Exploring group 1 metabotropic glutamate receptors in the pathology and treatment of schizophrenia

There is a growing body of evidence indicating developmental disturbances to the glutamatergic system may underlie the pathogenesis of schizophrenia. Genetic and environmental studies indicate schizophrenia is associated with reduced glutamatergic signalling, in particular via the primary ionotropic N-methyl-D-aspartate (NMDA) glutamate receptor. Therefore, upregulation of NMDA receptor activity is proposed to be a novel avenue for the treatment of schizophrenia. Group 1 metabotropic glutamate receptors (mGluR), which include mGluR1 and mGluR5, are homodimeric G-protein coupled receptors that co-localise with and in-directly potentiate NMDA receptor currents. Therefore, group 1 mGluRs have been implicated in the pathology of schizophrenia and identified as a novel treatment target. The aim of this thesis was to assess group 1 mGluRs, particularly the dimeric and monomeric forms, in the neurodevelopment, pathology and treatment of schizophrenia. In addition, this thesis aimed to identify the neurochemical changes induced by treatment with the mGluR5 positive allosteric modulator, CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide), in an attempt to better understand its potential preclinical antipsychotic efficacy.