title: Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats.
abstract: Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [14C]-iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. k.rutten@np.unimaas.nl
authors.forename: Kris
authors.initials: K
authors.lastname: Rutten
authors.forename: Eva L
authors.initials: EL
authors.lastname: Van Donkelaar
authors.forename: Linda
authors.initials: L
authors.lastname: Ferrington
authors.forename: Arjan
authors.initials: A
authors.lastname: Blokland
authors.forename: Eva
authors.initials: E
authors.lastname: Bollen
authors.forename: Harry Wm
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Paul At
authors.initials: PA
authors.lastname: Kelly
authors.forename: Jos Hhj
authors.initials: JH
authors.lastname: Prickaerts
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D018697:Nootropic Agents; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C521385:Pde4a protein, rat; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D005947:Glucose