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Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

Marcus W Meinhardt1, Simone Pfarr1, Grégory Fouquet2

  • 1Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.

Science Advances
|November 17, 2021
PubMed

Insights

Reduced prefrontal mGluR2 function impairs executive control and increases alcohol craving in alcoholism. Restoring mGluR2 levels with psilocybin shows promise for treating alcohol dependence and preventing relapse.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Addiction Research

Background:

  • Alcohol dependence is linked to executive dysfunction, which drives craving and relapse.
  • The underlying molecular mechanisms of executive dysfunction in alcoholism remain unclear.
  • Novel pharmacological treatments targeting these mechanisms are needed.

Purpose of the Study:

  • To investigate the causal role of prefrontal metabotropic glutamate receptor 2 (mGluR2) in executive dysfunction and alcohol craving.
  • To identify potential pharmacological interventions for alcoholism based on mGluR2 function.
  • To develop a biomarker strategy for personalized treatment selection.

Main Methods:

  • Utilized a bidirectional neuromodulation approach in rodent models.
  • Created neuron-specific prefrontal mGluR2 knockdown and viral restoration of mGluR2 levels.
  • Administered psilocybin and employed FDG-PET imaging for biomarker assessment.

Main Results:

  • Reduced prefrontal mGluR2 function causally linked to impaired cognitive flexibility and increased alcohol seeking.
  • Restoring prefrontal mGluR2 levels in alcohol-dependent rats reversed these pathological behaviors.
  • Psilocybin treatment restored mGluR2 expression and reduced relapse behavior in rats.

Conclusions:

  • Identified a shared molecular mechanism (prefrontal mGluR2 dysfunction) underlying executive dysfunction and alcohol craving in alcoholism.
  • Established mGluR2 as a therapeutic target for alcoholism.
  • Proposed a personalized, mGluR2-based intervention strategy and biomarker for medication development.

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