Tylš Filip, Vejmola Čestmír, Koudelka Vlastimil, Piorecká Václava, Kadeřábek Lukáš, Bochin Marcel, Novák Tomáš, Kuchař Martin, Bendová Zdeňka, Brunovský Martin, Horáček Jiří, Pálení Ček Tomáš
Psychedelic Research Centre, National Institute of Mental Health, Klecany, Czechia.
3rd Faculty of Medicine, Charles University in Prague, Prague, Czechia.
Front Neurosci. 2023 Jun 22;17:1152578. doi: 10.3389/fnins.2023.1152578. eCollection 2023.
Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT receptors, it has high binding affinity also to 5-HT and 5-HT receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model.
Selective antagonists of serotonin receptors (5-HT WAY100635, 5-HT MDL100907, 5-HT SB242084) and antipsychotics haloperidol, a D antagonist, and clozapine, a mixed D and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology.
Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1-25 Hz; however, decreases in 25-40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT antagonist while other drugs had no effect.
These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT-dependent mechanisms underlying the neurobiology of psychedelics.
裸盖菇素是研究最为广泛的致幻药物之一，具有广泛的治疗潜力。尽管其精神活性主要归因于对5-羟色胺（5-HT）受体的激动作用，但它对5-HT及5-HT受体也具有高结合亲和力，并间接调节多巴胺能系统。裸盖菇素及其活性代谢物脱磷酸裸盖菇素，以及其他血清素能致幻剂，在人类和动物的脑电图（EEG）中均会诱发宽带去同步化和断开连接。这些变化背后的血清素能和多巴胺能机制的作用尚不清楚。因此，本研究旨在阐明脱磷酸裸盖菇素在动物模型中诱发宽带去同步化和断开连接的药理学机制。
使用5-羟色胺受体的选择性拮抗剂（5-HT WAY100635、5-HT MDL100907、5-HT SB242084）以及抗精神病药物氟哌啶醇（一种D拮抗剂）和氯氮平（一种混合的D和5-HT受体拮抗剂），以阐明潜在的药理学原理。
在1-25赫兹频率范围内，所有使用的拮抗剂和抗精神病药物均使脱磷酸裸盖菇素诱发的脑电图平均绝对功率宽带降低恢复正常；然而，25-40赫兹的降低仅受氯氮平影响。5-HT拮抗剂可逆转脱磷酸裸盖菇素诱发的整体功能连接性降低，特别是额颞叶断开连接，而其他药物则无此作用。
这些发现表明，所研究的所有三种血清素能受体均参与其中，并且多巴胺能机制在功率谱/电流密度中发挥作用，只有5-HT受体在两个研究指标中均有效。这开启了关于致幻剂神经生物学中除5-HT依赖机制之外其他机制作用的重要讨论。
