Inhibition of phoshodiesterase type 2 or type 10 reverses object memory deficits induced by scopolamine or MK-801.

Abstract

The objective of this study was to assess the effects of phosphodiesterase type 2 (PDE2) and type 10 (PDE10) inhibition on memory function in the object recognition task using the scopolamine- and MK-801-induced memory deficit model. The effects of the PDE2 inhibitor BAY 60-7550 and the PDE10 inhibitor PQ-10 on object recognition performance were investigated in the scopolamine (0.1mg/kg, i.p.) or MK-801 (0.125 mg/kg, i.p.) model. BAY 60-7550 was tested at a dose of 0.3-3mg/kg (p.o.) in both models; PQ-10 was tested at doses of 0.1-1mg/kg (p.o.) in the scopolamine model and 0.3-3mg/kg in the MK-801 model. All compounds were injected 30 min before the learning trial. Both BAY 60-7550 (1mg/kg) and PQ-10 (0.3mg/kg) attenuated the scopolamine-induced memory deficit. The MK-801-induced memory deficit was reversed after treatment with each PDE inhibitor at a dose of 1mg/kg or higher. PQ10 was highly brain penetrant, whereas 60-7550 levels in the brain were very low after oral treatment. We concluded that since BAY 60-7550 and PQ10 reversed both scopolamine- and MK-801-induced memory deficits, this supports the notion that dual substrate PDE inhibitors might be suitable candidates for cognition enhancement.

• Authors: Olga A H Reneerkens, Kris Rutten, Eva Bollen, Thorsten Hage, Arjan Blokland, Harry W M Steinbusch, Jos Prickaerts
• Journal: Behavioural brain research (Behav Brain Res) Vol. 236 Issue 1 Pg. 16-22 (Jan 01 2013) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 22951181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• 2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one
• Excitatory Amino Acid Antagonists
• Imidazoles
• Muscarinic Antagonists
• Phosphodiesterase Inhibitors
• Triazines
• Dizocilpine Maleate
• Scopolamine
• PDE10A protein, rat
• Phosphoric Diester Hydrolases
• Cyclic Nucleotide Phosphodiesterases, Type 2

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (antagonists & inhibitors)
• Dizocilpine Maleate
• Excitatory Amino Acid Antagonists
• Exploratory Behavior (drug effects)
• Imidazoles (pharmacokinetics, pharmacology)
• Male
• Memory (drug effects)
• Memory Disorders (chemically induced, drug therapy, psychology)
• Muscarinic Antagonists
• Phosphodiesterase Inhibitors (pharmacokinetics, pharmacology)
• Phosphoric Diester Hydrolases (metabolism)
• Rats
• Rats, Wistar
• Recognition, Psychology (drug effects)
• Scopolamine
• Spectrometry, Mass, Electrospray Ionization
• Triazines (pharmacokinetics, pharmacology)