Department of Pharmacology, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Pharmacol Biochem Behav. 2012 May;101(3):311-9. doi: 10.1016/j.pbb.2012.01.017. Epub 2012 Jan 28.
Although there are number of studies showing that phosphodiesterase (PDE) 4 and 5 inhibitors affect different kinds of memory, their effects on spatial memory consolidation in conjunction with the cholinergic activity in the hippocampus have not been studied before. In the present study firstly, rats were evaluated for the effects of different doses of the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil on spatial memory consolidation in the water maze task. Rolipram or sildenafil was daily administered intraperitoneally 3 or 0 h after the last trial of training, respectively. Then in a separate related experiment the effect of the most efficient doses of rolipram or sildenafil accompanied by an intrahippocampally injected protein kinase A (PKA) or protein kinase G (PKG) inhibitor, respectively, was examined. Finally for determination of the hippocampal cholinergic activity the protein expression of hippocampal vesicular acetylcholine transporter (VAChT) and cholineacetyltransferase (ChAT) was measured. Rolipram at 0.03 mg/kg as well as sildenafil at 3 mg/kg increased spatial memory and their enhancing effect was completely blocked following inhibition of PKA and PKG, respectively. Furthermore, none of the treatments had a significant effect on the hippocampal ChAT and VAChT levels. Our data showed that rolipram and sildenafil enhanced spatial memory consolidation in an inverted U-shaped dose-response curve. This effect is dependent on the activity of cAMP/PKA- and cGMP/PKG-mediated pathways, respectively in the hippocampus. However, we did not find evidence for a chronic increase of cholinergic activity in the observed PDE inhibitor-induced memory improvement.
虽然有许多研究表明磷酸二酯酶（PDE）4 和 5 抑制剂会影响不同类型的记忆，但它们对海马胆碱能活动与空间记忆巩固的影响以前尚未研究过。在本研究中，首先评估了不同剂量的 PDE4 抑制剂罗利普兰（rolipram）和 PDE5 抑制剂西地那非（sildenafil）对水迷宫任务中空间记忆巩固的影响。罗利普兰或西地那非分别在训练最后一次试验后 3 或 0 小时每天腹膜内给药。然后，在一个单独的相关实验中，检查了最有效剂量的罗利普兰或西地那非与分别海马内注射蛋白激酶 A（PKA）或蛋白激酶 G（PKG）抑制剂组合的效果。最后，为了测定海马胆碱能活性，测量了海马囊泡乙酰胆碱转运体（VAChT）和胆碱乙酰转移酶（ChAT）的蛋白表达。0.03mg/kg 的罗利普兰和 3mg/kg 的西地那非均增加了空间记忆，并且它们的增强作用在分别抑制 PKA 和 PKG 后完全被阻断。此外，没有任何一种治疗方法对海马 ChAT 和 VAChT 水平有显著影响。我们的数据表明，罗利普兰和西地那非以倒 U 形剂量反应曲线增强了空间记忆巩固。这种作用依赖于 cAMP/PKA-和 cGMP/PKG 介导的途径在海马中的活性，分别。然而，我们没有发现观察到的 PDE 抑制剂诱导的记忆改善中胆碱能活性慢性增加的证据。
