Cleary C, Linde J A S, Hiscock K M, Hadas I, Belmaker R H, Agam G, Flaisher-Grinberg S, Einat H
Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA.
Brain Res Bull. 2008 Jul 30;76(5):469-73. doi: 10.1016/j.brainresbull.2008.03.005. Epub 2008 Apr 3.
Lithium, the prototypic mood stabilizer, was recently demonstrated to enhance autophagy in cells. Recent hypotheses regarding the source of therapeutic effects of lithium as well as other mood stabilizers and antidepressants suggest that they may stem from increased neuroprotection, cellular plasticity and resilience. Hence it is clearly a possibility that enhanced autophagy may be involved in the therapeutic action by contributing to increased cellular resilience. A well-documented mechanism to induce autophagy is by inhibition of mTOR, a negative modulator of autophagy and rapamycin (sirolimus) is a commonly used inhibitor of mTOR. Accordingly, the present study was designed to evaluate the effects of rapamycin in animal models of antidepressant activity. A dose-response experiment in the mice forced swim test was performed and followed by additional testing of mice and rats in an open field, the forced swim test and the tail suspension test. Results show that sub-chronic, but not acute, administration of rapamycin doses of 10mg/kg and above, have an antidepressant-like effect in both mice and rats and in both the forced swim and the tail suspension tests with no effects on the amount or distribution of activity in the open field. Whereas it is tempting to conclude that the antidepressant-like effects are related to mTOR inhibition, they may also be the consequences of interactions with other intracellular pathways. Additional studies are now planned to further explore the behavioral range of rapamycin's effects as well as the biological mechanisms underlying these effects.
锂作为典型的心境稳定剂，最近被证明可增强细胞自噬。最近关于锂以及其他心境稳定剂和抗抑郁药治疗作用来源的假说表明，它们可能源于神经保护作用增强、细胞可塑性和恢复力提高。因此，增强的自噬很有可能通过提高细胞恢复力参与治疗作用。一种诱导自噬的充分记录的机制是抑制mTOR，mTOR是自噬的负调节因子，雷帕霉素（西罗莫司）是常用的mTOR抑制剂。因此，本研究旨在评估雷帕霉素在抗抑郁活性动物模型中的作用。在小鼠强迫游泳试验中进行了剂量反应实验，随后在旷场、强迫游泳试验和悬尾试验中对小鼠和大鼠进行了额外测试。结果表明，10mg/kg及以上剂量的雷帕霉素亚慢性给药（而非急性给药）在小鼠和大鼠的强迫游泳试验和悬尾试验中均具有抗抑郁样作用，对旷场中的活动量或分布没有影响。虽然很容易得出抗抑郁样作用与mTOR抑制有关的结论，但它们也可能是与其他细胞内途径相互作用的结果。现在计划进行更多研究，以进一步探索雷帕霉素作用的行为范围以及这些作用背后的生物学机制。
