title: Object memory enhancement by combining sub-efficacious doses of specific phosphodiesterase inhibitors.
abstract: The second messengers cGMP and cAMP have a vital role in synaptic plasticity and memory processes. As such, phosphodiesterases inhibitors (PDE-Is), which prevent the breakdown of these cyclic nucleotides, represent a potential treatment strategy in memory decline. Recently it has been demonstrated that cGMP and cAMP signaling act in sequence during memory consolidation, with early cGMP signaling requiring subsequent cAMP signaling. Here, we sought to confirm this relationship, and to evaluate its therapeutic implications. Combining sub-efficacious doses of the cGMP-specific PDE type 5 inhibitor vardenafil (0.1 mg/kg) and cAMP-specific PDE type 4 inhibitor rolipram (0.01 mg/kg) during the early and late memory consolidation phase, respectively, led to improved memory performance in a 24 h interval object recognition task. Similarly, such a sub-efficacious combination treatment enhanced the transition of early-phase long-term potentiation (LTP) to late-phase LTP in hippocampal slices. In addition, both object memory and LTP were improved after administration of two sub-efficacious doses of the dual substrate PDE type 2 inhibitor BAY60 7550 (0.3 mg/kg) at the early and late consolidation phase, respectively. Taken together, combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is have an additive effect on long-term synaptic plasticity and memory formation and might prove a superior alternative to single PDE-I treatment.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Bollen
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Akkerman
authors.affiliation: Department of Biomedical and Biotechnological Sciences - Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Puzzo
authors.affiliation: Department of Biomedical and Biotechnological Sciences - Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: W
authors.initials: W
authors.lastname: Gulisano
authors.affiliation: Department of Biomedical and Biotechnological Sciences - Section of Physiology, University of Catania, 95125 Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Palmeri
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, 3000 Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, 3000 Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Balschun
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Blokland
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: jos.prickaerts@maastrichtuniversity.nl.
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride / Q000494:pharmacology
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D007093:Imidazoles; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000242:Cyclic AMP; D006152:Cyclic GMP; D020889:Rolipram
keywords: Memory; Phosphodiesterase inhibitors; Synaptic plasticity