Patients with alcohol use disorder (AUD) who seek treatment show highly variable outcomes. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.

• MeSH
• alkoholismus * farmakoterapie   patofyziologie   MeSH
• aminokyseliny MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   MeSH
• biologické markery MeSH
• evokované potenciály účinky léků   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech * MeSH
• prefrontální mozková kůra * účinky léků   patofyziologie   metabolismus   MeSH
• psilocybin * farmakologie   MeSH
• receptory metabotropního glutamátu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminokyseliny MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• biologické markery MeSH
• LY 379268 MeSH Prohlížeč
• metabotropic glutamate receptor 2 MeSH Prohlížeč
• psilocybin * MeSH
• receptory metabotropního glutamátu MeSH

Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.

• MeSH
• alkoholismus * diagnostické zobrazování   farmakoterapie   MeSH
• default mode network MeSH
• ethanol MeSH
• halucinogeny * farmakologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mozek diagnostické zobrazování   MeSH
• psilocybin farmakologie   MeSH
• recidiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ethanol MeSH
• halucinogeny * MeSH
• psilocybin MeSH

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.

• Klíčová slova
• global functional connectivity (GFC), model of acute psychosis, phase-lagged coherence, power spectra, psilocybin/psilocin, quantitative EEG, serotonergic psychedelics,
• Publikační typ
• časopisecké články MeSH

Psilocybin is a classical serotoninergic psychedelic that induces cognitive disruptions similar to psychosis. Gamma activity is affected in psychosis and is tightly related to cognitive processing. The 40 Hz auditory steady-state responses (ASSR) are frequently used as indicators to test the ability to generate gamma activity. Based on previous literature, we studied the impact of psilocybin on 40 Hz ASSR in healthy volunteers. The study was double blind and placebo controlled with a crossover design. A sample of 20 healthy subjects (10M/10F) received psilocybin orally 0.26 mg/kg or placebo. Participants were measured four times in total, one time before ingestion of psilocybin/placebo and one time after ingestion, during the peak of intoxication. A series of 500 ms click trains were used for stimulation. Psilocybin induced a psychedelic effect and decreased 40 Hz ASSR phase-locking index compared to placebo. The extent of the attenuation was related to Cognition and Affect on the Hallucinogen Rating Scale. The current study shows that psilocybin lowers the synchronization level and the amplitude of 40 Hz auditory steady-state responses, which yields further support for the role of gamma oscillations in cognitive processing and its disturbance.

• Klíčová slova
• EEG, auditory steady-state response, model of psychosis, psilocybin, psychedelics, serotonin,
• Publikační typ
• časopisecké články MeSH