title: PDE5 inhibition improves acquisition processes after learning via a central mechanism.
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.
authors.affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Akkerman
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Blokland
authors.affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: N P
authors.initials: NP
authors.lastname: van Goethem
authors.affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Cremers
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Worldwide Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Shaffer
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Worldwide Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Osgood
authors.affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands. Electronic address: jos.prickaerts@maastrichtuniversity.nl.
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D057967:Infusions, Intraventricular; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000201:enzymology; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D012601:Scopolamine; D013997:Time Factors; D000069058:Vardenafil Dihydrochloride / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000069058:Vardenafil Dihydrochloride; D012601:Scopolamine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: Acquisition; Central effects; Memory; Phosphodiesterase