D-serine In The Nucleus Accumbens Region Improves Social Avoidance And Anhedonia In Chronic Social Defeat Stress Model Mice

Objective:Depression is a group of mood disorders that are characterized by marked and persistent depression and lack of pleasure.D-serine is an important neurotransmitter secreted mainly by astrocytes.It is widely distributed in the nervous system and its main function is to regulate the function of NMDA receptors.Several previous studies have confirmed that endogenous D-serine may be related to the occurrence of depression;however,the specific mechanism of action involved has been rarely reported.The purpose of this study was to systematically assess the effects of D-serine on the nucleus accumbens(NAc)-mediated depression.Methods:After experiencing Chronic social defeat stress(CSDS)in the experimental group,C57 mice were divided into a susceptible group and a unsusceptible group based on the contact time of the social interaction test.The concentrations of D-serine in the nucleus accumbens(NAc)and hippocampus(Hip)of the control group,susceptible group,and unsusceptible group were determined by high performance liquid chromatography(HPLC).Then,saline,D-serine,and positive control fluoxetine were injected through the abdominal cavity,and the behavioral changes,social interaction rate,and sucrose preference were used to evaluate the depressive behavior.The expressions of serine racemase(SR),D-amino acid oxidase(DAAO),cAMP response element binding protein(CREB)and upstream kinase(ERK 、CAMKII)were analyzed by Western blot.The changes of long-term depression(LTD)in nucleus accumbens slices of mice were explored by electrophysiological methods.Results:(1)HPLC results showed that the D-serine concentration in the nucleus accumbens region of mice in the susceptible group was significantly reduced(p <0.05 vs.Control group);meanwhile,Western blot results showed that serine racemase SRexpression was significantly reduced(p <0.05 vs.Control group),and the expression of D-amino acid oxidase DAAO increased significantly(p <0.05 vs.Control group).(2)After intraperitoneal injection of D-serine in mice in the susceptible group,the social interaction rate and sucrose preference increased significantly(p <0.05 vs.NaCL group);continue to observe the three groups after different concentrations of D-serine and fluoxetine injection The social interaction rate and sucrose preference increased significantly and were dose-dependent(p <0.05 vs.Suscep group).(3)Western blot results showed that CREB and ERK phosphorylation increased in susceptible mice(p <0.05 vs.Control group),but no significant change in phosphorylation level of CAMKII(p> 0.05 vs.Control group);three groups D-serine at different concentrations could reduce the phosphorylation levels of CREB and ERK in susceptible mice(p<0.05 vs.Suscep group),but did not affect the phosphorylation levels of CAMKII(p> 0.05 vs.Suscep group).(4)Electrophysiological results showed that LTD damage in the nucleus accumbens region of mice in the susceptible group increased(p <0.05 vs.Control group),while D-serine and fluoxetine treatment could reverse LTD damage(p <0.05 vs.Suscep group).Conclusion:After chronic social defeat stress,the D-serine concentration in the nucleus accumbens region of mice in the susceptible group decreased,which may be related to the changes of its key enzymes SR and DAAO.Intraperitoneal injection of exogenous D-serine or the positive control fluoxetine could significantly improve Depression behavioral indicators(such as social interaction rate and sucrose preference)of mice in the susceptible group,and reversed the injury of LTD in the nucleus accumbens and the phosphorylation of ERK-CREB pathway related proteins in the nucleus accumbens.