N-methyl-D-aspartate acutely increases proenkephalin mRNA in the rat striatum

Studies in which glutamate (GLU) neurotransmission has been reduced at striatal synapses have shown that GLU influences the biosynthesis of certain peptide cotransmitters by striatal neurons. The present experiment was designed to test the effects of direct activation of the NMDA or AMPA types of GLU receptor on the levels of two mRNAs that encode the peptide cotransmitters met5-enkephalin (ME) and substance P (SP). In situ hybridization histochemistry of forebrain tissue sections from rats 8 h after a single intracerebroventricular infusion of NMDA or AMPA revealed a significant and dose-dependent elevation (to a maximum of almost 50%) of striatal ME mRNA when compared to vehicle-injected controls. SP mRNA was not significantly affected. NMDA was more effective than AMPA over the dose range used. Pretreatment with a potent and highly specific AMPA antagonist (NBQX) predictably blocked the AMPA-mediated elevation, and was only slightly effective against the NMDA-induced response. In striking contrast, pretreatment with a potent and highly selective NMDA antagonist (CGP37849) fully opposed both the NMDA- and the AMPA-mediated elevation of ME mRNA. These data further implicate the NMDA receptor in the regulation of peptide cotransmitter gene transcription. They suggest also that the AMPA receptor may play an indirect, synergistic role in the genetic responses of striatal neurons to GLU transmission.