A Preliminary Study On The Rapid Antidepressant Effects Of Ketamine And Its Mechanism

Background:At present,depression has become one of the ten major diseases causing death and disability(loss of work or life ability).Although depression severely threatens people,s heath and causes the massive social and economic burden to family and society,the current treatments to depression are not ideal with uncomplete understanding of the biological basis of the desease.The most common antidepressants used nowadays are increasing monoamine neurotransmitter.These medications are usally effctive in 50% of patients and exert their thyraputic actions after few weeks of administration.Increase of the risk of depression patients suicide attampts is a major concern during the antidepressants treatments.Thus,it is very important to develop new and fast antidepressant drugs.In recent years,some studies have found that a subanesthestic-dose of ketamine exhibites a rapid antidepressant effects in animal experiments and in clilical trials,but the effects of ketamine addiction and psychosis have limited its clinical application.The underlying mechamisms of Ketamine,s rapid antidepressive actions are still unclear,studies found that ketamine and traditional antidepressants share some common targets in their antidepressant actions,but the theraputic time has a very significant difference.Understand this will be conducive to understanding the mechanism of ketamine,s fast-acting antidepressant effects,as well as providesing the basis for the development of new antidepressant drugs.Aim:This study used gene mutant mice,Western blotting,behavioral experiments,to compare the distinctions between ketamine and traditional antidepressants imipramine in GluR1 phosphorylation and expression.This investigation provide important experimental evidence for the development of new rapid antidepressant.Methods:1.The forced swimming test and sucrose preference test were conducted to investigate the improvement of the behavior of rats after ketamine or imipramine administration.2.Western blot was performed to detect the distinctions in the level of GluR1 phosphorylation and expression after ketamine or imipramine treatment.3.We utilized the forced swimming test as antidepressant detecting assay on both GluR1 S845 A mice and GluR1 S831 A mice,to confirm whether GluR1 phosphorylation is necessary for the antidepressant actions of ketamine or imipramine.Results:1.A sigle dose of Ketamine injection can rapidly improve the behavior of depression in rats,while only appeared after 21 d consecutive administration of imipramine.2.Ketamine increased the phosphorylation of GluR1 at serine 845 and total GluR1 expression in hippocampus at early time,but ketamine did not alter the phosphorylation of GluR1 at serine 831.Both actue and chronic imipremine appication increased GluR1 Ser831 phosphorylation,but the phosphorylation of GluR1 Ser845 and total GluR1 express only appeared after chronic administration of imipramine.3.Ketamine failed to improve the behavior of depression in GluR1 S845 A mice,but imipramine still exhibited an antidepressant effect.4.In GluR1 S831 A mice,imipramine still exhibited an antidepressant effect.Conclusion:1.Increasing of GluR1 Ser845 phosphorylation and GluR1 expression at the early phase of treatment may be one of the more rapid mechanisms for ketamine than imipramine.2.The Phosphorylation of GluR1 Ser845 is necessary for the antidepressant actions of ketamine,but not for imipremine.3.The Phosphorylation of GluR1 Ser831 is not necessary for the antidepressant actions of imipramine.