A phosphodiesterase inhibitor, cilomilast, enhances cAMP activity to restore conditioned odor preference memory after serotonergic depletion in the neonate rat

In various learning and memory models, preventing the breakdown of cyclic adenosine monophosphate (cAMP) by using a phosphodiesterase (PDE) inhibitor promotes memory. In the rat pup odor preference learning model serotonin, acting through 5-HT2A/C receptors, has been shown to influence cAMP levels in the olfactory bulb initiated by β-adrenoceptor activation, as also seen in the neocortex. Since depletion of olfactory bulb serotonin prevents learning in the rat pup odor preference model, we ask whether a PDE inhibitor could restore that learning and also examined the influence of these manipulations on the temporal bulbar cAMP signal associated with successful learning. In this study, we found that a PDE4 inhibitor overcame learning deficits seen 24 h after a 10 min training trial on postnatal day 6 using the β-adrenoceptor agonist, isoproterenol as the unconditioned stimulus. We found in a previous study, that use of a PDE4 inhibitor during learning in normal pups extended memory to more than 48 h. However, in the present study the PDE4 treatment did not enable this memory extension in 5-HT depleted pups. An increase in the cAMP signal at the end of the 10 min training trial occurred in the presence of the PDE4 inhibitor. Such a cAMP increase has been associated with successful learning and is normally absent with bulbar 5-HT depletion. These results suggest PDE4 inhibitors may be useful therapeutically in disorders associated with reductions in serotonergic function.