Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats

• Published in: Frontiers in Neuroscience Vol. 17; p. 1152578
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media SA 22.06.2023; Frontiers Research Foundation; Frontiers Media S.A
• Subjects: Animal models; Antipsychotics; Clozapine; Dopamine D2 receptors; EEG; Electrodes; Fourier transforms; Haloperidol; Laboratory animals; LSD; Lysergic acid diethylamide; model of acute psychosis; Nervous system; Neural networks; Neuroscience; Neurosciences. Biological psychiatry. Neuropsychiatry; phase-lagged coherence; power spectra; Psilocybin; psilocybin/psilocin; Psychedelic drugs; Psychotropic drugs; quantitative EEG; RC321-571; Recovery (Medical); Registration; serotonergic psychedelics; Serotonin; Serotonin S1 receptors; Serotonin S2 receptors; Surgery; Synchronization; Czech Republic; Germany; global functional connectivity (GFC); power spectra; psilocybin/psilocin; serotonergic psychedelics; model of acute psychosis; phase-lagged coherence; quantitative EEG
• ISSN: 1662-453X; 1662-4548; 1662-453X
• DOI: 10.3389/fnins.2023.1152578

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.