The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents

被引：145

作者：

van der Staay, F. Josef ^{[1
]}

Rutten, Kris ^{[3
]}

Baerfacker, Lars ^{[2
]}

DeVry, Jean ^{[1
]}

Erb, Christina ^{[1
]}

Heckroth, Heike ^{[2
]}

Karthaus, Dagmar ^{[2
]}

Tersteegen, Adrian ^{[2
]}

van Kampen, Marja ^{[1
]}

Blokland, Arjan ^{[4
]}

Prickaerts, Jos ^{[3
]}

Reymann, Klaus G.

Schroeder, Ulrich H. ^{[5
]}

Hendrix, Martin ^{[2
]}

机构：

[1] Bayer HealthCare, Global Drug Discovery, Dept CNS Res, D-42096 Wuppertal, Germany

[2] Bayer HealthCare, Global Drug Discovery, Dept Chem Res, D-42096 Wuppertal, Germany

[3] Maastricht Univ, Dept Psychiat & Neuropsychol, NL-6200 MD Maastricht, Netherlands

[4] Maastricht Univ, Dept Psychol, NL-6200 MD Maastricht, Netherlands

[5] Leiden Inst Neurobiol, D-39118 Magdeburg, Germany

来源：

NEUROPHARMACOLOGY | 2008年 / 55卷 / 05期

关键词：

Phosphodiesterase; 9; inhibitor; Learning; Memory; LTP; Rat; Mouse; Social recognition; Object recognition; Passive avoidance; T-maze alternation; MK-801; Scopolamine;

D O I：

10.1016/j.neuropharm.2008.07.005

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 mu M, but not 30 mu M 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. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：908 / 918

页数：11

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