Metabotropic glutamate receptor genes as candidates for pharmacogenetic studies of current and future antipsychotic agents in schizophrenia

Recent research has linked the polymorphic metabotropic glutamate receptors to the pathogenesis of schizophrenia contributing to the development of the "glutamate hypothesis". These receptors regulate glutamate through NMDA inotropic receptors. At the neurotransmitter level, antipsychotics developed to treat schizophrenia have been found to significantly increase serum glutamate levels and potentially affect the expression of various metabotropic glutamate receptors (mGluRs). Additionally, type-3 metabotropic glutamate receptor gene (GRM3) polymorphisms have been associated with schizophrenia as well as being linked to reductions in prefrontal cortex N-acetylaspartate concentrations. Thus, glutamate has become an increasingly important area of interest for therapeutic intervention in schizophrenia and pharmaceutical companies are rapidly focusing on the development of agents that directly modulate this neurotransmitter; however the reality is that the clinical use of such drugs is still years away. Taken together, investigations of how genetic variability in genes coding for mGluRs relate to treatment outcomes are becoming increasingly important. The goal of this review is to discuss the genetics, pharmacology, and pharmacogenetics of the metabotropic glutamate receptors focusing on receptor subtypes with the most evidence for involvement with current and/or future antipsychotic activity.