Group II metabotropic glutamate receptors and schizophrenia

Abstract

Schizophrenia is one of the most common mental illnesses, with hereditary and environmental factors important for its etiology. All antipsychotics have in common a high affinity for monoaminergic receptors. Whereas hallucinations and delusions usually respond to typical (haloperidol-like) and atypical (clozapine-like) monoaminergic antipsychotics, their efficacy in improving negative symptoms and cognitive deficits remains inadequate. In addition, devastating side effects are a common characteristic of monoaminergic antipsychotics. Recent biochemical, preclinical and clinical findings support group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a new approach to treat schizophrenia. This paper reviews the status of general knowledge of mGluR2 and mGluR3 in the psychopharmacology, genetics and neuropathology of schizophrenia.

Fig. 1

This schematic presents a model for the neurotransmitter receptors and cellular subtypes implicated in the mechanism of action of metabotropic glutamate antipsychotics. The mGluR2 and the 5-HT_2A co-localize and form a receptor heterocomplex in cortical pyramidal neurons. The mGluR2, and not the mGluR3, is responsible for the antipsychotic-like effects induced by mGluR2/3 agonists in mouse models of schizophrenia. All atypical antipsychotics have in common a high affinity for the 5-HT_2A receptor, and a lower affinity for dopaminergic receptors. Further investigation is needed to understand the role of the 5-HT_2A-mGluR2 complex in the mechanism of action of atypical and glutamate antipsychotics, in addition to the cellular signaling pathways and neuronal circuits responsible for the antipsychotic effects. For the purpose of clarity, not all the neurotransmitter receptors implicated in schizophrenia are shown