Browsing by Author "Sommer, Wolfgang H."

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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.
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    Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial
    (Springer Nature, 2023-04-05) Spreer, Maik; Grählert, Xina; Klut, Ina-Maria; Al Hamdan, Feras; Sommer, Wolfgang H.; Plawecki, Martin H.; O’Connor, Sean; Böttcher, Michael; Sauer, Cathrin; Smolka, Michael N.; Zimmermann, Ulrich S.; Psychiatry, School of Medicine
    This registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen's d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = -0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen's d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone's effect might depend on reward contingency.