Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism
Year: 2021
Type: article
Abstract: 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.
Source: Science Advances
Authors: Marcus W. Meinhardt, Marcus W. Meinhardt, Simone Pfarr, Grégory Fouquet, Cathrin Rohleder, Manuela L. Meinhardt, Manuela L. Meinhardt, Janet Barroso-Flores, Rebecca Hoffmann, Jérôme Jeanblanc, Elisabeth Paul, Konstantin Wagner, Anita C. Hansson, Georg Köhr, Nils Meier, Oliver von Bohlen und Halbach, Richard L. Bell, Heike Endepols, Bernd Neumaier, Kai Schönig, Dusan Bartsch, Mickaël Naassila, Rainer Spanagel, Wolfgang H. Sommer
Institutions: Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Inserm, Université de Picardie Jules Verne, The University of Sydney, University of Cologne, Max Planck Institute for Metabolism Research, University Hospital Cologne, Universitätsmedizin Greifswald, Universität Greifswald, Indiana University Indianapolis, Indiana University School of Medicine, Forschungszentrum Jülich
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Systems Biology of Alcohol Addiction: Modeling and validating disease state networks in human and animal brains for understanding pathophysiolgy, predicting outcomes and improving therapy, G2106858102, SysMedSUDs - Ein systemmedizinischer Ansatz für die Untersuchung von Gemeinsamkeiten und Unterschieden bei Resilienz- und pathologischen Mechanismen von Substanzgebrauchsstörungen - Koordination, Signaturanalysen, neuronale Netzwerke, MR-Spektroskopie und Validierung, G3113304588, Preclinical Phase II Testing of Psilocybin in Alcohol Addiction and Epigenetic and Neuroimaging Studies on the Mode of Action, G3986097662, G434337789, G5555650700, G5930672377, PsiAlc - Präklinische Phase-II-Tests von Psilocybin bei Alkoholsucht, TRR 265: Verlust und Wiedererlangung der Kontrolle über den Drogenkonsum: Von Trajektorien über Mechanismen bis hin zu Interventionen
OpenAlex ID: W3213463597