Effects And Possible Mechanisms Of Agmatine In Depression And Post-traumatic Stress Disorder

ObjectiveDepression and post-traumatic stress disorder?PTSD?,two common affective disorders,characterized with high rates of morbidity,relapse,disability and lethality,as well as low rates of detection,treatment and cure,have brought heavy medical and health burdens to patients,families and society.Depression and PTSD show a high rate of comorbidity in clinic,suggesting that there may be common pathogenesis.Present clinical drugs against depression and PTSD mainly target the monoamine systems,with shortcomings such as slow effects,low efficacy and high adverse reactions,restricting the clinical treatment of depression and PTSD.The fundamental reason for the unsatisfactory treatment of these two disease is the ambiguous pathogenesis.Therefore,deeply studying on pathological mechanisms underlying depression and PTSD,discovering new neurotransmitter/neuromodulator systems and novel potential drug targets for the morbidity of depression and PTSD,will be of great scientific and potential application value to propose new strategies for the development of antidepressants and anti-PTSD drugs,as well as to improve the treatment of depression and PTSD.Depression and PTSD are two different diseases,but their pathogenesis has some similarities.As neuroplasticity disorders,upregulated glutamate neurotransmission and reduced hippocampal neuroplasticity may be common mechanisms underlying depression and PTSD,suggesting that the intervention of glutamate system function and neuroplasticity mayhave antidepressant and anti-PTSD effects simultaneously.Agmatine,an endogenous ligand of the imidazoline receptor,has been found as a possible novel neurotransmitter or neuromodulator with important physiological functions,and participates in pathological processes of various diseases including depression in recent years.Domestic and foreign laboratories,including our group,have shown that agmatine has antidepressant effects in various animal models of depression,and its antidepressant effect may be related to activation of the I₁imidazoline receptor?I₁R?and?₂ adrenergic receptor??₂AR?,but the precise receptor mechanism remained unclear.Downstream mechanisms may be related to modulating the glutamate system and neuroplasticity.Therefore,we speculated that agmatine may also have anti-PTSD effects other than its antidepressant effects.In sum,agmatine has antidepressant effects,while the mechanisms are not clear;there has not been report about anti-PTSD effects of agmatine.Based on the above issues,this study further validated and investigated the antidepressant and anti-PTSD effects of agmatine on a variety of animal models.In addition,the receptor mechanisms underlying agmatine's antidepressant and anti-PTSD effects were investigated using pharmacological antagonists.These research may provide experimental evidence for deeply understanding the pathological mechanisms of depression and PTSD,especially their similarities,and provide clues for exploring new ideas for prevention of depression and PTSD and developing ideal therapeutic drugs.Methods1 Using tail suspension test?TST?and forced swimming test?FST?,two acute depression models,and pharmacological antagonists to study receptor mechanisms underlying agmatine's antidepressant effects.2 Using learned helplessness?LH?test,a sub-acute depression model,and pharmacological antagonists to study the antidepressant effects of agmatine and its receptor mechanisms.3 Using time-dependent sensitization?TDS?model in rat and the inescapable electric foot-shock model in mice to study the anti-PTSD effect of agmatine.4 Using TDS model in rats and pharmacological antagonists to study the receptor mechanisms of agmatine against PTSD.Results1 Receptor mechanisms underlying agmatine's antidepressant effects in acute depression models:in TST and FST,acute administration of agmatine?20 and 40mg/kg,p.o.?significantly shortened the immobility time?P<0.05,n=9?.Concurrent administrationofefaroxan?1mg/kg,i.p.?completelyabolishedthe antidepressant-like effects of agmatine?40 mg/kg,p.o.??P<0.01,n=9-10?,whereas yohimbine?5 mg/kg,i.p.?failed to exert similar effects?P>0.05,n=9-10?,suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by I₁R but not?₂AR.2 Antidepressant effects of agmatine and its receptor mechanisms in sub-acute depression models:in LH test,repeated administration of agmatine?20 mg/kg,p.o.,q.d.?for 5 days significantly decreased the escape latency and the number of escape failure?P<0.05,n=7-11?,and these effects were respectively abolished by concurrent administration of efaroxan?0.5 mg/kg,i.p.,q.d.??P<0.01,n=8?and yohimbine?3 mg/kg,i.p.,q.d.??P<0.05,n=7-8?for 5 days,suggesting that the antidepressant-like actions of agmatine in LH test was achieved through activation of both I₁R and?₂AR.3 Anti-PTSD effects of agmatine:in the rat TDS model,repeated administration of agmatine alone?5-20 mg/kg,p.o.,q.d.?had no significant effects on the number of crossings and rearings in the open field test?P>0.05,n=12-13?,suggesting that agmatine did not affect the spontaneous activities of the experimental rats within this dose range;repeated administration of agmatine?20 mg/kg,p.o.,q.d.?significantly shortened the freezing time in contextual fear test?P<0.05,n=12-13?,increased the percentage of duration in open-arm in the elevated plus maze experiment?P<0.01,n=8-12?.Repeated administration of agmatine?5-40 mg/kg,p.o.,b.i.d.?had no significant effects on the number of crossings and rearings in the open field test?P>0.05,n=7-10?;repeated administration agmatine?5,40 mg/kg,p.o.,b.i.d.?significantly shortened freezing time in contextual fear test?P<0.01 and P<0.001,n=7-10?;agmatine?5,10 and 40 mg/kg,p.o.,b.i.d.?significantly increased the percentage of duration in open-arm in the elevated plus maze experiment?P<0.05,n=5-8?.The above results suggested that in the rat TDS model,agmatine played a role in reducing the formation of PTSD,manifesting as reducing fear and anxiety-like behavior.In the inescapable electric foot-shock model in mice,repeated administration of agmatine?10-40 mg/kg,p.o.,q.d.?had no significant effects on the number of crossings and rearings in the open field test?P>0.05,n=9-11?;on the15th day of the experiment,agmatine?10,20 mg/kg,p.o.,q.d.?significantly shortened the contextual freezing time?P<0.05,n=9-11?;agmatine?10 mg/kg,p.o.,q.d.?significantly increased percentage of duration in open-arm in the elevated plus maze experiment?P<0.05,n=7-9?.These results suggested that in the inescapable electric foot-shock model in mice,agmatine played a role in reducing PTSD formation,manifested as reducing situational fear and anxiety-like behavior.4 Receptor mechanisms underlying agmatine's anti-PTSD effects:in the rat TDS model,repeated administration of agmatine?20 mg/kg,p.o.,q.d.?,efaroxan?0.5mg/kg,p.o.,i.p.?and yohimbine?2 mg/kg,p.o.,i.p.?had no significant effects on the number of crossings and rearings in the open field test?P>0.05,n=7-10?,suggesting that agmatine,efaroxan and yohimbine didn't affect the spontaneous activities of the experimental rats within this dose range;agmatine?20 mg/kg,p.o.,q.d.?significantly shortened freezing time in contextual fear test?P<0.001,n=7-10?,and these effects were respectively abolished by concurrent administration of efaroxan?0.5 mg/kg,i.p.,q.d.?and yohimbine?2 mg/kg,i.p.,q.d.?;agmatine?20mg/kg,p.o.,q.d.?significantly increased the percentage of duration in open-arm in the elevated plus maze experiment?P<0.01,n=7-10?,and these effects were abolished by concurrent administration of yohimbine?2 mg/kg,i.p.,q.d.??P<0.05,n=9-10?;efaroxan?0.5 mg/kg,i.p.,q.d.?significantly increased the percentage of duration in open-arm in the elevated plus maze experiment?P<0.01,n=7-10?;concurrent administration of efaroxan?0.5 mg/kg,i.p.,q.d.?had no significant effects on agmatine in open-arm in the elevated plus maze experiment?P>0.05,n=7-10?.These results suggested that the anti-PTSD effects of agmatine was achieved through activation of both I₁R and?₂AR.Conclusions1 Agmatine had an antidepressant effect.Its receptor mechanisms in acute and sub-acute depression models were not exactly same.In the acute model,it was mainly mediated by activating I₁R;but in the sub-acute models,it was related with activation of both I₁R and?₂AR.2 The anti-PTSD effects of agmatine were reported for the first time in the rat TDS model and the mice inescapable electric foot-shock model.The receptor mechanisms were partially mediated by I₁R and?₂AR.In summary,this study found that agmatine,I₁R and?₂AR participated in the pathological processes of depression and PTSD,further suggesting that there may be a common pathological mechanism between depression and PTSD,and providing some clues for understanding the core mechanisms of these two diseases and exploring new treatment strategies.