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

Neurobiol Learn Mem. 2009 Jul;92(1):63-9. doi: 10.1016/j.nlm.2009.02.003. Epub 2009 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Carboxylic Acids / pharmacology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Cyclic AMP / metabolism*
  • Cyclohexanecarboxylic Acids
  • Female
  • Immunoenzyme Techniques
  • Immunohistochemistry
  • Male
  • Memory / drug effects*
  • Memory / physiology
  • Nitriles / pharmacology*
  • Odorants
  • Olfactory Bulb / drug effects*
  • Olfactory Bulb / physiopathology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / deficiency*
  • Time Factors


  • Carboxylic Acids
  • Cyclohexanecarboxylic Acids
  • Nitriles
  • Phosphodiesterase Inhibitors
  • Serotonin
  • Cilomilast
  • Cyclic AMP