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

描述（由申请方提供）：本探索性开发提案的目标是获得支持R 01申请的初始数据，该申请系统地检查了人类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的血清素（5-HT）神经毒性作用的药物，被年轻人广泛使用。了解成瘾药物的神经后果对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的增加。皮质兴奋性的增加对大脑有着深远的影响，将MDMA毒性与癫痫发作、痴呆和精神疾病联系起来。这种假定的MDMA相关的皮质兴奋性增加与MDMA的终生消耗量和MDMA的戒断持续时间呈正相关。我们现在通过探索性发展（R21）机制申请资金，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中使用经颅磁刺激（TMS）来证明MDMA使用者具有增加的皮层兴奋性，2）使用磁共振波谱（MRS）来确定MDMA使用者是否有皮质谷氨酸（Glu）增加和皮质γ-氨基-谷氨酸（Glu）减少。丁酸（GABA）。我们将连接功能磁共振成像（fMRI），TMS和MRS的结果，以证明是否增加任务诱发激活先前证明与功能磁共振成像与皮质兴奋性增加和皮质谷氨酸和GABA的变化。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和MDMA毒性的特定机制，我们开发了一个翻译神经科学模型来构建和解释所提出的研究结果。我们推测，MDMA诱导的皮质5-HT轴突的损失导致5-HT抑制的净损失，这将与Glu和GABA浓度增加有关。该探索性应用的结果将用于支持R 01应用，以系统地检查MDMA在产生皮质神经生理学改变中的作用。

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.