PDE5 inhibition improves object memory in standard housed rats but not in rats housed in an enriched environment: implications for memory models?

PLoS One. 2014 Nov 5;9(11):e111692. doi: 10.1371/journal.pone.0111692. eCollection 2014.


Drug effects are usually evaluated in animals housed under maximally standardized conditions. However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions. In the present study, we examined the acute cognition enhancing effects of vardenafil, a PDE5 inhibitor, which stimulates protein kinase G/CREB signaling in cells, in three different groups of male Wistar rats tested in an object recognition task (ORT). Rats were either housed solitarily (SOL) or socially (SOC) under standard conditions, or socially in an EE. Although EE animals remembered object information longer in the vehicle condition, vardenafil only improved object memory in SOL and SOC animals. While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2-3 or CA1. Neither were there any differences in markers for pre- and postsynaptic density. No changes in PDE5 mRNA- and protein expression levels were observed. Basal pCREB levels were increased in EE rats only, whereas β-catenin was not affected, suggesting specific activation of the MAP kinase signaling pathway and not the AKT pathway. A possible explanation for the inefficacy of vardenafil could be that CREB signaling is already optimally stimulated in the hippocampus of EE rats. Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

MeSH terms

  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Discrimination Learning
  • Environment*
  • Imidazoles / pharmacology
  • Male
  • Memory / drug effects*
  • Memory / physiology
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Piperazines / pharmacology
  • Rats
  • Recognition, Psychology / drug effects
  • Sulfones / pharmacology
  • Time Factors
  • Triazines / pharmacology
  • Vardenafil Dihydrochloride


  • Imidazoles
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Sulfones
  • Triazines
  • Vardenafil Dihydrochloride
  • Cyclic Nucleotide Phosphodiesterases, Type 5

Grant support

The authors have no support or funding to report.