Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats
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 dopaminerg...
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| Published in | Frontiers in Neuroscience Vol. 17; p. 1152578 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
Frontiers Media SA
22.06.2023
Frontiers Research Foundation Frontiers Media S.A |
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| Online Access | Get full text |
| ISSN | 1662-453X 1662-4548 1662-453X |
| DOI | 10.3389/fnins.2023.1152578 |
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| Abstract | 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. |
|---|---|
| AbstractList | 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-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A 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-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 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-HT2A 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-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics. 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-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A 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.IntroductionPsilocybin 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-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A 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-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology.MethodsSelective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 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-HT2A antagonist while other drugs had no effect.ResultsPsilocin-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-HT2A 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-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.DiscussionThese 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-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics. 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. IntroductionPsilocybin 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-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A 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.MethodsSelective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology.ResultsPsilocin-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-HT2A antagonist while other drugs had no effect.DiscussionThese 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-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics. |
| Author | Lukáš Kadeřábek Martin Kuchař Vlastimil Koudelka Tomáš Novák Martin Brunovský Václava Piorecká Filip Tylš Tomáš Pálení ček Marcel Bochin Jiří Horáček Zdeňka Bendová Čestmír Vejmola |
| AuthorAffiliation | 2 3rd Faculty of Medicine, Charles University in Prague , Prague , Czechia 4 Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague , Prague , Czechia 1 Psychedelic Research Centre, National Institute of Mental Health , Klecany , Czechia 3 Faculty of Biomedical Engineering, Czech Technical University in Prague , Kladno , Czechia |
| AuthorAffiliation_xml | – name: 3 Faculty of Biomedical Engineering, Czech Technical University in Prague , Kladno , Czechia – name: 4 Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague , Prague , Czechia – name: 1 Psychedelic Research Centre, National Institute of Mental Health , Klecany , Czechia – name: 2 3rd Faculty of Medicine, Charles University in Prague , Prague , Czechia |
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| BackLink | https://cir.nii.ac.jp/crid/1870020693269592448$$DView record in CiNii https://www.ncbi.nlm.nih.gov/pubmed/37425017$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2023 Tylš, Vejmola, Koudelka, Piorecká, Kadeřábek, Bochin, Novák, Kuchař, Bendová, Brunovský, Horáček and Pálení ček. 2023. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Copyright © 2023 Tylš, Vejmola, Koudelka, Piorecká, Kadeřábek, Bochin, Novák, Kuchař, Bendová, Brunovský, Horáček and Pálení ček. 2023 Tylš, Vejmola, Koudelka, Piorecká, Kadeřábek, Bochin, Novák, Kuchař, Bendová, Brunovský, Horáček and Pálení ček |
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| Keywords | global functional connectivity (GFC) power spectra psilocybin/psilocin serotonergic psychedelics model of acute psychosis phase-lagged coherence quantitative EEG |
| Language | English |
| License | Copyright © 2023 Tylš, Vejmola, Koudelka, Piorecká, Kadeřábek, Bochin, Novák, Kuchař, Bendová, Brunovský, Horáček and Pálení ček. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Snippet | Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly... IntroductionPsilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is... |
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| SubjectTerms | 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 |
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| Title | Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats |
| URI | https://cir.nii.ac.jp/crid/1870020693269592448 https://www.ncbi.nlm.nih.gov/pubmed/37425017 https://www.proquest.com/docview/2828058249 https://www.proquest.com/docview/2839249182 https://pubmed.ncbi.nlm.nih.gov/PMC10325866 https://doaj.org/article/ad15f5638c4f48e7bb7ca5492d89072c |
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