Background: Psychedelic compounds such as methylenedioxymethamphetamine have attracted increasing interest in recent years due to their therapeutic potential in psychiatric disorders. To understand the acute effects of psychedelic drugs in vivo, blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD-fMRI) has been widely used in recent years. In particular, fMRI studies have suggested that methylenedioxymethamphetamine leads to inhibition of brain activity, challenging previous hypotheses indicating mainly excitatory effects based, among others, on increased metabolism shown by ¹⁸F-fluorodeoxyglucose functional positron emission tomography (¹⁸F-FDG-fPET). However, interpretation of hemodynamic changes induced by psychedelics is difficult due to their potent vascular effects. Methods: We aimed to delineate the acute effects of methylenedioxymethamphetamine using simultaneous PET/fMRI in rats. For this purpose, hemodynamic changes measured by BOLD-fMRI were related to alterations in glucose utilization and serotonin transporter (SERT) occupancy using ¹⁸F-FDG-fPET/fMRI and ¹¹C-DASB-PET/fMRI. Results: We show that methylenedioxymethamphetamine induces localized increases in glucose metabolism in limbic projection areas involved in emotional processing. The increased glucose metabolism was accompanied by global cerebral and extracerebral hemodynamic decreases. We further demonstrate a strong correlation between SERT occupancies and regional BOLD reductions after acute methylenedioxymethamphetamine. Discussion: Our data indicate that hemodynamic decreases after acute methylenedioxymethamphetamine are of non-neuronal nature and initiated peripherally. Within the brain, methylenedioxymethamphetamine induces neuronal activation in limbic projection areas, while increased serotonin levels induced by SERT blockage cause neurovascular uncoupling through direct vascular effects. Correct understanding of the in vivo mechanism of methylenedioxymethamphetamine not only supports ongoing research but also warrants a reassessment of previous studies on neuronal effects of psychedelics relying on neurovascular coupling and recommends ¹⁸F-FDG-fPET as a potentially more robust measure for pharmacological research.

背景：近年来，亚甲二氧基甲基苯丙胺等迷幻化合物因其在精神疾病的治疗潜力而受到越来越多的关注。为了了解迷幻药物在体内的急性作用，血氧水平依赖性功能磁共振成像（BOLD-fMRI）近年来得到广泛应用。特别是，fMRI 研究表明，亚甲二氧基甲基苯丙胺会导致大脑活动的抑制，挑战先前的假设，表明主要基于兴奋作用，除其他外，18 F-氟脱氧葡萄糖功能性正电子发射断层扫描显示的代谢^增加（¹⁸F-FDG-fPET）。然而，由于迷幻剂对血管的强效作用，很难解释由迷幻剂引起的血流动力学变化。方法：我们的目的是在大鼠中同时使用 PET/fMRI 来描述亚甲二氧基甲基苯丙胺的急性作用。为此，使用¹⁸ F-FDG-fPET/fMRI 和¹¹ C-DASB-PET/fMRI，通过 BOLD-fMRI 测量的血流动力学变化与葡萄糖利用和血清素转运蛋白 (SERT) 占用率的变化相关。 结果：我们表明，亚甲二氧基甲基苯丙胺会导致参与情绪处理的边缘投射区域的葡萄糖代谢局部增加。葡萄糖代谢增加伴随着全脑和脑外血流动力学下降。我们进一步证明了急性亚甲二氧基甲基苯丙胺后 SERT 占用率与区域 BOLD 减少之间的强相关性。 讨论：我们的数据表明，急性亚甲二氧基甲基苯丙胺后血流动力学下降是非神经性的，并且是从外周开始的。在大脑中，亚甲二氧基甲基苯丙胺诱导边缘投射区域的神经元激活，而 SERT 阻断诱导的血清素水平升高通过直接血管效应导致神经血管解偶联。正确理解亚甲二氧基甲基苯丙胺的体内机制不仅支持正在进行的研究，而且还需要重新评估以前关于依赖于神经血管耦合的致幻剂神经元效应的研究，并推荐 18 F-FDG-fPET 作为药理学研究的潜在更强有力的^措施。