权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of sudden onset of malignant MDMA neurotoxicity

MDMA 恶性神经毒性突然发生的机制

基本信息

批准号：
7980976
负责人：
RUI TAO
金额：
$ 28.78万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Although recreational uses of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") are usually well- tolerated, some users are occasionally struck by severe and malignant neurotoxicity, particularly under the influence of external factors such as physical activity and a warm ambient temperature. Such a sudden onset of malignant neurotoxic responses cannot be explained simply as a result of drug overdose. Motivated by the fact that physical activity and warm ambient temperature are usually coincidental with malignant reactions, it is hypothesized that these two external factors exacerbate MDMA-induced neurotoxicity. Despite this notion for many years it has been very challenging to investigate the mechanism underlying the action of these two factors on neurotoxic effects of MDMA. In the current proposal, we have developed a novel rat model that allows us to recapitulate the mechanistic role of these two external factors. To better characterize this model and understand the mechanisms, we propose several hypotheses focused on two specific aims that we will test. Aim 1: To investigate the role of each external factor and their combination in the MDMA-induced neurotoxicity. Specifically, we hypothesize that the combination of these two external factors is more serious than each one alone in exacerbating the MDMA-induced neurotoxicity. Animals will be examined under the influence of physical activity, warm ambient temperature or their combination. Changes in body temperature and electroencephalography (EEG) will be determined in response to MDMA at recreationally relevant doses. We predict that physical activity or warm ambient temperature alone has little exacerbating effect on the severity of neurotoxicity induced by MDMA at recreationally relevant doses. However, the combined condition will promote recreationally relevant doses of MDMA to produce a sudden onset of malignant neurotoxicity, showing hyperthermia, seizure-like EEG activity and even death. We will test that 5HT2ARs are crucial for such reactions and further test that external factors cause an alteration or adaptation of 5HT2AR activity, which then promotes neurotoxic effects when MDMA is taken under these conditions. Aim 2: To characterize changes in 5HT efflux and test that the neurotoxic severity is pathophysiologically associated with secondary 5HT efflux and 5HT2AR-mediated signal transduction. We will test that MDMA-produced excessive 5HT efflux can be theoretically described as a composition of two components: primary and secondary 5HT effluxes in correlation with benign and malignant neurotoxicity, respectively. To test this hypothesis, animals will be examined under different experimental conditions while the prefrontal cortical 5HT will be determined using in vivo microdialysis. Supported by our preliminary results, three related hypotheses will be tested. 1) MDMA produces external factor-independent and - dependent increases in 5HT efflux in the CNS. Hypothetically, external factor-independent 5HT efflux is primarily due to depletion of 5HT-containing vesicles (defined as primary efflux), whereas external factor-dependent 5HT efflux is derived from a 5HT2AR-facilitated neural circuit (as secondary efflux). 2) The amount of secondary efflux is positively proportional to the severity of MDMA-induced neurotoxicity. Our hypothesis predicts that the rank order of the amount of secondary efflux will be: physical activity in the warm ambient temperature >physical activity =warm ambient temperature alone >standard experimental condition. 3) We will test that there will be a sudden onset of malignant MDMA neurotoxicity while hypothetical secondary primary efflux. To further understand the underlying molecular mechanisms, we will analyze changes in 5HT2AR protein/mRNA expression and PLC activity in response to physical activity in the warm ambient temperature. In summary, this proposal describes both local and circuitry mechanisms underlying the neurotoxic interaction between environments and MDMA neurotoxicity at recreationally relevant doses. PUBLIC HEALTH RELEVANCE: 3,4-Methylenedioxymethamphetamine (MDMA "ecstasy") neurotoxicity associated with serotonin (5HT) efflux is primarily due to depleting 5HT-containing vesicles. This effect depends on doses. However, a sudden onset of malignant MDMA neurotoxicity depends not only on doses but also physical activity and ambient temperature. How these two external factors influence MDMA-evoked neurotoxicity is not well understood. Using a rat model, this application proposes to test the hypothesis that increased physical activity in combination with warm ambient temperatures markedly enhances the responsivity of 5HT2ARs and subsequently a 5HT2AR-facilitated neural circuit. As a result, there is a great amount of secondary increase in 5HT efflux in the CNS due to the sensitized 5HT2AR- facilitated circuit and thereby promoting the neurotoxic effect of MDMA, which may be the mechanism underlying the sudden onset of malignant neurotoxicity at recreationally relevant doses that usually produce only a benign response.

描述（由申请人提供）：虽然娱乐性使用3，4-亚甲二氧基甲基安非他明（MDMA;“摇头丸”）通常耐受性良好，但有些使用者偶尔会受到严重和恶性神经毒性的影响，特别是在身体活动和温暖的环境温度等外部因素的影响下。这种恶性神经毒性反应的突然发作不能简单地解释为药物过量的结果。由于体力活动和温暖的环境温度通常与恶性反应相一致，因此假设这两个外部因素加剧了MDMA诱导的神经毒性。尽管这一概念多年来，它一直是非常具有挑战性的调查这两个因素对MDMA的神经毒性作用的作用机制。在目前的建议中，我们已经开发了一种新的大鼠模型，使我们能够概括这两个外部因素的机制作用。为了更好地描述这个模型并理解其机制，我们提出了几个假设，重点是两个具体的目标，我们将测试。目的1：探讨各种外界因素及其联合作用在MDMA神经毒性中的作用。具体而言，我们假设这两个外部因素的组合比单独使用更严重地加剧了MDMA诱导的神经毒性。将在体力活动、温暖环境温度或其组合的影响下检查动物。将确定体温和脑电图（EEG）变化对娱乐相关剂量MDMA的反应。我们预测，单独的体力活动或温暖的环境温度对MDMA在娱乐相关剂量下诱导的神经毒性的严重程度几乎没有加重作用。然而，这两种情况的结合会促进娱乐相关剂量的MDMA产生恶性神经毒性的突然发作，表现出高热、癫痫样EEG活动，甚至死亡。我们将测试5 HT 2AR对这些反应至关重要，并进一步测试外部因素导致5 HT 2AR活性的改变或适应，然后在这些条件下服用MDMA时促进神经毒性作用。目标二：表征5 HT外排的变化，并检测神经毒性严重程度与继发性5 HT外排和5 HT 2AR介导的信号转导的病理生理学相关性。我们将测试MDMA产生的过量5 HT流出理论上可以描述为两个组成部分的组合物：分别与良性和恶性神经毒性相关的原发性和继发性5 HT流出。为了检验这一假设，将在不同的实验条件下检查动物，同时使用体内微透析测定前额叶皮质5 HT。在初步研究结果的支持下，我们将检验三个相关的假设。1)MDMA可使CNS中的5 HT外排产生外部因素非依赖性和依赖性增加。假设，外部因子非依赖性5 HT外排主要是由于含5 HT囊泡的耗竭（定义为初级外排），而外部因子依赖性5 HT外排来自5 HT 2AR促进的神经回路（作为次级外排）。2)继发性外排的量与MDMA诱导的神经毒性的严重程度成正比。我们的假设预测，次级外排量的排序将是：在温暖的环境温度下的身体活动>身体活动=单独的温暖的环境温度>标准实验条件。3)我们将测试恶性MDMA神经毒性的突然发作，同时假设继发性原发性外排。为了进一步了解潜在的分子机制，我们将分析在温暖的环境温度下，响应于身体活动的5 HT 2AR蛋白/mRNA表达和PLC活性的变化。总之，该提案描述了在娱乐相关剂量下环境与MDMA神经毒性之间的神经毒性相互作用的局部和电路机制。公共卫生相关性：与5-羟色胺（5-HT）外排相关的3，4-亚甲二氧基甲基苯丙胺（MDMA“摇头丸”）神经毒性主要是由于耗尽含5-HT的囊泡。这种效果取决于剂量。然而，恶性MDMA神经毒性的突然发作不仅取决于剂量，还取决于体力活动和环境温度。这两个外部因素如何影响MDMA诱发的神经毒性尚不清楚。使用大鼠模型，本申请提出测试以下假设：增加的身体活动与温暖的环境温度相结合显著增强了5 HT 2AR的响应性，随后增强了5 HT 2AR促进的神经回路。因此，由于致敏的5-HT 2AR-易化回路，CNS中的5-HT流出大量继发性增加，从而促进了MDMA的神经毒性作用，这可能是在通常仅产生良性反应的娱乐相关剂量下突然发生恶性神经毒性的潜在机制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Changes in intensity of serotonin syndrome caused by adverse interaction between monoamine oxidase inhibitors and serotonin reuptake blockers.

单胺氧化酶抑制剂和血清素再摄取阻滞剂之间的不良相互作用引起血清素综合征强度的变化。

DOI：
10.1038/npp.2014.49
发表时间：
2014
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Tao,Rui;Rudacille,Mary;Zhang,Gongliang;Ma,Zhiyuan
通讯作者：
Ma,Zhiyuan

Environment Influencing Serotonin Syndrome Induced by Ecstasy Abuse.

环境影响摇头丸滥用引起的血清素综合症。