Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

Marcus W. Meinhardt (1) , Simone Pfarr (1) , Gregory Fouquet (2) , Cathrin Rohleder (1, 3, 4) , Manuela L. Meinhardt (1) , Janet Barroso-Flores (1) , Rebecca Hoffmann (1) , Jerome Jeanblanc (2) , Elisabeth Paul (1) , Konstantin Wagner (1) , Anita C. Hansson (1) , Georg Koehr (1) , Nils Meier (5) , Oliver von Bohlen Und Halbach (5) , Richard L. Bell (6) , Heike Endepols (3, 7) , Bernd Neumaier (3, 5) , Kai Schoenig (1) , Dusan Bartsch (1) , Mickaël Naassïla (2) , Rainer Spanagel (1) , Wolfgang H. Sommer (1)

1 Universität Heidelberg [Heidelberg]
2 GRAP - Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247
3 University of Cologne
4 The University of Sydney
5 Universitätsmedizin Greifswald
6 Indiana University School of Medicine
7 INM-1 - Institute of Neuroscience and Medicine [Jülich]

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. Here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. A neuron-specific prefrontal mGluR2 knockdown in rats generated a phenotype of reduced cognitive flexibility and excessive alcohol seeking. Conversely, virally restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. In the search for a pharmacological intervention with high translational potential, psilocybin was capable of restoring mGluR2 expression and reducing relapse behavior. Last, we propose a FDG-PET biomarker strategy to identify mGluR2 treatment-responsive individuals. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving and provided a personalized mGluR2 mechanism-based intervention strategy for medication development for alcoholism.

Domaines: Sciences du Vivant [q-bio]

Marcus W. Meinhardt, Simone Pfarr, Gregory Fouquet, Cathrin Rohleder, Manuela L. Meinhardt, et al.. Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism. Science Advances , 2021, 7 (47), ⟨10.1126/sciadv.abh2399⟩. ⟨hal-03584900⟩