Meinhardt, Marcus W.Pfarr, SimoneRohleder, CathrinVengeliene, ValentinaBarroso-Flores, JanetHoffmann, RebeccaMeinhardt, Manuela L.Paul, ElisabethHansson, Anita C.Köhr, GeorgMeier, Nilsvon Bohlen und Halbach, OliverBell, Richard L.Endepols, HeikeNeumaier, BerndSchönig, KaiBartsch, DusanSpanagel, RainerSommer, Wolfgang H.2022-02-082022-02-082020Meinhardt, M. W., Pfarr, S., Rohleder, C., Vengeliene, V., Barroso-Flores, J., Hoffmann, R., ... & Sommer, W. H. (2020). A common molecular mechanism for cognitive deficits and craving in alcoholism. bioRxiv. https://doi.org/10.1101/2020.07.13.200519https://hdl.handle.net/1805/27719Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.enPublisher Policyalcoholismcognitive deficitsmolecular mechanismArticle