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PDE5 inhibition improves object memory in standard housed rats but not in rats housed in an enriched environment: implications for memory models?

Akkerman S, Prickaerts J, Bruder AK, Wolfs KH, De Vry J, Vanmierlo T, Blokland A - PLoS ONE (2014)

Bottom Line: However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions.While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2-3 or CA1.Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.

ABSTRACT
Drug effects are usually evaluated in animals housed under maximally standardized conditions. However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions. In the present study, we examined the acute cognition enhancing effects of vardenafil, a PDE5 inhibitor, which stimulates protein kinase G/CREB signaling in cells, in three different groups of male Wistar rats tested in an object recognition task (ORT). Rats were either housed solitarily (SOL) or socially (SOC) under standard conditions, or socially in an EE. Although EE animals remembered object information longer in the vehicle condition, vardenafil only improved object memory in SOL and SOC animals. While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2-3 or CA1. Neither were there any differences in markers for pre- and postsynaptic density. No changes in PDE5 mRNA- and protein expression levels were observed. Basal pCREB levels were increased in EE rats only, whereas β-catenin was not affected, suggesting specific activation of the MAP kinase signaling pathway and not the AKT pathway. A possible explanation for the inefficacy of vardenafil could be that CREB signaling is already optimally stimulated in the hippocampus of EE rats. Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

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Related in: MedlinePlus

ORT 24 h intervals.Discrimination performance (d2, mean + SEM) of SOL (A), SOC (B) and EE (C) rats after administration of different doses of vardenafil in the object recognition task. All housing conditions were tested in a 24 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis). A difference from zero is indicated with hash symbols (one-sample t-test; #: p<0.05; ##: p<0.01; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with an asterisk (Tukey HSD; *: p<0.05). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
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pone-0111692-g003: ORT 24 h intervals.Discrimination performance (d2, mean + SEM) of SOL (A), SOC (B) and EE (C) rats after administration of different doses of vardenafil in the object recognition task. All housing conditions were tested in a 24 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis). A difference from zero is indicated with hash symbols (one-sample t-test; #: p<0.05; ##: p<0.01; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with an asterisk (Tukey HSD; *: p<0.05). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.

Mentions: One-sample t-tests showed that SOL animals treated with 0.3 or 1 mg/kg vardenafil had a d2 value significantly higher than zero. The same was true for SOC animals treated with 0.3 mg/kg vardenafil. In EE animals, the vehicle condition and all of the included vardenafil doses resulted in a d2 that was higher than zero. The effects of vardenafil in the 24 h retention interval are graphically presented in Figure 3.


PDE5 inhibition improves object memory in standard housed rats but not in rats housed in an enriched environment: implications for memory models?

Akkerman S, Prickaerts J, Bruder AK, Wolfs KH, De Vry J, Vanmierlo T, Blokland A - PLoS ONE (2014)

ORT 24 h intervals.Discrimination performance (d2, mean + SEM) of SOL (A), SOC (B) and EE (C) rats after administration of different doses of vardenafil in the object recognition task. All housing conditions were tested in a 24 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis). A difference from zero is indicated with hash symbols (one-sample t-test; #: p<0.05; ##: p<0.01; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with an asterisk (Tukey HSD; *: p<0.05). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221101&req=5

pone-0111692-g003: ORT 24 h intervals.Discrimination performance (d2, mean + SEM) of SOL (A), SOC (B) and EE (C) rats after administration of different doses of vardenafil in the object recognition task. All housing conditions were tested in a 24 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis). A difference from zero is indicated with hash symbols (one-sample t-test; #: p<0.05; ##: p<0.01; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with an asterisk (Tukey HSD; *: p<0.05). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
Mentions: One-sample t-tests showed that SOL animals treated with 0.3 or 1 mg/kg vardenafil had a d2 value significantly higher than zero. The same was true for SOC animals treated with 0.3 mg/kg vardenafil. In EE animals, the vehicle condition and all of the included vardenafil doses resulted in a d2 that was higher than zero. The effects of vardenafil in the 24 h retention interval are graphically presented in Figure 3.

Bottom Line: However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions.While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2-3 or CA1.Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.

ABSTRACT
Drug effects are usually evaluated in animals housed under maximally standardized conditions. However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions. In the present study, we examined the acute cognition enhancing effects of vardenafil, a PDE5 inhibitor, which stimulates protein kinase G/CREB signaling in cells, in three different groups of male Wistar rats tested in an object recognition task (ORT). Rats were either housed solitarily (SOL) or socially (SOC) under standard conditions, or socially in an EE. Although EE animals remembered object information longer in the vehicle condition, vardenafil only improved object memory in SOL and SOC animals. While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2-3 or CA1. Neither were there any differences in markers for pre- and postsynaptic density. No changes in PDE5 mRNA- and protein expression levels were observed. Basal pCREB levels were increased in EE rats only, whereas β-catenin was not affected, suggesting specific activation of the MAP kinase signaling pathway and not the AKT pathway. A possible explanation for the inefficacy of vardenafil could be that CREB signaling is already optimally stimulated in the hippocampus of EE rats. Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs.

Show MeSH
Related in: MedlinePlus