title: A phosphodiesterase inhibitor, cilomilast, enhances cAMP activity to restore conditioned odor preference memory after serotonergic depletion in the neonate rat.
abstract: 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-HT(2A/C) receptors, has been shown to influence cAMP levels in the olfactory bulb initiated by beta-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 24h after a 10min training trial on postnatal day 6 using the beta-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 48h. 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 10min 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.
authors.affiliation: Division of BioMedical Sciences, Memorial University of Newfoundland, Newfoundland and Labrador, Canada. mclean@mun.ca
authors.forename: John H
authors.initials: JH
authors.lastname: McLean
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Stacey
authors.initials: S
authors.lastname: Rogers
authors.forename: Kimberley
authors.initials: K
authors.lastname: Clarke
authors.forename: Andrea
authors.initials: A
authors.lastname: Darby-King
authors.forename: Carolyn W
authors.initials: CW
authors.lastname: Harley
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002264:Carboxylic Acids / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids; D005260:Female; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D009812:Odorants; D009830:Olfactory Bulb / Q000187:drug effects* / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000172:deficiency*; D013997:Time Factors
chemical_list: D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D012701:Serotonin; C433247:Cilomilast; D000242:Cyclic AMP