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: 8604148
• 负责人: RONALD L COWAN
• 金额: $ 19.5万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604148
• 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）：此探索性发展建议的目的是获取初始数据，以支持R01应用程序，该应用程序系统地研究了人类MDMA（狂喜）用户中皮质兴奋性增加的神经生物学。 MDMA是一种在啮齿动物和非人类灵长类动物中具有很好的羟色胺（5-HT）神经毒性作用的药物，被年轻人广泛使用。了解成瘾性药物的神经后果对于NIDA减少药物使用及其负面影响至关重要。我们较早的研究发现，MDMA导致皮质兴奋性可能增加。皮质兴奋性的增加对大脑具有深远的影响，将MDMA毒性与癫痫发作，痴呆症和精神病病有关。这种推定的MDMA相关皮质兴奋性的增加与消耗的MDMA量以及MDMA禁欲的持续时间均与寿命数量呈正相关。现在，我们通过探索性发育（R21）机制要求资助这些发现的神经机制：1）通过在视觉和运动皮层中使用经颅磁刺激（TMS）来证明MDMA使用者具有增加的皮质兴奋性，并且，2）使用磁共振光谱（MRS）来确定MDMA使用者是否增加了皮质谷氨酸（GLU）并减少皮质γ-氨基氨基酸（GABA）。我们将将功能性磁共振成像（fMRI），TMS和MRS结果联系起来，以证明先前用fMRI证明的任务引起的激活是否与皮质兴奋性的增加和皮质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在脑神经生理学和MDMA毒性的特定机制中的作用，我们开发了一种转化神经科学模型来构架和解释拟议的发现。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，这将与GLU和GABA浓度升高有关。该探索性应用程序的发现将用于支持R01应用，以系统地检查MDMA在产生皮质神经生理学改变的作用。