A single injection of the psychostimulant, amphetamine, upregulates immediate early gene (IEG) and opioid peptide gene expression in the rat striatum. These genomic responses may be important in neuronal plasticity related to long-term changes in behavior. In exploring intracellular signaling pathways trans-mitting surface receptor stimulation to nuclear gene expression, we recently found that metabotropic glutamate receptors (mGluR) which are coupled to multiple second messenger systems through G proteins and are highly expressed in the striatum, regulate acute amphetamine-stimulated IEG as well as opioid gene expression in the striatum. Based on this encouraging finding, we propose in this project to further characterize the regulation of amphetamine-stimulated striatal gene expression by mGluRs and mGluR-linked intracellular signaling pathways. The hypothesis is that striatal mGluR activity contributes to the ability of acute amphetamine to stimulate IEG and opioid gene expression in the rat striatum and that increases in phosphoinositide hydrolysis, the best known and most thoroughly investigated cellular response to mGluR activation, serve as the signaling pathway bridging surface mGluR stimulation to nuclear gene expression. This hypothesis will be tested in two aims which are to (1) examine the effects of enhancement and reduction of striatal mGluR activity by injections of mGluR selective agonists and antagonists, respectively, on acute amphetamine-stimulated striatal IEG and opioid gene expression in a well characterized rat in vivo model, and (2) evaluate the contribution of the mGluR phosphoinositide-linked signaling pathways, i.e., intracellular Ca2+ mobilization and protein kinase C, to mGluR-sensitive gene expression in primary striatal cultured neurons from neonatal rats with both pharmacological (activators/inhibitors) and molecular (antisense technique) approaches. We will rely on in situ hybridization to analyze striatal mRNA expression in vivo and in vitro. This project should provide new insight into the signal transduction coupling stimulus-transcription in response to amphetamine, and improve understanding of the molecular plasticity underlying psychostimulant-induced long-term changes in behavior.
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