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，“冰毒”)和3，4-亚甲基二氧基甲基苯丙胺(MDMA，“摇头丸”)的使用目前在欧洲有所增加。以前的工作表明，冰毒和MDMA使用者在各种脉冲控制功能方面都存在重叠但也不同的缺陷，这些功能与药物对单胺、谷氨酸和伽马氨基丁酸(GABA)系统的特定慢性影响有关。特别是，认知障碍会影响用户的社会功能。该项目的主要目标是比较冰毒和MDMA对社会和非社会背景对冲动行为不同方面的调节以及对潜在大脑功能机制的慢性影响。这些比较是通过采用多方法方法实现的，该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。在需要抑制控制机制的冲突监控过程中，我们考察了不同情绪内容(如愤怒和快乐)的影响。在第二个实验范式中，我们使用计算模型研究了奖赏获得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调节冲动行为不同方面的心理生理过程与冰毒和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。这使得可以在结构特定的神经化学水平上与神经生理学和行为进行全面的评估和比较机械因素。鉴于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，关注基底神经节的GABA能和谷氨酸能变化是重要的。因此，该项目对于发现新的治疗方法至关重要，以便：1)改善冰毒和摇头丸使用者日常生活中的冲动控制缺陷和相关的社会问题；2)更好地治疗迄今为止尚未得到批准的药物治疗的冰毒成瘾。

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.