Browsing by Subject "molecular mechanism"

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    A common molecular mechanism for cognitive deficits and craving in alcoholism
    (Cold Spring Harbor Laboratory Press, 2020) Meinhardt, Marcus W.; Pfarr, Simone; Rohleder, Cathrin; Vengeliene, Valentina; Barroso-Flores, Janet; Hoffmann, Rebecca; Meinhardt, Manuela L.; Paul, Elisabeth; Hansson, Anita C.; Köhr, Georg; Meier, Nils; von Bohlen und Halbach, Oliver; Bell, Richard L.; Endepols, Heike; Neumaier, Bernd; Schönig, Kai; Bartsch, Dusan; Spanagel, Rainer; Sommer, Wolfgang H.; Psychiatry, School of Medicine
    Alcohol-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.