Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice.

ABSTRACT

Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor and is expressed in the medium spiny projection neurons of mouse striatum. To define the role of mGluR1 in actions of psychostimulant, we compared both motor behavior and striatal neuropeptide mRNA expression between mGluR1 mutant and wild-type control mice after a single injection of amphetamine. We found that acute amphetamine injection increased motor activity in both mutant and control mice in a dose-dependent manner (1, 4, and 12 mg/kg, i.p.). However, the overall motor responses of mGluR1 -/- mice to all three doses of amphetamine were significantly greater than those of wild-type +/+ mice. Amphetamine also induced a dose-dependent elevation of preprodynorphin mRNA in the dorsal and ventral striatum of mutant and wild-type mice as revealed by quantitative in situ hybridization. In contrast to behavioral responses, the induction of dynorphin mRNA in both the dorsal and ventral striatum of mutant mice was significantly less than that of wild-type mice in response to the two higher doses of amphetamine. In addition, amphetamine elevated basal levels of substance P mRNA in the dorsal and ventral striatum of mGluR1 mutant mice to a similar level as that of wild-type mice. There were no differences in basal levels and distribution patterns of the two mRNAs between the two genotypes of mice treated with saline. These results demonstrate a clear augmented behavioral response of mGluR1 knockout mice to acute amphetamine exposure that is closely correlated with reduced dynorphin mRNA induction in the same mice. It appears that an intact mGluR1 is specifically critical for full dynorphin induction, and impaired mobilization of inhibitory dynorphin system as a result of lacking mGluR1 may contribute to an augmentation of motor stimulation in response to acute administration of psychostimulant.