Ketamine exhibits rapid and sustained antidepressant responses, but its repeated use may cause adverse effects. Augmentation strategies have been postulated to be useful for the management/reduction of ketamine's dose and its adverse effects. Based on the studies that have suggested that ketamine and guanosine may share overlapping mechanisms of action, the present study investigated the antidepressant-like effect of subthreshold doses of ketamine and guanosine in mice subjected to repeated administration of corticosterone (CORT) and the role of mTORC1 signaling for this effect. The ability of the treatment with ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) to counteract the depressive-like behavior induced by CORT (20 mg/kg, p.o., for 21 days) in mice, was paralleled with the prevention of the CORT-induced reduction on BDNF levels, Akt (Ser⁴⁷³) and GSK-3β (Ser⁹) phosphorylation, and PSD-95, GluA1, and synapsin immunocontent in the hippocampus. No changes on mTORC1 and p70S6K immunocontent were found in the hippocampus and prefrontal cortex of any experimental group. No alterations on BDNF, Akt/GSK-3β, mTORC1/p70S6K, and synaptic proteins were observed in the prefrontal cortex of mice. The antidepressant-like and pro-synaptogenic effects elicited by ketamine plus guanosine were abolished by the pretreatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTORC1 inhibitor). Our results showed that the combined administration of ketamine and guanosine at low doses counteracted CORT-induced depressive-like behavior and synaptogenic disturbances by activating mTORC1 signaling. This study supports the notion that the combined administration of guanosine and ketamine may be a useful therapeutic strategy for the management of MDD.

氯胺酮表现出快速和持续的抗抑郁反应，但重复使用可能会导致不良反应。已假定增强策略可用于管理/减少氯胺酮的剂量及其副作用。基于表明氯胺酮和鸟苷可能具有重叠作用机制的研究，本研究调查了亚阈值剂量的氯胺酮和鸟苷在反复给予皮质酮 (CORT) 的小鼠中的抗抑郁样作用以及 mTORC1 的作用。发出这种效果的信号。用氯胺酮 (0.1 mg/kg, ip) 加鸟苷 (0.01 mg/kg, po) 治疗小鼠 CORT (20 mg/kg, po, 21 天) 诱导的抑郁样行为的能力，⁴⁷³ ) 和 GSK-3β (Ser ⁹) 磷酸化，以及海马中的 PSD-95、GluA1 和突触蛋白免疫含量。在任何实验组的海马和前额叶皮层中未发现mTORC1和p70S6K免疫含量的变化。在小鼠前额叶皮层中未观察到 BDNF、Akt/GSK-3β、mTORC1/p70S6K 和突触蛋白的变化。用雷帕霉素（0.2 nmol/位点，icv，一种选择性 mTORC1 抑制剂）预处理消除了氯胺酮加鸟苷引起的抗抑郁样和促突触作用。我们的研究结果表明，低剂量氯胺酮和鸟苷的联合给药通过激活 mTORC1 信号传导来抵消 CORT 诱导的抑郁样行为和突触发生障碍。