Antidepressant Effect Of Phencyclonyl Hydrochloride And Its Mechanism

Depression is a high-prevalence psycho-affective disorder while the pathogenesis of depression is still not clear,and the development of more new therapatic drugs is urgently.The neural plasticity hypothesis of depression states that the changes in glutamate synapses and dendritic spines in multiple brain regions of the neural circuit caused by chronic stress,is the critical reason leading to neural circuit dysfunction and depression-like symptoms.The density of dendritic spines in hippocampus,prefrontal cortex,amygdala and nucleus accumbens are all changed significantly in stress-induced rat model of depression,suggesting that neural plasticity of these brain regions are all related to stressinduced depression.Some structural plasticity related protein,such as Kalinin-7,a guanylate exchange factor,has been found playing a critical role in the morphological changes of dendritic spines under stress.At the same time,morphological changes in structural plasticity accompanied by some functional changes in synaptic transmission.Changes in the glutamate system,including glutamate levels and their receptors in the hippocampus and PFC have been focused.Many researches indicated that excessive release of glutamate and over-activation of NMDA receptors play critival rols in the development of stress induced depression.In addition,downregulation of AMPA receptors and mTOR signaling pathways are also involved.All these structural and functional plasticity-related proteins are potential targets for new antidepressants.At present,the commonly used antidepressants are 5-HT reuptake inhibitors(SSRIs)It usually takes at lease 2 to 4 weeks before the benefit can be felt.While some new rapid antidepressant,such as ketamine has a hallucinogenic effect with its advantage of rapid onset.Therefore,it is urgent to find new antidepressants with faster onset,longer effect and few side effects.Phencynonate Hydrochloride is a new drug developed by the Institute of Toxicology and Medicine of the Academy of Military Medical Sciences,which can go through the blood-brain barrier.Cell experiments confirmed that it can protect cells from NMDA toxicity with limited inhibitory effect on central neural system and PC 12 cells,and few side effects.It is currently solded as a motion sickness drug,and its efficacy against epilepsy and Parkinson's disease has also been reported.Our previous studies have shown that it can alleviate depression-like behavior in rats,but the neurobiological mechanism related to its antidepressant effect is unknown.OBJECTIVE:The aims of this study is(1)to cofirm the antidepressive effects of PCH on rat model of stress-induced depression,(2)to investigate the effect of PCH on structrual plasticity in stress-sensitive brain regions;dendritic spine density in stress-sensitive brain regions such as hippocampus,medial prefrontal cortex,amygdala and nucleus accumbens of rats,and also the expression of Kalinin7;(3)to investigate the effect of PCH on the glutamate system in hippocampus;and(4)to confirm the antidepressive effect of PCH on NMDA-induced depression-like behaviors.Finally,we'd like(5)to illustrate the mechanism of PCH on depressionlike behaviors induced by stress.METHODS:We used CUMS to establish rat model of depression,and treated them with continuous administration of PCH(i.p.)for 2 days after CUMS.Behavioral tests were conducted after the treatment of PCH or saline.Golgistaining was used to detect the changes in dendritic spine density of neurons in four brain regions(mPFC,Hip,NAc and Amy).Expression of Kalinin-7 was also detected by western blot.The expression changes of NR1 and NR2B in PFC and hippocampal were further detected,and the changes of Glutamate level in hippocampus was measured by HPLC.Brain microinjection technology was used to deliver NMDA,a NMDA receptor agonist into CA1 of rat hippocampus,in order to establish a NMDA over-activated model of depression.We pretreated the rats with PCH(i.p.)before microinjection of NMDA to block the effect of excessive activation of NMDA.To assess the antidepressive effect of PCH,a series of behavioral tests were conducted(open field test,tail suspension test,the Noveltysuppressed feeding test and the Sucrose preference test)RESULTS:1.The rats in the CUMS group showed depression-like behaviors.PCH treatment can alleviat the depression-like behavior in rats.It increases the sucrose preference rate,and decreased the immobility time in tail suspension test.2.Compared with the control group,the density of dendritic spines in the medial prefrontal cortex and hippocampus decreased in the CUMS group.At the same time,the expression of Kalinin-7 in the mPFC and hippocampus were significantly decreased in the CUMS group than in the control group,either.PCH reversed the effects of CUMS on both spine density and kalirin-7.The density of dendritic spines in NAc and amygdala increased in CUMS group compared with the control,while the kalirin-7 decreased.PCH treatment decreased the spine density in NAc and amygdale,and elevated the kairin-7 level.3.The expressions of NR1 and NR2B subunits in hippocampus of CUMS group were significantly higher than those in control group.PCH treatment reversed the expressions of NR1 and NR2B in hippocampus.While the glutamate levels in the hippocampus show no defference among groups.The expression of NR2B subunits in the medial prefrontal cortex of the CUMS group was also significantly higher than that of the control,but there was no change of NR1 expression.4.After the microinjection of NMDA receptor agonists into the hippocampus,compared with the control group,the number of rearing decreased significantly,the immobility time of tail suspension test significantly prolonged,the latency to feed of Novelty-suppressed feeding test significantly prolonged,and some of the significantly depressed behaviors.Pretreatment with 8 mg/kg PCH before microinjection of NMDA receptor agonist into rat hippocampal CA1,can significantly prevent the number of rearing caused by direct microinjection of NMDA,significantly reduce the time of tail suspension,and novelty.Inhibition of behaviors such as significantly prolonged incubation period has a good antidepressant effect.CONCLUSION:Phencynonate Hydrochloride has antidepressive effect on both CUMS depression model and NMDA depression model.PCH can regulate dendritic spine densities and Kalinin-7 expressions in hippocampus and medial prefrontal cortex caused by CUMS.At the same time,the antidepressaiv effect of PCH may be mainly achieved by regulating the expression of NMDA receptors in the hippocampus and exerting as an inhibitor of NMDA receptor.