Neurochemistry and Neurophysiology of MDMA (ecstasy)

描述（由申请人提供）：3，4-亚甲二氧基甲基苯丙胺（MDMA/“摇头丸”）是一种流行的“娱乐性”药物，具有相当大的滥用倾向，包括针对中枢神经系统的潜在神经毒性。虽然很多注意力都集中在MDMA的神经毒性作用及其促进单胺递质释放的能力上，但人们对这种药物在高神经毒性剂量或被认为是“娱乐”剂量范围内如何影响神经回路和大脑功能知之甚少。例如，MDMA使用者报告说，摇头丸自我给药的主要令人愉快的结果之一是增强触觉，但没有解释药物如何产生这种令人满意的和备受追捧的感官体验。由于MDMA摄入后可能对神经系统造成长期损害，因此迫切需要了解人类自我施用该药剂的动机背后的神经基质。这项研究的长期目标是更好地了解摇头丸作用的神经生理学基础。目前的建议的直接目标是开发和验证程序，用于评估MDMA对感觉信号处理的VPM丘脑的完整大鼠的影响。该项目采用药物浓度的血浆水平分析，以及在完整的麻醉或清醒大鼠中VPM细胞功能的电生理测定。多通道，多神经元细胞外记录，全身给药，传入三叉神经体感通路的激活，和基于计算机的分析的尖峰序列数据被用来评估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，将在急性和慢性剂量下确定药物效应，所述急性和慢性剂量：1）接近人类自我给药方案，2）产生已知的药物血浆水平，和3）引起大脑感觉回路内单胺流出的可测量变化。了解MDMA给药、单胺递质外排和躯体感觉系统操作之间的关系，将为了解药物对触觉感知（特别是）和神经回路功能（一般）影响的神经生理学机制提供基础。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，是至关重要的，以便为公众提供有关娱乐使用这种流行化合物及其衍生物相关风险的准确信息。此外，一旦建立，这些方法将用于未来的研究，以确定MDMA在其他大脑网络（前额叶皮层，边缘系统）中的作用和更复杂的行为分析（感觉辨别，自我管理，渴望和恢复），作为进一步澄清其滥用倾向的一种手段。沃特豪斯，巴里D. 3，4-亚甲二氧基甲基苯丙胺（MDMA/ 'ecstasy'）是一种越来越受欢迎的“娱乐性”毒品，对国民健康构成重大威胁，因为它：1）对行为和生理功能的急性和慢性不良影响，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。虽然很多注意力都集中在MDMA的神经毒性作用及其促进内源性递质释放的能力上，但对于这种药物在高神经毒性剂量或被认为是“娱乐”剂量范围内如何影响神经回路和大脑功能的运作，人们知之甚少。由于潜在的成瘾性和长期损害神经系统的MDMA摄入后，有迫切需要了解的神经基板的动机，人类自我管理的这种代理。拟议项目的目标是开发和验证程序，这将有助于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.