NMDA receptors mediate amphetamine-induced upregulation of zif/268 and preprodynorphin mRNA expression in rat striatum.

The role of N-methyl-D-aspartate (NMDA) excitatory amino acid receptors in D-amphetamine (AMPH)-induced behavioral changes and increased expression of the nuclear transcription factors, c-fos and zif/268, and preprodynorphin (PPD) mRNA in various regions of rat forebrain was investigated with quantitative in situ hybridization histochemistry. Three hours after a single injection of AMPH (5 mg/kg, i.p.), the mRNA expression of zif/268, but not c-fos, in dorsal striatum (caudate nucleus) and cerebral cortex (sensorimotor cortex), and PPD mRNA in dorsal striatum, was upregulated. Pretreatment of rats with MK-801 (0.5 mg/kg, i.p.) attenuated AMPH-induced striatal and cortical expression of zif/268 mRNA and striatal expression of PPD mRNA, without affecting the behavioral alterations induced by AMPH. A similar, dose-dependent suppression of AMPH-induced zif/268 and PPD mRNA in striatum and cortex was also revealed after systemic administration of (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at doses of 5 and 10 mg/kg. CPP, only at the higher dose, slightly attenuated behavioral activity induced by AMPH. MK-801 and CPP (at higher dose) alone suppressed basal (constitutive) zif/268 mRNA levels in both striatum and cortex regions. No significant effect of either antagonist was found on constitutive expression of striatal PPD mRNA. These studies indicate that NMDA receptors mediate, at least in part, activation of zif/268 and PPD gene expression in striatum and sensorimotor cortex by a single injection of AMPH. Furthermore, NMDA receptor-mediated gene regulation more likely is involved in long-term neuronal plasticity to drug exposure than in acute drug effects since NMDA receptor antagonists had little or no effect on the acute behavioral actions of AMPH.