Augmentation of cAMP signaling through inhibition of phosphodiesterases (PDE) is known to enhance plasticity and memory. Inhibition of PDE4 enhances consolidation into memory, but less is known about the role of other cAMP specific PDEs. Here, we tested the effects of oral treatment with a selective inhibitor of PDE7 of nanomolar potency on spatial and contextual memory. In an object location task, doses of 0.3–3 mg/kg administered 3 h after training dose-dependently attenuated time-dependent forgetting in rats. Significant enhancement of memory occurred at a dose of 3 mg/kg with corresponding brain levels consistent with PDE7 inhibition. The same dose given prior to training augmented contextual fear conditioning. In mice, daily dosing before training enhanced spatial memory in two different incremental learning paradigms in the Barnes Maze. Drug treated mice made significantly less errors locating the escape in a probe-test 24 h after the end of training, and they exhibited hippocampal-dependent spatial search strategies more frequently than controls, which tended to show serial sampling of escape locations. Acquisition and short-term memory, in contrast, were unaffected. Our data provide evidence for a role of PDE7 in the consolidation of hippocampal-dependent memory. We suggest that targeting PDE7 for memory enhancement may provide an alternative to PDE4 inhibitors, which tend to have undesirable gastrointestinal side-effects.

已知通过抑制磷酸二酯酶 (PDE) 来增强 cAMP 信号可以增强可塑性和记忆力。PDE4 的抑制增强了记忆的巩固，但对其他 cAMP 特异性 PDE 的作用知之甚少。在这里，我们测试了使用具有纳摩尔效力的 PDE7 选择性抑制剂口服治疗对空间和情境记忆的影响。在物体定位任务中，在训练后 3 小时给予 0.3–3 mg/kg 剂量的大鼠，剂量依赖性地减弱了时间依赖性遗忘。在 3 mg/kg 的剂量下，记忆力显着增强，相应的脑水平与 PDE7 抑制一致。训练前给予的相同剂量增强了情境恐惧条件反射。在小鼠中，训练前的每日给药增强了巴恩斯迷宫中两种不同增量学习范式的空间记忆。在训练结束 24 小时后的探针测试中，药物治疗的小鼠在定位逃逸方面的错误显着减少，并且它们比对照更频繁地展示海马依赖性空间搜索策略，后者倾向于显示逃逸位置的连续采样。相比之下，习得和短期记忆不受影响。我们的数据为 PDE7 在巩固海马依赖性记忆中的作用提供了证据。我们建议针对 PDE7 增强记忆力可能提供 PDE4 抑制剂的替代方案，PDE4 抑制剂往往具有不良的胃肠道副作用。它倾向于显示逃生地点的连续采样。相比之下，习得和短期记忆不受影响。我们的数据为 PDE7 在巩固海马依赖性记忆中的作用提供了证据。我们建议针对 PDE7 增强记忆力可能提供 PDE4 抑制剂的替代方案，PDE4 抑制剂往往具有不良的胃肠道副作用。它倾向于显示逃生地点的连续采样。相比之下，习得和短期记忆不受影响。我们的数据为 PDE7 在巩固海马依赖性记忆中的作用提供了证据。我们建议针对 PDE7 增强记忆力可能提供 PDE4 抑制剂的替代方案，PDE4 抑制剂往往具有不良的胃肠道副作用。