Neural mechanisms of increased cortical excitability in human MDMA/Ecstasy users

人类 MDMA/摇头丸使用者皮质兴奋性增加的神经机制

• 批准号: 8444212
• 负责人: RONALD L COWAN
• 金额: $ 23.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444212
• 关键词: Abstinence; Accommodation phosphene; American; Anxiety; Axon; Brain; Brain Injuries; Butyric Acids; Chronic; Data; Dementia; Development; Drug usage; Epilepsy; Equipment and supply inventories; Exploratory/Developmental Grant; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Functional Magnetic Resonance Imaging; Funding; Generations; Gliosis; Glutamates; Goals; Human; Investigation; Link; Magnetic Resonance Spectroscopy; Measures; Mediating; Mental Depression; Metric; Mission; Modeling; Motor; Motor Cortex; N-acetylaspartate; Neocortex; Neurobiology; Neurons; Neurotransmitters; Outcome; Pharmaceutical Preparations; Positron-Emission Tomography; Public Health; Research; Risk; Rodent; Role; Secondary to; Serotonin; Signal Transduction; Suicide attempt; Toxic effect; Transcranial magnetic stimulation; Visual; Visual Cortex; base; design; ecstasy; myoinositol; nerve supply; neuromechanism; neuron loss; neurophysiology; neurotoxic; nonhuman primate; programs; public health relevance; receptor; relating to nervous system; translational neuroscience; visual motor; young adult

DESCRIPTION (provided by applicant): The goal of this exploratory developmental proposal is to obtain initial data to support an R01 application that systematically examines the neurobiology of increased cortical excitability in human MDMA (Ecstasy) users. MDMA, a drug that has well-demonstrated serotonin (5-HT) neurotoxic effects in rodents and non-human primates, is widely used by young adults. Understanding the neural consequences of addictive drugs is of critical importance to NIDA's mission to reduce drug use and its negative effects. Our earlier research found that MDMA leads to probable increases in cortical excitability. Increased cortical excitability has profound implications for the brain, relating MDMA toxicity to seizure disorders, dementia, and psychiatric conditions. This putative MDMA-associated increase in cortical excitability correlates positively both with lifetime quantity of MDMA consumed and also with the duration of abstinence from MDMA. We now request funding via the Exploratory Developmental (R21) mechanism to explore the neural mechanism for these findings by: 1) by using transcranial magnetic stimulation (TMS) in visual and motor cortex to demonstrate MDMA users have increased cortical excitability and, 2) to use magnetic resonance spectroscopy (MRS) to determine if MDMA users have increased cortical glutamate (Glu) and decreased cortical gamma-amino- butyric acid (GABA). We will link functional magnetic resonance imaging (fMRI), TMS, and MRS results to demonstrate whether the increased task-evoked activation previously demonstrated with fMRI is correlated with increased cortical excitability and changes in cortical Glu and GABA. We will also explore the link between these measures and depression and anxiety. Based upon the role of 5-HT in brain neurophysiology and upon the specific mechanism of MDMA toxicity, we have developed a translational neuroscience model to frame and interpret the proposed findings. We hypothesize that MDMA-induced loss of cortical 5-HT axons leads to a net loss of 5-HT inhibition that will be associated with increased Glu and GABA concentrations. Findings from this exploratory application will be used to support an R01 application to systematically examine the role of MDMA in producing altered cortical neurophysiology.

描述（由申请人提供）：该探索性开发提案的目标是获得初始数据来支持 R01 应用，该应用系统地检查人类 MDMA（摇头丸）使用者皮质兴奋性增加的神经生物学。 MDMA 是一种已被证明对啮齿动物和非人类灵长类动物具有血清素 (5-HT) 神经毒性作用的药物，被年轻人广泛使用。了解成瘾药物对神经的影响对于 NIDA 减少药物使用及其负面影响的使命至关重要。我们早期的研究发现 MDMA 可能会导致皮质兴奋性增加。皮质兴奋性的增加对大脑具有深远的影响，将 MDMA 毒性与癫痫症、痴呆和精神疾病联系起来。这种假定的与 MDMA 相关的皮质兴奋性增加与终生消耗的 MDMA 数量以及戒除 MDMA 的持续时间呈正相关。我们现在通过探索性发展（R21）机制请求资金，通过以下方式探索这些发现的神经机制：1）通过在视觉和运动皮层使用经颅磁刺激（TMS）来证明MDMA使用者的皮质兴奋性增加，2）使用磁共振波谱（MRS）来确定MDMA使用者是否增加了皮质谷氨酸（Glu）和减少了皮质 γ-氨基丁酸（GABA）。我们将把功能磁共振成像 (fMRI)、TMS 和 MRS 结果联系起来，以证明先前通过 fMRI 证明的任务诱发激活的增加是否与皮质兴奋性的增加以及皮质 Glu 和 GABA 的变化相关。我们还将探讨这些措施与抑郁和焦虑之间的联系。基于 5-HT 在脑神经生理学中的作用以及 MDMA 毒性的具体机制，我们开发了一个转化神经科学模型来框架和解释所提出的发现。我们假设 MDMA 诱导的皮质 5-HT 轴突损失导致 5-HT 抑制的净损失，这与 Glu 和 GABA 浓度增加有关。这一探索性应用的结果将用于支持 R01 应用，以系统地研究 MDMA 在产生皮质神经生理学改变中的作用。