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

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