The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents.
The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 microM, but not 30 microM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.
van der Staay
F Josef
FJ
BAYER HealthCare AG, Global Drug Discovery, Department of CNS Research, D-42096 Wuppertal-Elberfeld, Germany. f.j.vanderstaay@uu.nl
Rutten
Kris
K
Bärfacker
Lars
L
Devry
Jean
J
Erb
Christina
C
Heckroth
Heike
H
Karthaus
Dagmar
D
Tersteegen
Adrian
A
van Kampen
Marja
M
Blokland
Arjan
A
Prickaerts
Jos
J
Reymann
Klaus G
KG
Schröder
Ulrich H
UH
Hendrix
Martin
M
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010364:Pattern Recognition, Visual / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology
C507056:BAY 73-6691; D018680:Cholinergic Antagonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D016291:Dizocilpine Maleate; D012601:Scopolamine