The Schizophrenia Ketamine Rat Model Of Behavior And Neural Biological Mechanisms Preliminary Study And Antipsychotic Drugs On The Rat Model Of Social Interaction Impact

PARTⅠSubchronic application of ketamine-inducedchanges in rat behaviour and neurobiologyObjectives SD rats are repeated injection of NMDA receptorantagonist ketamine as pharmacological animal model of schizophrenia.Through testing the changes of behaviour and neurobiology in this model,the face validity and construction validity of the model are investigated.Methods Adult male Sprague-Dawley rats were randomlyassigned to normal control group, 5mg/kg/d(low dose) ketamine group,30mg/kg/d (subanesthetic dose) ketamine group and 60mg/kg/d(subanesthetic dose) ketamine group.Animals were injected withketamine i.p. daily for five consecutive days,animals were injected withsaline daily for ten consecutive days from the sixed day.The control groupwere injected saline for fifteen consecutive days. The rats were assessedby the Elevated Plus-Maze test, the Social Interaction test, the ForcedSwimming test , the Morris Water Maze test and the Attentional setshifting test.The release of the neurotransmitters(DA,Glu) and theirmetabolites(DOPAC,GABA) in homogenates obtained from themedialfrontal cortex, hippocampus was assessed by CoulArray, and tocalculate the utilization ratios.Parvalbumin and PTEN protein expressionwere assessed in the medial frontal cortex and hippocampus CA1. Datawas analyzed using ANOVA.Results In the Elevated Plus-Maze test, no differences wereobserved in the time spent in the close/open arms withins groups(P＞0.05) .In the Social interaction test, no differences were observed inthe activity and time spent in the social interaction (P＞0.05) .But thepercentage of non-aggressive behaviours of subanesthetic-dose ketamine groups(30mg/kg/d,60mg/kg/d) were significantly lower than normalcontrol group (P＜0.01).Compared with control group, subanesthetic-doseketamine groups were observed significant deviant in the immobility time(P＜0.01),escape latency(P＜0.01) and time spended in aimed-quadrant(P＜0.01) and the number of trails to reach the criterion of sixconsecutive in EDS(P＜0.01).In the subanesthetic-dose ketamine groups,the level of neurotransmitters(DA,DOPAC,GABA) in the medial frontalcortex and hippocampus CA1 were significantly lower than that of thecontrol (P＜0.01 or P＜0.05),but the level of Glu in these brain regionswere significantly higher than that of the control (P＜0.01 or P＜0.05). Thesubanesthetic-dose ketamine groups have exhibited a lower utilizationlever when compared with the saline control group (P＜0.01). There wassignificantly highed Parvalbumin immunoreactivity in thesubanesthetic-dose ketamine groups rats (P＜0.05) but not in the salinecontrol group, no differences were observed in PTEN immunoreactivitywithins groups (P＞0.05).Conclusions (1)The SD rat treated with subchronic andsubanaesthetic-dose ketamine can partly model the negative symptoms ofschizophrenia.(2)The SD rat treated with subchronic andsubanaesthetic-dose ketamine can partly model the cognitive imparimentof schizophrenia.(3)The SD rat treated with subchronic andsubanaesthetic-dose ketamine can partly model the neurobiologyimpariment of schizophrenia.(4)Ketamine SD rat model of schizophreniahas some face validity and construction validity. PARTⅡEffects of antipsychotic drugs to ketamine-inducedalterations to rat in social behaviourObjectives Previously, it was shown that subchronic application ofthe NMDA receptor antagonist ketamine induces schizophrenia-relatedalterations, e.g. decreased non-aggressive behaviour in the SocialInteraction test, which might be a useful animal model in the study ofnegative symptoms of this disease. In order to further evaluate thepredictive validity of this model, the anxioloytic diazepam, the classicneuroleptic haloperidol and the atypical neuroleptics clozapine andrisperidone were tested after acute and subchronic treatment.Methods Adult male Sprague-Dawley rats were randomlyassigned to normal control group. Animals were injected with ketamine30mg/kg i.p. daily for five consecutive days.From the sixed day ,animalswere injected with antipsychotics(haloperidol,clozapine,risperidone) anddiazepam daily for ten consecutive days.The control group were injectedwith saline in the same way.In two time points(the fifteenth day, thesixteenth day),the acute and subchronic effects of antipsychotics(haloperidol,clozapine,risperidone) and diazepam were tested in theSocial Interactin test.Results The experiments demonstrated that haloperidol did notnormalise the behavioural effects of ketamine (P＞0.05) . After acuteadministration, diazepam was ineffective in control animals (P＞0.05) butincreased non-aggressive behaviour in Ket-treated animals(P＜0.01).Similar effects were found in animals injected with eitherclozapine(P＜0.01) or risperidone(P＜0.01). Twenty-four hours after discontinuation of subchronic treatment with both substances, there wasan increase in the percentage of non-aggressive behaviour in the ketaminegroup(P＜0.01) and a decrease in the control animals(P＜0.01). Thisdecrease was explained in terms of withdrawal. Different effects in thecontrol groups and the Ket groups were found when the test wasperformed 1 h after subchronic clozapine or risperidone treatment(P＜0.01).Conclusions (1)The data suggest that atypical antipsychotic drugseffectively counteract Ket-induced alterations in social behaviour.(2)Anxiolytic drugs without antipsychotic efficacy may have false-positiveeffects in the test.(3) this model may have some predictive validity foridentifying anxiolytic effects of novel antipsychotic compounds.