NMDA receptor-induced cAMP and cGMP are selectively hydrolyzed by PDE4 and PDE2, respectively, in rat primary cerebral cortical and hippocampal cultures. Because cAMP levels regulate the expression of PDE4 in rat primary cortical cultures, we examined the manner in which NMDA receptor activity regulates the age-dependent increase in the expression of PDE4A observed in vivo and in vitro. Inhibiting the activity of NR2B subunit with ifenprodil blocked NMDA receptor-induced cGMP synthesis and increased NMDA receptor-induced cAMP levels in a manner that reduced PDE4 activity. Therefore, NR1/NR2B receptor-induced cGMP signaling is involved in an acute cross-talk regulation of NR1/NR2A receptor-induced cAMP levels, mediated by PDE4. Chronic inhibition of NMDA receptor activity with MK-801 reduced PDE4A1 and PDE4A5 expression and activity in a time-dependent manner; this effect was reversed by adding the PKA activator dbr-cAMP. Inhibiting GABA receptors with bicuculline increased NMDA receptor-induced cAMP synthesis and PDE4A expression in cultures treated between DIV 16 and DIV 21 but not in cultures treated between DIV 8 and DIV 13. This effect was due to a high tone of NMDA receptor-induced cGMP in younger cultures, which negatively regulated the expression of PDE4A by a PKG-mediated process. The present results are consistent with behavioral data showing that both PDE4 and PDE2 are involved in NMDA receptor-mediated memory processes.