Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway
Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway
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DOI：
10.1016/j.expneurol.2020.113459
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发表时间：
2020-12-01
影响因子：
5.3
通讯作者：
Rodrigues, Ana Lucia S.
中科院分区：
文献类型：
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作者：
Camargo, Anderson;Dalmagro, Ana Paula;Rodrigues, Ana Lucia S.
据报道，氯胺酮通过调节鸟苷嘌呤能系统对应激诱导的抑郁样行为发挥预防作用。然而，其预防作用的分子途径以及鸟苷是否也具有类似的作用仍有待确定。在这里，我们研究了氯胺酮和鸟苷对皮质酮（CORT - 20 mg/kg，p.o.）的预防作用。在小鼠中诱导抑郁样行为。此外，我们的特点，如果预防性反应可能与mTORC 1驱动的信号在海马和前额皮质。单次给予氯胺酮（5 mg/kg，i. p.），但不包括鸟苷（1或5 mg/kg，p.o.），在药物应激前1周给药，可防止悬尾试验（TST）和飞溅试验（SPT）中CORT诱导的抑郁样行为。氟西汀治疗3周并不能阻止皮质醇诱导的行为效应。单次给予阈下剂量的氯胺酮（lmg/kg，i. p.）加鸟苷（5 mg/kg，p.o.）部分防止皮质激素诱导的抑郁样行为的SPT。此外，CORT降低了海马中Akt（Ser（473））和GSK-3 β（Ser（9））磷酸化以及PSD-95、GluA 1和突触蛋白免疫含量，但在前额叶皮层中没有。各实验组mTORC 1/p70 S6 K免疫组化结果均未见明显改变。皮质醇诱导的PSD-95，GluA 1和突触蛋白免疫含量的减少仅通过氯胺酮治疗来防止。总的来说，这些发现表明氯胺酮而不是鸟苷对抑郁样行为发挥预防作用，这种作用与海马体中持久的促突触发生信号的刺激有关。
Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT - 20 mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5 mg/kg, i.p.), but not guanosine (1 or 5 mg/kg, p.o.), given 1 week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3 weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1 mg/kg, i.p.) plus guanosine (5 mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser(473)) and GSK-3 beta (Ser(9)) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus.