ABSTRACT
Previous studies have shown memory enhancing effects of phosphodiesterase type 5 (PDE5) inhibitors in rats. However, differences in nitric oxide (NO)-mediated cyclic GMP (cGMP) signaling in the hippocampus have been described between rats and mice. In the present study we investigated the memory enhancing effects of the PDE5 inhibitor, sildenafil on memory performance in Swiss mice using the object recognition task. Sildenafil (0.3, 1 and 3 mg/kg) was administered orally directly after the first trial. The memory for the objects was retested 24 h later when mice show no memory for the familiar object. Sildenafil improved the object discrimination performance of Swiss mice at a dose of 1 mg/kg. Hippocampal slices of Swiss mice incubated with sildenafil (10 microM) increased cGMP levels in varicosities in the CA3 region of the hippocampus and a number of short, thin fibers. Addition of DEA/NO, an NO donor (10 microM), in the presence of sildenafil (10 microM) strongly increased cGMP immunoreactivity of varicosities in the CA3 region. Double immunostaining of cGMP with the presynaptic marker synaptophysin did not reveal any co-localization of these markers under any circumstance. Taken together, inhibition of PDE5 improves object recognition memory in mice. Furthermore, a postsynaptic role of cGMP could be involved in this respect.
Subject(s)
Cyclic GMP/metabolism , Enzyme Inhibitors/pharmacology , Hippocampus/metabolism , Memory/drug effects , Piperazines/pharmacology , Recognition, Psychology/drug effects , 3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5 , Discrimination Learning/drug effects , Discrimination Learning/physiology , Dose-Response Relationship, Drug , Form Perception/drug effects , Form Perception/physiology , Hippocampus/drug effects , Immunohistochemistry , Male , Memory/physiology , Mice , Nitric Oxide/metabolism , Phosphoric Diester Hydrolases/drug effects , Phosphoric Diester Hydrolases/metabolism , Purines , Recognition, Psychology/physiology , Sildenafil Citrate , SulfonesABSTRACT
The effect of diazepam on NO-mediated cGMP synthesis was studied in rat brain slices. It was found that diazepam dose-dependently decreased cGMP synthesis in cerebellar slices, with an inhibition of 90% at 1 mM diazepam. cGMP levels in the presence of diazepam were not restored to control levels by the addition of 0.1 mM sodium nitroprusside, whereas the decrease in cerebellar cGMP levels induced by 0.1 mM L-NAME was restored by the simultaneous application of NO-donors. In addition to the decrease of cGMP levels in neuronal structures induced by 1 mM diazepam, we observed increased cGMP immunoreactivity in glial cells in the cerebellum, the hippocampus, and the cerebral cortex. The significance of this observation is discussed.