Kiyatkin Eugene A, Ren Suelynn E
Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, NIH, 333 Cassell Drive, Baltimore, MD, 21224, USA.
Curr Top Behav Neurosci. 2017;32:183-207. doi: 10.1007/7854_2016_35.
Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential dangers of MDMA in humans and the development of pharmacological tools to alleviate drug-induced hyperthermia - potentially saving the lives of highly intoxicated individuals.
精神运动性兴奋剂常被人们用于增强不同类型社交互动的主观体验。由于精神运动性兴奋剂会加快新陈代谢并升高体温，在生理激活状态以及温暖潮湿环境下使用这些药物可能会导致病理性体温过高，这是急性药物中毒的一种危及生命的症状。在此，我们将描述摇头丸（MDMA）、3,4-亚甲基二氧吡咯戊酮（MDPV）和甲烯二氧吡咯戊酮（methylene）这三种结构相关的娱乐性药物对大脑的升温作用，这些药物在狂欢派对及其他社交聚会形式中常被年轻人使用。在简要介绍大脑温度及其生理波动的基本机制后，我们将探讨MDMA、MDPV和甲烯二氧吡咯戊酮如何影响清醒自由活动大鼠的大脑和体温。在此，我们将讨论药物引起的大脑产热（由于大脑代谢激活）以及外周血管收缩导致的散热减少这两个主要因素在这些药物升温作用中的作用。然后，我们将考虑在模拟人类药物使用的条件（社交互动和温暖的环境温度）下，这些药物的升温作用是如何被调节的。由于社交互动会导致大脑和身体产热，同时皮肤血管收缩会阻碍热量散失到外部环境，这些生理变化与药物引起的产热和散热变化相互作用，导致每种受试药物的升温作用发生明显变化。最后，我们展示我们最近的数据，其中我们比较了不同药理学策略在逆转MDMA引起的大脑和身体体温过高方面的效果。具体而言，我们证明了中枢作用的非典型抗精神病化合物氯氮平比外周作用的血管扩张剂药物卡维地洛具有更高的疗效。这些数据对于理解MDMA对人类的潜在危险以及开发缓解药物引起的体温过高的药理学工具可能具有重要意义——有可能挽救重度中毒个体的生命。
