Akkerman Sven, Prickaerts Jos, Bruder Ann K, Wolfs Kevin H M, De Vry Jochen, Vanmierlo Tim, Blokland Arjan
Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
PLoS One. 2014 Nov 5;9(11):e111692. doi: 10.1371/journal.pone.0111692. eCollection 2014.
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.
药物效应通常在处于最大标准化条件下饲养的动物中进行评估。然而，与最大标准化的实验室条件相比，富集环境（EE）被认为更接近人类环境。在本研究中，我们在一项物体识别任务（ORT）中测试了三组雄性Wistar大鼠，研究了磷酸二酯酶5（PDE5）抑制剂伐地那非的急性认知增强作用，该药物可刺激细胞中的蛋白激酶G/CREB信号通路。大鼠分别单独饲养（SOL）或在标准条件下群居（SOC），或在富集环境中群居。尽管在给予溶剂的情况下，处于富集环境的动物能更长时间记住物体信息，但伐地那非仅改善了单独饲养和群居动物的物体记忆。虽然处于富集环境的动物背侧海马体更重，但我们发现实验组在齿状回、CA2-3或CA1的细胞总数上没有差异。突触前和突触后密度标记物也没有差异。未观察到PDE5 mRNA和蛋白表达水平的变化。仅在处于富集环境的大鼠中基础pCREB水平升高，而β-连环蛋白未受影响，这表明丝裂原活化蛋白激酶信号通路而非AKT通路被特异性激活。伐地那非无效的一个可能解释是，在处于富集环境的大鼠海马体中，CREB信号通路已经受到最佳刺激。由于先前的数据表明急性PDE5抑制并不能改善人类的记忆表现，因此使用处于富集环境的动物可被视为测试认知增强药物的更有效模型。
