networks (prefrontal cortex, limbic) and more sophisticated behavioral assays (sensory discrimination, self-administration, craving and re-instatement) as a means of further clarifying its abuse liability. Waterhouse, Barry D. PROJECT NARRATIVE ()3,4-methylenedioxymethamphetamine (MDMA/ 'ecstasy') is an increasingly popular "recreational" drug that poses a significant threat to the nation's health because of its: 1) adverse acute and chronic effects on behavior and physiological functions, 2) neurotoxicity toward selected neurotransmitter systems in the brain, and 3) overall addictive potential. Although much attention has focused on MDMA's neurotoxic effects and its' ability to promote release of endogenous transmitters, little is known about how the drug affects the operation of neural circuits and brain function either at high neurotoxic doses or doses considered to be in the "recreational" range. Because of the potential for addiction and long term damage to the nervous system after MDMA ingestion, there is a pressing need to understand the neural substrates underlying the motivation for human self-administration of this agent. The goal of the proposed project is to develop and validate procedures that will help us better comprehend the neurophysiological basis for ecstasy's effects in human drug users.

描述（由申请人提供）：3,4-甲基二甲基甲基苯丙胺（MDMA/'狂喜'）是一种流行的“休闲”药物，具有相当大的虐待责任，包括针对中央血清素能系统的潜在神经毒性。尽管非常关注MDMA的神经毒性效应及其促进单胺发送器释放的能力，但对于该药物如何影响神经回路和脑功能的运作鲜明，在高神经毒性剂量或剂量上如何影响被认为是在“休闲”范围内。例如，MDMA用户报告说，摇头丸自我给药的主要愉悦结果之一是增强的触觉感觉，但是对于该药物如何产生这种可取的和广受欢迎的感官体验的触感。由于MDMA摄入后可能会长期损害神经系统，因此有必要理解该药物人类自我给药动机的基础的神经底物。拟议的研究的长期目标是更好地了解摇头丸的神经生理学的影响。本提案的直接目标是制定和验证程序，以评估MDMA对完整大鼠VPM丘脑中感觉信号处理的影响。该项目采用药物浓度的血浆水平分析，并在完整麻醉或醒来的大鼠中对VPM细胞功能的电生理测定。多通道，多神经元外记录，全身药物给药，传入三叉色体感应途径的激活以及基于计算机的尖峰训练数据分析用于评估MDMA对感觉信号处理的影响。这种多维方法的一个重要特征是，将在急性和慢性剂量下确定药物作用：1）近似人类的自我给药方案，2）产生已知的血浆水平，3）3）在大脑的感觉电路中产生可测量的单胺外突化的变化。了解MDMA给药，单胺发射器外排和体感系统的运行之间的关系将为理解药物对触觉感觉感知作用的影响的神经生理机制提供基础。通常，神经回路功能。对于MDMA对细胞和神经回路功能的影响，包括其对感觉神经生理学的影响，对于为公众提供有关与这种流行化合物及其衍生物相关的风险的准确信息至关重要的详细知识至关重要。此外，一旦建立，这些方法将在以后的研究中使用，以表征其他大脑网络（前额叶皮层，边缘）和更复杂的行为测定（感觉歧视，自我管理，渴望和重新加入）中的MDMA动作，以进一步阐明其虐待责任。 Waterhouse，Barry D.项目叙事（）3,4-甲基二甲基甲基苯丙胺（MDMA/'狂喜'）是一种日益流行的“娱乐性”药物，对国家的健康构成了重大威胁：1）不利的急性和慢性效应对行为和生理功能的影响，对选择的神经毒性对神经毒性进行了整体构建和3个神经毒性的影响。尽管非常关注MDMA的神经毒性效应及其促进内源性发射器释放的能力，但对于该药物如何影响神经回路和大脑功能的运作鲜为人知，要么在高神经毒性剂量或剂量下被认为是在“休闲”范围内。由于MDMA摄入后的神经系统会造成成瘾和长期损害，因此有必要理解该药物对人类自我管理动机的基础的神经底物。拟议项目的目的是制定和验证程序，以帮助我们更好地理解狂喜人在人类吸毒者中的影响的神经生理基础。