NMDA RECEPTORS MEDIATE AMPHETAMINE-INDUCED UP-REGULATION OF ZIF 268 AND PREPRODYNORPHIN MESSENGER-RNA EXPRESSION IN RAT STRIATUM/

The role of N-methyl-D-aspartate (NMDA) excitatory amino acid receptor s in D-amphetamine (AMPH)-induced behavioral changes and increased exp ression of the nuclear transcription factors, c-fos and zif/268, and p reprodynorphin (PPD) mRNA in various regions of rat forebrain was inve stigated with quantitative in situ hybridization histochemistry. Three hours after a single injection of AMPH (5 mg/kg, i.p.), the mRNA expr ession of zif/268, but not c-fos, in dorsal striatum (caudate nucleus) and cerebral cortex (sensorimotor cortex), and PPD mRNA in dorsal str iatum, was upregulated. Pretreatment of rats with MK-801 (0.5 mg/kg, i .p.) attenuated AMPH-induced striatal and cortical expression of zif/2 68 mRNA and striatal expression of PPD mRNA, without affecting the beh avioral alterations induced by AMPH. A similar, dose-dependent suppres sion of AMPH-induced zif/268 and PPD mRNA in striatum and cortex was a lso 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 indu ced by AMPH. MK-801 and CPP (at higher dose) alone suppressed basal (c onstitutive) zif/268 mRNA levels in both striatum and cortex regions. No significant effect of either antagonist was found on constitutive e xpression of striatal PPD mRNA. These studies indicate that NMDA recep tors mediate, at least in part, activation of zif/268 and PPD gene exp ression in striatum and sensorimotor cortex by a single injection of A MPH. Furthermore, NMDA receptor-mediated gene regulation more likely i s involved in long-term neuronal plasticity to drug exposure than in a cute drug effects since NMDA receptor antagonists had little or no eff ect on the acute behavioral actions of AMPH. (C) 1994 Wiley-Liss, Inc.