Browsing by Author "Meinhardt, Marcus W."

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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.
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    Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism
    (American Association for the Advancement of Science, 2021) Meinhardt, Marcus W.; Pfarr, Simone; Fouquet, Grégory; Rohleder, Cathrin; Meinhardt, Manuela L.; Barroso-Flores, Janet; Hoffmann, Rebecca; Jeanblanc, Jérôme; Paul, Elisabeth; Wagner, Konstantin; Hansson, Anita C.; Köhr, Georg; Meier, Nils; von Bohlen und Halbach, Oliver; Bell, Richard L.; Endepols, Heike; Neumaier, Bernd; Schönig, Kai; Bartsch, Dusan; Naassila, Mickaël; 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. 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.