Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats

Rationale: Inhibition of cyclic AMP ( cAMP)specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory. Objective: Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain. Methods: The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-D-aspartate ( NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined. Results: In the radial-arm maze, MEM1018 and MEM1091 (0.1 - 2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 ( 0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram ( 0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 ( 10 - 30 mu M) and MEM1091 ( 10 mu M) enhanced the ability of NMDA ( 30 mu M) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar. Conclusions: The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.