Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficitsassociated with NMDA receptor antagonism

Rolipram, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE 4), completely reversed the amnesic effects of MK-801 on working and refere nce memory (F[4,64] = 11.10; p < .0001 and F[4,64] = 2.53; p < .05, respect ively) at doses of 0.01-0.1 mg/kg ill the radial-arm maze task. Similar ant agonism by rolipram of the effects of MK-801 was observed oil inhibitory av oidance behavior (F[3,35] = 190.8; p < .0001). In vitro evidence suggests t hat an increase ill cAMP concentrations may mediate the observed behavioral effects of rolipram. In the absence of PDE4 inhibition, NMDA did not incre ase cAMP concentrations in primary cultures of rat cerebral cortical neuron s. However, when PDE4 was inhibited with rolipram, NMDA markedly elevated c AMP. These observations suggest that PDE4 is all integral component of the NMDA receptor-mediated signal transduction pathway involved in memory proce sses. Inhibitors of PDE4 may act on this pathway to produce their effects o n memory and may represent a new class of cognitive enhancers. (C) 2000 Ame rican College of Neuropsychopharmacology. Published by Elsevier Science Inc . All rights reserved.