Glutamate-regulated Behavior, Transmitter Release, Gene Expression and Addictive Plasticity in the Striatum: Roles of Metabotropic Glutamate Receptors

Abstract

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and are densely expressed in medium spiny projection neurons of striatum. Emerging evidence demonstrates a significant role of mGluRs in the regulation of striatal functions. Activation of mGluRs alters local transmitter release and behaviors of experimental animals. In particular, mGluRs regulate phosphorylation of several key signaling proteins (protein kinases and transcription factors) resulting in significant changes in immediate early gene and neuropeptide gene expression in striatal neurons. The prominent involvement of mGluRs in genomic responses to synaptic stimulation is considered to play a pivotal role in the development of synaptic/neuronal plasticity underlying long-term adaptive changes in cellular physiology related to a variety of neurologic disorders. Available data indicate that the eight subtypes of mGluRs have distinct effects on gene expression. The group I subtypes (mGluR1/5) facilitate, whereas group II (mGluR2/3) and III (mGluR4/6/7/8) subtypes inhibit, gene expression. Due to their significance in regulating drug action, mGluRs have been considered as promising targets for the development of novel therapeutic drugs for the treatment of drug addiction. The present review summarizes the roles of mGluRs in the regulation of behavior, transmitter release and particularly genomic responses in striatal neurons to dopamine stimulation, following a description of anatomical organization of mGluRs in the striatum. The possible pre- and postsynaptic mechanisms that process mGluR modulatory effects are also discussed in detail. Finally, potential of mGluRs as targets for the development of therapeutic drugs for addictive and other mental illnesses concludes this review.