Antipsychotic Pharmacodynamics Study Of Compound TPN8

ObjectivesSchizophrenia is a chronic common mental disorder which several neuro-transmitters participates.In this thesis,we established different animal models ofpositive,negative and cognitive symptoms of schizophrenia induced by phencyc-lidine treatment,a NMDA receptor antagonist.In addition,evaluated a new comp-ound TPN8on these models and made a compare with antischizophrenic drugssuch as ziprasidone(Zip) and stepholidine(Spd),aripiprazole(Ari),lurasidone(L-UR).The model of positive symptom investigated the locomotive activity(LM-A),model of negative symptom adopted the social interaction(SI) test and usedthe novel object recognition(NOR) test as cognitive model.MethodsLocomotive activity(LMA) test:male ICR mice were divided into control group and PCP groups (7mg/kgand10mg/kg、15mg/kg、20mg/kg) and treated by intraperitoneal injection withsaline or PCP,respectively and dose.ICR mice120min activities in the innerchamber,was measured as the total distances (cm).Results indicated that acute7mg/kg PCP treated mice appeared more hyperlocomotive significantly (P<0.05).Antipsychotic drug ziprasidone3mg/kg could approximatively restoredthemice activities to be normal PCP(P<0.05), while10mg/kg dose significantlyinhibited mice spontaneous activity (P<0.01).The novel object recognition (NOR) test:76pairs normal male ICR mice faced8objects with different shapes、colors,but similar in size in a open field test chamber for5min to explore thefamiliar and novel objects in preliminary screening and validation test.Weestablished the NOR model by repeat treated10mg/kg PCP for10days (s.c.,qd),then with7days wash-out period.The exploration time(s) to the objectsin training and testing period was noted to calculate Discrimination Index (DI)and Preference Index (PI).The results suggested that normal ICR mice exploredthe novel object significant more than the familiar one through the initialscreening study (P<0.001).With10mg/kg PCP chronic treatment in novel objectrecognition experiments there is no significant difference in the explore time totwo identical objects of model group and saline control group in the trainingperiod.However,the different was significantly between the familiar and novelobjects in exploring period(P<0.001) in saline group,the PCP model group thanthe saline control group identification capability decreased and discriminationindex(DI)and Preference Index (PI) wre a significant differences (P<0.01).The social interaction(SI) test:By Wistar rats injected intraperitoneally once a day for14consecutive dayswith PCP10mg/kg and wash-out period for seven days.The day before the testmaleWistar rats placed in the test case for30min to familiar the environmemt.Inthe test day,a pair of not familiar rats were placed in the same test case tomeasured the social activities positive time(s) for10min.Results indicated thesocial activities with positive social time(s) of model group significantly redu-ced(P<0.01).thus PCP model rats produce social interaction withdrawal in thenegative symptoms of schizophrenia.Finally,to the acute or chronic animal models,with a single dose of20or10mg/kg compound TPN8respectively measured the total distance(cm) of eachtime period in120min,the difference between the Preference Index (PI)of thecognitive model and positive social time(s) in10min in social interaction exp-eriment,compared with ziprasidone,stepholidine,aripiprazole and lurasidone res-pectively.ResultsResults indicated that20mg/kg TPN8and100mg/kg the stepholidine cansignificantly reduce the total distance of the hyperactivity PCP model groupinduced,the mice’s ability to identify new objects with1mg/kg of aripiprazole nodifference but increased significantly explore time and preference index PI(P<0.05) to new objects of test phase in the NOR test,further social interactionexperimental discovered TPN820mg/kg increase rat’positive social time. ConclusionsThe above results suggested that the compound TPN8was effective intreating positive and negative symptoms and cognitive deficit of schizophren-ia,and could be a potential candidates for schizophrenia.