Comparative neuropsychopharmacology of methamphetamine (“Crystal Meth”) and MDMA (“Ecstasy”) on facets of cognitive control and impulsive behavior in social and non-social contexts: integrating behavior, psychophysiology, and neurochemistry

甲基苯丙胺（冰毒）和3,4-亚甲基二氧甲基苯丙胺（摇头丸）的使用目前在欧洲有所增加。先前的研究表明，甲基苯丙胺和MDMA使用者在各种冲动控制功能上都存在重叠但不同的缺陷，这些缺陷与药物对单胺、谷氨酸和γ -氨基丁酸（GABA）系统的特定慢性影响有关。特别是，认知障碍会影响使用者的社交功能。该项目的主要目标是比较甲基安非他明和MDMA在社会和非社会环境下对冲动行为不同方面的调节的慢性影响，以及潜在的大脑功能机制。这些比较是通过采用多种方法将行为和电生理（EEG）数据与来自磁共振波谱（MRS）的神经化学信息相结合来实现的。我们研究了不同的情绪内容（如愤怒和快乐）在冲突监测过程中需要抑制控制机制的影响。在第二个实验范式中，我们使用计算模型研究了奖励获取和损失避免背景下的过早反应冲动性（PRI）。我们将社会和非社会环境对冲动行为不同方面的调节的心理生理过程与甲基安非他明和MDMA使用者纹状体GABA和GLU水平的结构神经生化变化联系起来。这允许在神经生理学和行为的结构特异性神经化学水平上对机制因素进行全面的评估和比较。考虑到调节这些系统的化合物可能是治疗兴奋剂成瘾的有趣候选者，关注基底神经节中gaba能和谷氨酸能的变化是重要的。因此，该项目对于发现新的治疗方法至关重要，以便i)改善冲动控制缺陷和甲基安非他明和MDMA使用者日常生活中的相关社会问题，ii)更好地治疗迄今为止尚未批准的药物治疗方法。

The use of methamphetamine (METH, “Crystal Meth”) and 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) currently increases in Europe. Previous work has shown that both METH and MDMA users suffer from overlapping but also different deficits in a variety of impulse control functions that are related to the specific chronic effects of the drugs on monoamine, glutamate, and gamma-aminobutyric acid (GABA) systems. In particular, cognitive impairments impact the social functions of the users. The main goal of this project is to compare the chronic effects of METH and MDMA on the modulation of different facets of impulsive behavior by social and non-social contexts, as well as on the underlying functional brain mechanisms. These comparisons are achieved by employing a multi-method approach integrating behavioral and electrophysiological (EEG) data with neurochemical information derived from magnetic resonance spectroscopy (MRS). We investigate the effect of varying emotional contents (such as angriness and happiness) during conflict monitoring processes requiring inhibitory control mechanisms. In a second experimental paradigm we examine premature responding impulsivity (PRI) during contexts of reward acquisition and loss avoidance using computational modelling. We relate psychophysiological processes underlying modulations of different facets of impulsive behavior by social and non-social contexts to structural-neurobiochemical changes at the striatal GABA and GLU level in METH and MDMA users. This allows a comprehensive evaluation and comparison of mechanistic factors at a structure-specific neurochemical level with neurophysiology and behavior. The focus on the GABAergic and glutamatergic changes in the basal ganglia is important, given that compounds modulating these systems may be interesting candidates in the treatment of stimulant addiction. Thus, the project is crucial to discover new therapeutic approaches in order to i) improve impulse control deficits and related social problems in the daily life of the METH and MDMA users and ii) to better treat METH addiction for which no approved pharmacological treatment exists so far.