Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany.
Transl Psychiatry. 2012 Mar 13;2(3):e89. doi: 10.1038/tp.2012.17.
Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl-D-aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP.
近年来，磷酸二酯酶 4 型（PDE4）的抑制剂罗利普兰（4-（3-（环戊氧基）-4-甲氧基苯基）-吡咯烷-2-酮）一直是许多行为和分子研究的焦点。罗利普兰在啮齿动物中表现出增强记忆的作用。体外研究表明，长时程增强（LTP）可能构成学习的细胞基础，也被罗利普兰增强。然而，在体内尚未评估其效果。罗利普兰具有抗精神病特性。精神病会影响认知，在精神病的动物模型中，LTP 受损。在这项研究中，我们调查了 PDE4 抑制是否可以改善健康动物体内的 LTP，以及 PDE4 抑制是否可以挽救受损的 LTP 并防止精神病动物模型中的物体识别记忆缺陷。记录取自成年自由活动的 Wistar 大鼠的海马体。在罗利普兰或载体处理 30 分钟后，给予内侧穿通路径强直刺激以在齿状回中诱发短期增强（STP）。此时，放射免疫测定显示罗利普兰显著提高了背侧海马中的环腺苷单磷酸水平，与其他人报告的罗利普兰介导的 PDE4 活性降低一致。在健康动物中，脑室内和皮下给予罗利普兰均可促进 STP 向 LTP 转变，表明 PDE4 抑制可能在与学习和记忆相关的可塑性机制中具有许可作用。单次全身给予不可逆 N-甲基-D-天冬氨酸拮抗剂 MK801 一周后，LTP 和物体识别记忆明显受损，但可通过 PDE4 抑制挽救。这些数据表明，罗利普兰对精神病模型中认知障碍的缓解可能部分是通过挽救海马 LTP 介导的。
