Sensitization of the striatal dopaminergic system induced by chronic administration of a glutamate antagonist in the rat

Abstract

The aim of the present study was to assess in the rat the pharmacological, biochemical and molecular (including in situ hybridization) consequences in the striatum of a prolonged (50 days) treatment with dizocilpine maleate (MK-801), an N-methyl- d-aspartate (NMDA) antagonist. We observed a sensitization-like effect characterized by a behavioural hyperresponsiveness to an acute injection of haloperidol (0.25 mg/kg), a dopaminergic antagonist. In rats chronically treated with MK-801, this hyperresponsiveness was associated with an increased D2 receptor (D2R) density in the striatum. At the transcriptional level, the D2R mRNA was also enhanced in the striatum. Quantitative in situ hybridization studies revealed that the number of neurons expressing the D2R mRNA was significantly enhanced in treated rats, whereas the mean amount of message per cell was unchanged. These changes could represent the neurobiological substrate of the observed sensitization. These results suggest that the D2R gene is under glutamate control via NMDA receptor in striatal neurons.