Direct and indirect interactions of the dopamine D3 receptor with glutamate pathways: Implications for the treatment of schizophrenia

Abstract

This article, based on original data as well as on previously reported preclinical and clinical data that are reviewed, describes direct and indirect interactions of the D3 receptor with N-methyl-d-aspartate receptor (NMDA) signaling and their functional consequences and therapeutic implications for schizophrenia. D3 receptor immunoreactivity at ultrastructural level with electron microscopy was identified at presumably glutamatergic, asymmetric synapses of the medium-sized spiny neurons of the nucleus accumbens. This finding supports the existence of a direct interaction of the D3 receptor with glutamate, in line with previously described interactions with NMDA signaling involving Ca2+/calmodulin-dependent protein kinase II at post-synaptic densities (Liu et al. 2009). Indirect interactions of the D3 receptor with glutamate could involve a negative control exerted by the D3 receptor on mesocortical dopamine neurons and the complex regulation of the glutamatergic pyramidal cells by dopamine in the prefrontal cortex. This could be exemplified here by the regulation of pyramidal cell activity in conditions of chronic NMDA receptor blockade with dizocilpine (MK-801). BP897, a D3 receptor-selective partial agonist, reversed the dysregulation of cortical c-fos mRNA expression and pyramidal cell hyperexcitability, as measured by paired-pulse electrophysiology. At the behavioral level, blockade of the D3 receptor, by known D3 receptor antagonists or the novel D3 receptor-selective antagonist F17141, produces antipsychotic-like effects in reversing hyperactivity and social interaction deficits induced by NMDA receptor blockade by MK-801 in mice. The glutamate-D3 receptor interactions described here offer a conceptual framework for developing new D3 receptor-selective drugs, which may appear as an original, efficacious, and safe way to potentially indirectly target glutamate in schizophrenia. © 2012 The Author(s).