The Effects And Underlying Mechanism Of PSD-95 Signaling Pathway On Aggressive Behavior In Rats

OBJECTIVES1.To explore the effects of postsynaptic density-95(PSD-95)blockade(ZL006)on different type of aggressive behaviors based on different rat models of aggression.2.To explore the mediated effect of PSD-95 signaling pathway on pathological aggression reduced by serotonin 1A(5-HT1A)receptor agonist in rats.METHODS1.Fifty-four 21-day-old male Sprague-Dawley rats were randomized into 3 groups:pathological aggression group(PA),normal aggression group(NA)and Control group(feed as usual,Ctrl).Eighteen instrumental rats were feed as usual.After establishment of model,resident-intruder test was used to assess aggressive behaviors.Then,choose 12 rats from every model randomly,and divided them into 2 groups:PA+ZL006,PA+Saline,NA+ZL006,NA+ Saline,Ctrl+ZL006,Ctrl+ Saline.ZL006(1.0 mg/kg i.p.)and Saline(2ml/per)were given respectively once every three days for 2 weeks.Aggressive behaviors were tested by resident-intruder test.Expression of PSD-95,neuronal nitric oxide synthase(nNOS)and glucocorticoid receptor(GR)were tested by Western Blot.The level of glucocorticoid(GC)in serum was examed by GC ELISA kit.Rats who had no intervention were executed immediately after establishment of models.2.Twenty-four pathological aggression rats were randomly assigned to 4 groups,that is,8-OH-DPAT,8-OH-DPAT+ZL006,ZL006,and Saline group.The rats were given corresponding treatment,1 mg/kg 5-HT1A receptor agonist(8-OH-DPAT)i.p.for 2 consecutive weeks,1 mg/kg PSD-95 blockade(ZL006)i.p.every 3 days for 2 weeks.Resident-intruder test was taken respectively before intervention,in 1 and 2 weeks after intervention.After the test,blood sample was harvested from posterior orbital vein.Expression of serotonin 1A receptor(5-HT1AR),PSD-95 and GR in prefrontal cortex,hippocampus and hypothalamus were measured by Western blot.The serum level of glucocorticoid was tested by GC ELISA Kit.RESULTS1 Aggressive behavior1.1 The amount of aggressive behaviors,total time of attack,amount of attack on vulnerable parts and amount of restrike after yield of PA were all higher than NA and Ctrl(P<0.01)after establishment of models.The amount of aggressive behaviors and total time of attack of NA showed higher than Ctrl(P<0.01).A decline of amount of aggressive behaviors and total time of attack were found in NA+ZL006,compared with NA+Saline(P<0.01)and latency of first attack of PA+ZL006 was shorter than PA+Saline(P<0.01).1.2 After multiple intervention,total time of attack,amount of attack on vulnerable parts were all decreased in the 8-OH-DPAT group in 1 and 2 weeks after intervention(P<0.05).The decline was only found in 1 week after intervention of 8-OH-DPAT+ZL006(P<0.05).There were no significant differences among 3 periods of ZL006 and Saline group(P>0.05).2 Western blot2.1 The expression of PSD-95.nNOS in PA were lower(P<0.01),whereas in NA were higher(P<0.01,P<0.05),compared with Ctrl in hippocampus.While in prefrontal cortex,the expression of nNOS and PSD-95 in NA were lower than Ctrl(P<0.01,P<0.05).The expression of GR in PA was higher than NA and Ctrl in both hippocampus and prefrontal cortex.The expression of PSD-95,nNOS in PA were both higher than Ctrl in hypothalamus(P<0.01).2.2 The expression of 5-HT1AR in prefrontal cortex and hippocampus were significantly higher in the 8-OH-DPAT and 8-OH-DPAT+ZL006 groups than the other 2 groups(P<0.05).The 8-OH-DPAT group had higher expression level of PSD-95 in the prefrontal cortex and hippocampus,but lower hippocampal expression of GR when compared with the other 3 groups(P<0.05).There were no significant differences in the 5-HT1AR and PSD-95 level in the hypothalamus among the 4 groups(P>0.05).3 ELISA3.1 After establishment of models,the concentration of glucocorticoid in serum in PA was significantly lower than Ctrl(P<0.01),while in NA showed higher than Ctrl(P<0.05).We just found that the concentration of glucocorticoid in serum in NA+ZL006 was significant lower than NA+Saline(P<0.01).3.2 The results of ELISA showed the serum glucocorticoid level was obviously increased in the 8-OH-DPAT group in 2 weeks after treatment(P<0.05),but no such increase was seen in the other 3 groups(P>0.05).Conclusions1.ZL006 can reduce aggressive behavior of normal aggression rats models,but no obvious effects on pathological aggressive behavior were found on same dosage of ZL006,probably due to different level of expression of GR in hippocampus and concentration of glucocorticoid in serum.2.PSD-95 signaling pathway takes part in and mediates the attenuation of pathological aggressive behaviors induced by 5-HT1A receptor agonist(8-OH-DPAT),which probably through its increasing effect on serum glucocorticoid.