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.

Biotechnology Center Technische Universität Dresden Dresden Germany

Department of Molecular Neuroimaging Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Heidelberg Germany

Department of Psychiatry and Psychotherapy Faculty of Medicine Carl Gustav Carus Technische Universität Dresden Dresden Germany

Else Kröner Fresenius Center for Digital Health Faculty of Medicine Carl Gustav Carus Technische Universität Dresden Dresden Germany

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Prague Czech Republic

German Center for Mental Health partner site Mannheim Heidelberg Ulm Mannheim Germany

Institute of Psychopharmacology Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Leibniz Institute of Polymer Research Dresden Dresden Germany

Psychedelic Research Center National Institute of Mental Health Klecany Czech Republic

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