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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 48 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 48 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis), EE animals also received 0.03 mg/kg vardenafil. A difference from zero is indicated with hash symbols (one-sample t-test; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with asterisks (Tukey HSD; **: p<0.01; ***: p<0.001). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
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pone-0111692-g004: ORT 48 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 48 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis), EE animals also received 0.03 mg/kg vardenafil. A difference from zero is indicated with hash symbols (one-sample t-test; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with asterisks (Tukey HSD; **: p<0.01; ***: p<0.001). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.

Mentions: The discrimination performance of the animals is shown in Figures 2–4. A two-way ANOVA (Interval×Housing) was performed, incorporating only vehicle treated groups. There was a significant main effect of Interval on discrimination performance (F(2,161) = 21.33, p<0.001). Post-hoc analysis revealed that the overall d2 value was higher at the 1 h interval compared to the 24 h and 48 h intervals. There was also a significant main effect of Housing on d2 (F(2,161) = 3.05, p<0.05). Post-hoc analysis revealed that EE animals showed better overall object discrimination (d2 was higher) compared to SOC animals. No significant Interval by Housing interaction effects were found for d2 (F(4,161) = 0.50, n.s).


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 48 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 48 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis), EE animals also received 0.03 mg/kg vardenafil. A difference from zero is indicated with hash symbols (one-sample t-test; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with asterisks (Tukey HSD; **: p<0.01; ***: p<0.001). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111692-g004: ORT 48 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 48 h retention interval in combination with 0, 0.1, 0.3 and 1 mg/kg vardenafil (x-axis), EE animals also received 0.03 mg/kg vardenafil. A difference from zero is indicated with hash symbols (one-sample t-test; ###: p<0.001), differences from the vehicle condition (0 mg/kg) within the same retention interval are indicated with asterisks (Tukey HSD; **: p<0.01; ***: p<0.001). Of note, the 0 mg/kg vardenafil conditions are identical to those used in Figure 2.
Mentions: The discrimination performance of the animals is shown in Figures 2–4. A two-way ANOVA (Interval×Housing) was performed, incorporating only vehicle treated groups. There was a significant main effect of Interval on discrimination performance (F(2,161) = 21.33, p<0.001). Post-hoc analysis revealed that the overall d2 value was higher at the 1 h interval compared to the 24 h and 48 h intervals. There was also a significant main effect of Housing on d2 (F(2,161) = 3.05, p<0.05). Post-hoc analysis revealed that EE animals showed better overall object discrimination (d2 was higher) compared to SOC animals. No significant Interval by Housing interaction effects were found for d2 (F(4,161) = 0.50, n.s).

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