Activation of metabotropic glutamate receptor mediates upregulation of transcription factor mRNA expression in rat striatum induced by acute administration of amphetamine.

Metabotropic glutamate receptors (mGluRs) are densely expressed on the medium spiny projection neurons of rat striatum. Intrastriatal injection of an mGluR agonist increases motor activity and dopamine release in the striatum. This study investigated the roles of mGluRs in the regulation of behavioral activity and transcription factor gene expression in striatal neurons in normal and amphetamine-treated rats. Acute injection of a behaviorally active dose of amphetamine (4.0 mg/kg, i.p.) elevated basal levels of the transcription factor c-fos and zif/268 mRNAs in the dorsal striatum as revealed by quantitative in situ hybridization. Pharmacological blockade of mGluRs with bilateral injections of a non-selective mGluR antagonist, (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), into the dorsal striatum at 10 but not 0.4 nmol significantly attenuated amphetamine-stimulated c-fos mRNA expression in this area. In contrast to c-fos, striatal zif/268 induction stimulated by amphetamine was not altered by pretreatment with MCPG. MCPG by itself did not affect basal levels of either gene expression in the striatum. No significant effects of MCPG were found on spontaneous or amphetamine-stimulated behavioral activities. These data indicate that blockade of total mGluRs in the dorsal striatum has a selective effect on dopamine-stimulated gene expression. Activation of the MCPG-sensitive mGluRs is required for the upregulation of transcription factor c-fos, although not zif/268, mRNA expression in the striatum in response to acute injection of amphetamine.