Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Pharmacol Biochem Behav. 2013 Apr;105:177-82. doi: 10.1016/j.pbb.2013.02.016. Epub 2013 Mar 5.
Despite extensive investigations, molecular mechanisms underlying the formation of fear memory are not completely understood. We have previously investigated the role of protein kinase AII (PKAII) in spatial acquisition and memory retention using Morris water maze. In the current study, we have further analyzed the role of PKA in memory consolidation using a fear conditioning response model. Experiments were performed using intrahippocampal infusions of dibutyryl cyclic AMP (bucladesine), a cell permeable analog of cAMP and H89, as a selective PKAII inhibitor, in male rats. The animals were trained for one session which included 4 consecutive trials of tone-shock pairing on the training day. Fear to the context and tone was evaluated by measuring freezing behavior 24h and 48h after training respectively. Bilateral infusion of 100 and 300μM/side of bucladesine immediately after training increased freezing percentage in rats, which indicated an improvement in memory consolidation. Administration of 10μM/side (but not 5μM/side) of H-89 impaired contextual and cued fear conditioning significantly compared to the control animals. Moreover, administration of bucladesine (100 and 300μM/side), 5min after H-89 infusion (10μM/side) reversed the impairment of contextual and auditory-cued fear conditioning in rats and freezing percentage increased to those of control animals. Altogether, these results indicate that PKA inhibitor-induced memory deficit was attenuated by a cAMP analog and that the cAMP/PKA signaling pathway has an important role for memory consolidation in fear conditioning response model.
尽管进行了广泛的研究，但恐惧记忆形成的分子机制仍不完全清楚。我们之前使用 Morris 水迷宫研究了蛋白激酶 AII（PKAII）在空间获取和记忆保留中的作用。在当前的研究中，我们使用恐惧条件反射反应模型进一步分析了 PKA 在记忆巩固中的作用。实验使用细胞可渗透的 cAMP 类似物二丁酰环 AMP（bucladesine）和 PKAII 选择性抑制剂 H89 对雄性大鼠进行海马内输注。动物在训练日接受了包括 4 次连续的声音-电击配对的一个疗程的训练。在训练后 24 小时和 48 小时分别通过测量冻结行为来评估对环境和声音的恐惧。训练后立即输注 100 和 300μM/侧的 bucladesine 会增加大鼠的冻结百分比，表明记忆巩固得到改善。与对照组动物相比，10μM/侧（但不是 5μM/侧）的 H-89 给药显著损害了情境和提示性恐惧条件反射。此外，在 H-89 输注（10μM/侧）后 5 分钟给予 bucladesine（100 和 300μM/侧）可逆转大鼠情境和听觉提示性恐惧条件反射的损害，冻结百分比增加到对照组动物的水平。总的来说，这些结果表明，PKA 抑制剂引起的记忆缺陷可被 cAMP 类似物减弱，并且 cAMP/PKA 信号通路在恐惧条件反射反应模型中的记忆巩固中具有重要作用。
