AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 μg/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, (0.01 μg/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3β signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr³⁸⁹) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3β.

AZD6765（lanicemine）是一种非竞争性NMDA受体拮抗剂，可诱​​导速效抗抑郁作用而无拟精神病药作用。但是，影响其作用的机制仍有待建立。在这种情况下，我们证明了一次给药AZD6765（1 mg / kg，ip）能够在进行尾部悬吊试验（TST）的小鼠中诱导抗抑郁样作用，这种作用被LY294002（可逆PI3K抑制剂）逆转，10 nmol /位点，icv），渥曼青霉素（不可逆PI3K抑制剂，0.1μg/位点，icv）和雷帕霉素（选择性mTOR抑制剂，0.2 nmol /位点，icv）。此外，亚有效剂量的AZD6765（0.1 mg / kg，ip）与氯化锂（非选择性GSK-3β抑制剂，10 mg / kg，口服）或AR-A014418（选择性GSK-3β）联合给药抑制剂，（0。01μg/位点，icv）产生类似抗抑郁药的协同作用。这些结果表明PI3K / Akt / mTOR /GSK3β信号传导参与了AZD6765类抗抑郁药的作用。此外，蛋白质印迹分析显示，服用AZD6765 30分钟后，前额叶皮层中突触蛋白的免疫含量增加，海马中该蛋白的免疫含量增加，但在P70S6K（Thr中未观察到AZD6765的显着作用³⁸⁹）磷酸化和GluA1免疫含量。与氯胺酮（1 mg / kg，ip）一样，单剂量AZD6765（3 mg / kg，ip）减少了新奇抑制喂养（NSF）测试的进食潜伏期，该行为范式可评估抑郁/焦虑-相关行为。雷帕霉素的给药可逆转这种作用，表明在NSF试验中mTOR信号的激活对AZD的作用具有影响。此外，单次服用AZD6765（1 mg / kg，ip）或氯胺酮（1 mg / kg，ip）可逆转由慢性不可预测压力（CUS）诱发的抑郁样行为。总之，这些结果通过可能依赖于PI3K / Akt / mTOR /GSK3β的机制为AZD6765的速效抗抑郁药提供了证据。