摘要
創傷後壓力症候群（PTSD）是經歷過創傷事件的人有可能產生的心理疾病。然而，現今的藥物治療方式效用有限。蘿特琳（rotterlin）和順丁烯二酸鹽（MK-801）被發現具有抗憂鬱的效果。蘿特琳會抑制真核延伸因子2 （eEF2）磷酸化，順丁烯二酸鹽是NMDAR的非競爭性結抗劑，兩者皆會增加海馬迴中腦源性神經營養因子（BDNF）蛋白質表現，能減緩憂鬱症狀。更者，背側海馬中的NMDAR是跟建立抑制性逃避行為（inhibitory avoidance）的長期記憶有關。因此，本研究旨在探討蘿特琳和順丁烯二酸鹽對抑制性逃避記憶的調節作用。我們發現由腹腔注射蘿特琳會損害小鼠嫌惡性記憶的習得、固化與提取，但不影響記憶的再固化。順丁烯二酸鹽會損害嫌惡性記憶之習得，然而此記憶損害表現是因為該藥物同時影響了小鼠的電擊敏感度。順丁烯二酸鹽促進了嫌惡行記憶的固化與提取而不影響其記憶再固化。此外，將蘿特琳微量注射入小鼠的海馬迴內，結果與腹腔給藥的結果一致，能顯著地抑制記憶的習得、固化與提取的表現，同時降低小鼠海馬迴內eEF2磷酸化，促使BDNF蛋白質表現的上升。另一方面，在海馬迴注入順丁烯二酸鹽，會促進記憶習得、固化與提取。此結果指出蘿特琳與順丁烯二酸鹽是透過海馬迴影響嫌惡性記憶。順丁烯二酸鹽對於記憶的促進與mTOR的磷酸化表現增加有關，但不影響BDNF的表現。顯示出兩者對於嫌惡性記憶固化相反的影響可能是因為他們走不同的分子路徑。總結上述的實驗結果，調控BDNF與mTOR在腦中的表現量可能將成為未來治療PTSD重要的治療標的之一。

Abstract
Post-traumatic stress disorder (PTSD) is the psychopathological outcome of a traumatic event exposure. However, the current pharmalogical treatments are not effective. Rottlerin and MK-801 have previously been shown to possess antidepressive effects. The eEF2K, which phosphorylates eukaryotic elongation factor 2 (eEF2), is one of the downstream signaling molecules of the N-methyl-D-aspartic acid receptor (NMDAR). Rottlerin inhibits eukaryotic elongation factor 2 kinase (eEF2K), hence increases the levels of brain-derived neurotrophic factor (BDNF) protein in the hippocampus. Likewise, MK-801, a non-competitive antagonist of NMDAR, exerts a fast-acting antidepressive effect through the eEF2K inhibition-mediated increase of BDNF protein in the hippocampus. Furthermore, the NMDA receptors in the dorsal hippocampus are involved in the establishment of long-term memory of the inhibitory avoidance task. The inhibitory avoidance task is widely used in the preclinical research to assess aversive memory and avoidance behavior, which is one of the symptom clusters in the PTSD. Therefore, the present study aimed to investigate the modulatory effects of rottlerin and MK-801 on inhibitory avoidance memory. We first showed that systemic rottlerin impaired memory acquisition, consolidation and retrieval of the inhibitory avoidance memory, whereas had no effect on memory reconsolidation. Systemic MK-801 impaired acquisition of the same aversive memory, which was confounded by MK-801-induced increase of shock sensitivity. Intriguingly, MK-801 (0.25 mg/kg) facilitated memory consolidation and retrieval of the inhibitory avoidance memory without affecting memory reconsolidation. Moreover, the intra-hippocampal infusion of rottlerin significantly impaired memory acquisition, consolidation and retrieval of aversive memory, which was accompanied by decrease of eEF2 and increase of BDNF protein levels in the hippocampus. On the other hand, the intra-hippocampal infusion of MK-801 significantly faciliated memory acquisition, consolidation and retrieval of aversive memory. The memory facilitating effect of MK-801 is correlated with the increase of mTOR protein phosphorylation without changing BDNF levels in the hippocampus. Rottlerin and MK-801 may affected distinct signaling pathways that produced the opposite effects on IA memory consolidation.Taken together, despite having similar antidepressive function, rottlerin and MK-801 display oppositive effects on inhibitory avoidance memory, which are mediated by different signaling pathways in mouse hippocampus. Rottlerin may be a remedy for PTSD via increase of BDNF protein in the hippocampus. By contrast, MK-801 may enhance aversive memory, hence worsen PTSD symptoms through activating hippocampal mTOR signaling pathways. Our results suggest that hippocampal BDNF and mTOR signaling pathways may serve as a potential therapeutic target for PTSD.

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