POTENTIATION OF D2-DOPAMINE RECEPTOR-MEDIATED SUPPRESSION OF ZIF-268 BY NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS IN RESERPINIZED RATS

Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction betw een corticostriatal glutamatergic input and dopaminergic systems. Rece nt hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was des igned to examine, in vivo, the interaction between D2-dopamine recepto rs and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons . We tested whether coadministration of NMDA antagonists interacted wi th the actions of the D2 agonist, quinpirole, on IEG expression follow ing dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of rese rpine induction of zif 268 mRNA was potentiated in all regions examine d. MK 801 alone had no significant effect on reserpine induction of zi f 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist , CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no signific ant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel s ystem and the D2-dopamine system on a molecular level in striatopallid al neurons carrying output from the basal ganglia. (C) 1998 Elsevier S cience B.V. All rights reserved.