The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices.
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.
Rutten
K
K
Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, Maastricht University, The Netherlands. k.rutten@np.unimass.nl
Vente
J De
JD
Sik
A
A
Ittersum
M Markerink-Van
MM
Prickaerts
J
J
Blokland
A
A
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005556:Form Perception / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D000068677:Sildenafil Citrate; D013450:Sulfones
D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006152:Cyclic GMP