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

描述(由申请人提供)：这一探索性开发提案的目标是获得初始数据，以支持R01应用程序，该应用程序系统地检查人类MDMA(摇头丸)使用者皮质兴奋性增加的神经生物学。MDMA是一种在啮齿动物和非人类灵长类动物中具有良好证明的5-羟色胺(5-HT)神经毒性作用的药物，被年轻人广泛使用。了解成瘾药物的神经后果对于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可能导致皮质兴奋性的增加。皮质兴奋性的增加对大脑有深远的影响，将MDMA的毒性与癫痫障碍、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MDMA的终生消耗量和戒断MDMA的持续时间都呈正相关。我们现在通过探索性发育(R21)机制申请资金，以探索这些发现的神经机制：1)通过在视觉和运动皮质进行经颅磁刺激(TMS)来证明MDMA使用者的皮质兴奋性增加，以及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)和降低了皮质伽马氨基丁酸(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fMRI显示的任务诱发激活增加是否与皮质兴奋性增加以及皮质Glu和GABA的变化相关。我们还将探索这些措施与抑郁和焦虑之间的联系。基于5-羟色胺在脑神经生理学中的作用和MDMA毒性的具体机制，我们开发了一个翻译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-羟色胺轴突的丢失导致5-羟色胺抑制的净丧失，这将与Glu和GABA浓度的增加有关。这一探索性应用的发现将被用于支持R01应用，以系统地研究MDMA在产生改变的皮质神经生理学中的作用。

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.