THE NMDA RECEPTOR ANTAGONIST MK-801 MARKEDLY REDUCES THE INDUCTION OF C-FOS GENE BY HALOPERIDOL IN THE MOUSE STRIATUM

The influence of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), on the haloperidol-induced increase of c-fos mRNA levels in the striata of mice was examined using the quantitative Northern blot analysis method, Administration of haloperidol (1 mg/kg, i.p.) increased striatal c-fos mRNA hybridization signal about 7-fold, as measured 30 min after injection. MK-801 (0.2-4.5 mg/kg, i.p.) dose-dependently reduced this effect of the dopamine antagonist. Higher doses of MK-801 (1.5-4.5 mg/kg) diminished c-fos mRNA increase produced by haloperidol by 80%. Such a marked inhibition of this haloperidol effect by MK-801 has not been previously reported. It suggests that the induction of c-fos gene occurring in the striatum after dopamine D2 receptor blockade is mediated in great part by endogenous glutamate acting at NMDA receptors. Since the c-fos gene protein product (Fos) is a transcription factor, our results also indicate the involvement of glutamate in the regulation of expression of other genes in the striatum.