Neurochemistry and Neurophysiology of MDMA (ecstasy)

描述(由申请人提供)：3，4-亚甲基二氧基甲基苯丙胺(MDMA/‘摇头丸’)是一种受欢迎的“娱乐”药物，具有相当大的滥用可能性，包括对中枢5-羟色胺能系统的潜在神经毒性。尽管人们对MDMA的神经毒性作用及其促进单胺递质释放的能力有很大的关注，但人们对该药物如何影响神经回路的运作和大脑功能知之甚少，无论是在高神经毒性剂量下，还是在被认为是“娱乐”剂量范围内。例如，摇头丸使用者报告说，摇头丸自我给药的主要愉悦结果之一是增强触觉，但没有解释这种药物是如何产生这种令人向往和备受追捧的感觉体验的。由于摄入MDMA后可能对神经系统造成长期损害，迫切需要了解人类自我给药动机背后的神经底物。这项拟议研究的长期目标是更好地了解摇头丸效果背后的神经生理学。本提案的直接目标是开发和验证评估MDMA对正常大鼠VPM丘脑感觉信号处理的影响的程序。该项目使用药物浓度的血浆水平分析，以及对完整麻醉或清醒大鼠的VPM细胞功能的电生理学测定。多通道、多神经元细胞外记录、全身给药、三叉神经体感传入通路的激活以及基于计算机的棘波训练数据分析被用来评估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，药物效果将在急性和慢性剂量下确定：1)接近人类自我给药方案，2)产生已知的药物血浆水平，以及3)在大脑感觉回路中引起单胺流出的可测量变化。了解MDMA给药、单胺递质外流和躯体感觉系统运行之间的关系，将为了解药物对触觉感觉的潜在神经生理机制，特别是对一般神经回路功能的影响提供基础。详细了解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，对于向公众提供有关娱乐使用这种受欢迎的化合物及其衍生物相关风险的准确信息是至关重要的。此外，一旦确定，这些方法将用于未来的研究，以表征MDMA在其他大脑网络(前额叶皮质，边缘)的活动，以及更复杂的行为分析(感觉辨别、自我管理、渴望和重新陈述)，作为进一步澄清其滥用责任的手段。沃特豪斯，巴里D.项目叙事()3，4-亚甲基二氧基甲基苯丙胺(MDMA/‘摇头丸’)是一种越来越受欢迎的“娱乐”药物，它对国家的健康构成了重大威胁，因为它：1)对行为和生理功能的急性和慢性不利影响，2)对大脑中选定的神经递质系统的神经毒性，以及3)总体成瘾潜力。尽管人们的注意力主要集中在MDMA的神经毒性作用及其促进内源性递质释放的能力上，但人们对该药物如何影响神经回路的运作和大脑功能知之甚少，无论是在高神经毒性剂量下，还是在被认为是“娱乐”剂量范围内。由于摄入MDMA后可能会上瘾和长期损害神经系统，迫切需要了解人类自我给药动机背后的神经底物。拟议项目的目标是开发和验证程序，帮助我们更好地理解摇头丸对人类吸毒者影响的神经生理学基础。

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.