Nejvíce citovaný článek - PubMed ID 11557170
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
Serotonergic psychedelics are recently gaining a lot of attention as a potential treatment of several neuropsychiatric disorders. Broadband desynchronization of EEG activity and disconnection in humans have been repeatedly shown; however, translational data from animals are completely lacking. Therefore, the main aim of our study was to assess the effects of tryptamine and phenethylamine psychedelics (psilocin 4 mg/kg, LSD 0.2 mg/kg, mescaline 100 mg/kg, and DOB 5 mg/kg) on EEG in freely moving rats. A system consisting of 14 cortical EEG electrodes, co-registration of behavioral activity of animals with subsequent analysis only in segments corresponding to behavioral inactivity (resting-state-like EEG) was used in order to reach a high level of translational validity. Analyses of the mean power, topographic brain-mapping, and functional connectivity revealed that all of the psychedelics irrespective of the structural family induced overall and time-dependent global decrease/desynchronization of EEG activity and disconnection within 1-40 Hz. Major changes in activity were localized on the large areas of the frontal and sensorimotor cortex showing some subtle spatial patterns characterizing each substance. A rebound of occipital theta (4-8 Hz) activity was detected at later stages after treatment with mescaline and LSD. Connectivity analyses showed an overall decrease in global connectivity for both the components of cross-spectral and phase-lagged coherence. Since our results show almost identical effects to those known from human EEG/MEG studies, we conclude that our method has robust translational validity.
- MeSH
- elektroencefalografie MeSH
- krysa rodu Rattus MeSH
- LSD * farmakologie MeSH
- meskalin * MeSH
- psilocybin analogy a deriváty farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- LSD * MeSH
- meskalin * MeSH
- psilocin MeSH Prohlížeč
- psilocybin MeSH
The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.
- Klíčová slova
- Bayesian, computational, hallucinations, psychedelics, psychosis, serotonin,
- MeSH
- halucinace chemicky indukované diagnostické zobrazování etiologie patofyziologie MeSH
- halucinogeny škodlivé účinky MeSH
- lidé MeSH
- nervová síť diagnostické zobrazování účinky léků patofyziologie MeSH
- schizofrenie komplikace diagnostické zobrazování patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- srovnávací studie MeSH
- Názvy látek
- halucinogeny MeSH
RATIONALE: Mescaline is a nonselective serotonin receptor agonist. It has relatively delayed onset of action and prolonged duration. Mescaline attenuates various behavioral parameters in rats; however, no information is available about its pharmacokinetics in rats and its relation to the behavioral changes produced by the drug. OBJECTIVES: The present study evaluates the spontaneous locomotor activity and sensorimotor gating in relation to mescaline concentrations in the serum and the brain of rats MATERIALS AND METHODS: Behavioral changes induced by mescaline [10, 20, and 100 mg/kg subcutaneously (s.c.)] were evaluated in an open-field test and testing of the prepulse inhibition of acoustic startle reaction (PPI) 15 and 60 min after drug administration. The time disposition of mescaline 20 mg/kg s.c. in rat serum and brain homogenates was analyzed by gas chromatography-mass spectrometry. RESULTS: Mescaline produced significant inhibitory effects on locomotion in low doses and a biphasic effect with the highest dose. In the PPI test, only when tested 60 min after drug administration, all doses of mescaline disrupted PPI. Besides the experimental protocol, we have observed that approximately 50% of animals receiving 100 mg/kg died within 12 h post-injection. The serum levels of mescaline rapidly increased within 30 min and subsequently quickly decreased; however, the brain concentrations reached a maximum 1 h after administration and remained high for an additional 60 min. CONCLUSIONS: Mescaline had a delayed onset of the main behavioral changes in rats compared to other hallucinogens. Behavioral changes correlated with the pharmacokinetics of the drug.
- MeSH
- časové faktory MeSH
- habituace (psychofyziologie) účinky léků MeSH
- halucinogeny farmakokinetika toxicita MeSH
- inhibice (psychologie) MeSH
- injekce subkutánní MeSH
- krysa rodu Rattus MeSH
- meskalin farmakokinetika toxicita MeSH
- metabolická clearance fyziologie MeSH
- mozek účinky léků metabolismus MeSH
- orientace účinky léků MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- úleková reakce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- halucinogeny MeSH
- meskalin MeSH
