An investigation into the effect of the type IV phosphodiesterase inhibitor rolipram in the modulation of glutamate release from rat prefrontocortical nerve terminals.

The present study was conducted to explore the influence of rolipram, a specific inhibitor of the phosphodiesterase type 4 (PDE4) isoform, on glutamate release in the rat prefrontal cortex, using isolated nerve terminal (synaptosome) preparation. In prefrontocortical nerve terminals, rolipram potentiated the Ca(2+)-dependent release of glutamate evoked by 4-aminopyridine (4AP) in a concentration-dependent manner. This potentiation of release was occluded by the activation of PKA by Sp-cAMP or beta-adrenergic receptor agonist and prevented by the inhibition of PKA by Rp-cAMP or KT5720, indicating a PKA-mediated mechanism. The rolipram-mediated potentiation of glutamate release is associated with an increase both in the 4AP-evoked depolarization of the synaptosomal plasma membrane potential and in 4AP-evoked Ca(2+) influx into synaptosomes. Moreover, Ca(2+) ionophore ionomycin-induced glutamate release was also facilitated by rolipram. These results concluded that phosphodiesterase 4 inhibited by rolipram produces an increase in PKA activation, which subsequently enhances the voltage-dependent Ca(2+) influx by increasing terminal excitability as well as the vesicular release machinery to cause an increase in evoked glutamate release from rat prefrontocortical nerve terminals.