PDE5 inhibition improves acquisition processes after learning via a central mechanism. (October 2015)

• Record Type: Journal Article
• Authors: Akkerman, S.; Blokland, A.; van Goethem, N.P.; Cremers, P.; Shaffer, C.L.; Osgood, S.M.; Steinbusch, H.W.M.; Prickaerts, J.
• Is Part Of: Neuropharmacology. Volume 97(2015)
• Page Start: 233
• Page End: 239
• Publication Date: 2015-10
• Subjects: Phosphodiesterase -- Memory -- Central effects -- Acquisition; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.04.019
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: In previous studies, we have shown that phosphodiesterase type 5 inhibitors (PDE5-Is) can improve early consolidation of object memory. These conclusions were based on the timing of drug administration relative to the learning trial (i.e. before or after). However, there are very little pharmacological data available about the pharmacokinetic profile of orally administered PDE5-Is in the rat. Furthermore, there is still debate whether these effects are achieved via central or peripheral mechanisms and if acquisition processes are improved. In the current study, we tested the effects of the PDE5-I vardenafil in a cholinergic-deficit model and compared the effects after intracerebroventricular (ICV) versus oral (PO) administration. We found that PO vardenafil restored a scopolamine-induced memory impairment when dosed within 2 min after the learning trial while ICV vardenafil was able to restore memory when injected within 4 min after learning. Because the test trial was within 10 min after the learning trial, this suggests that these effects on object memory are related to acquisition processes that may still be ongoing in a time window after the learning trial. To further elucidate the extent of this acquisition window, we investigated the pharmacokinetic profile of vardenafil after PO administration where it was detected within 4 min post-dose. Taken together, our data suggest that PDE5 is involved in acquisition processes, which may linger for at least 4–6 min after learning. Further studies are needed to exclude that these effects could also be explained on basis of an effect on early consolidation processes. Additionally, the effectiveness of ICV-administered vardenafil provides further experimental evidence that PDE5-Is improve memory via a central mechanism. Highlights: PDE5 inhibition has been found to improve consolidation processes. This study shows that PDE5 can also improve acquisition processes in a cholinergic deficit model. After oral administration PDE5 can be found in the brain after 4 min. The effects of PDE5 on acquisition are likely to be mediated by central effects.