The Effect Of MK-801on Schizophrenia Cognitive Deficit Model Rats And Therapeutic Mechanism Of Atypical Antipsychotics

Part â… MK-801induces the alterations of hippocampal synapse in adolescent ratsBackground:Cognitive deficits are the core symptoms of schizophrenia. Spine deficits have been found in hippocampus of schizophrenia patients, and were associated with cognitive impairments. NMDARs had been known to play a critical role in synaptic pruning and stabilization during adolescence.Objective:To explore if the blockade of NMDA receptors during adolescence might lead to decay of the synapses in hippocampus and result in cognitive deficits involved in schizophrenia.Method:In the present study, male adolescent rats were exposed to dizocilpine (MK-801)(0.2mg/kg i.p qd) or0.9%saline for14days. Then spatial memory, morphological changes and biomarker protein (SYP and PSD-95) levels in synapses of hippocampal neurons and RhoA, Rac1, Cdc42mRNA levels in hippocampus were measured.Result:As a result, MK-801impaired spatial memory in the adolescent rats and reduced the spine head diameter and the protein levels of SYP and PSD-95in the hippocampal synapses. MK-801also reduced the expression levels of Rac1and Cdc42mRNA and upregulated RhoA mRNA level in hippocampus.Conclusion:The results of this research supports that blockade of NMDA receptors during adolescence might lead to decay of the synapses in hippocampus and result in cognitive deficits involved in schizophrenia. Furthermore, the results of this research imply that the decay of the synapses in hippocampal neurons might due to the reduction of the expression of RhoA, Racl and Cdc42mRNA induced by subchronic MK-801administration during adolescence. Part â…¡Effect of olanzapine, risperidone and quetiapine on MK-801-induced disruptions in cognition and hippocampal parvalbumin interneurons in ratBackground:Cognitive deficits are the core symptoms of schizophrenia, which can be attenuated by atypical APDs. However, the mechanism underlying the therapeutical effect of atypical APDs is not known. PV interneurons is known to be critical for cognitive deficits in schizophrenia. Subchronic administration of MK-801to adolescent rats induces enduring schizophrenia-like cognitive deficits and pathophysiological changes that resemble some features of schizophrenia, such as decreased PV interneurons.Object:The present study was aimed to determine if olanzapine, risperidone or quetiapine can block the effects of MK-801on cognitive function and parvalbumin interneurons in the hippocampus.Method:40male SD rats were randomly assigned into five group (n=8):Control group, MK-801group and three drug-treated group Olanzapine, Risperidon and Qutiapine group. Rats in control group were exposed to or saline for14days. Other rats were all exposed to MK-801(0.2mg/kg i.p qd) for14days. Then the rats in the control and MK-801group received ddH2O for10days by g.i. qd (1ml/Kg); the rats in the three drug-treated groups respectively received Olanzapine (2.5mg/kg), Risperidone (1mg/kg) or Quetiapine (25mg/kg) for10days by g.i. qd. Morris water maze test and immunohistochemistry were applied to assess spatial memory and hippocampal PV interneurons density.Result:In the present study, MK-801impaired spatial memory and reduced the number of hippocampal PV interneurons in the rats. Risperidone and quetiapine could reverse these changes.Conclusion:These results show the protective effect of risperidon and quetiapine in decreasing PV interneurons induced by MK-801, and this effect might partly explain the effect of these atypical antipsychotics in cognitive deficits in schizophrenia. Part â…¢Quetiapine reverses cognitive impairments induced by MK-801through activating5-HT1a presynaptic receptorBackground:In clinic, atypical APDs are commonly used for the treatment of cognitive deficits. Reduction of5-HTla receptors in brain was found in some post-mortem studies on schizophrenia. These findings suggested that5-HT1a receptor was involved into the neuropathology of schizophrenia. PKA in hippocampus is closely related with cognitive function, and is a key factor of cAMP-PKA signal pathway, which is regulated by5-HTla receptor. PKA activiey in hippocampus is upregulated when5-HTla presynaptic receptor is activated, while it is downregulated when5-HT1a postsynaptic receptor is activated. Quetiapine is a5-HTla receptor partial agonist, and shows an outstanding effect on cognitive deficits in schizophrenia.Object:The present study was aimed to determine if quetiapine attenuate cognitive deficits in schizophrenia through activating5-HTla receptors. Thus PKA activity in hippocampus was measured in this research to explore the mechanism underlying the therapeutical effect of quetiapine.Method:50male SD rats were randomly assigned into five groups (n=10):control group, MK-801group, qutiapine group, tandospirone group and WAY100635group. Rats in control group were exposed to saline (1ml/kg i.p qd) for14days. Other rats were all exposed to MK-801(0.2mg/kg i.p qd) for14days. In the next10days, the rats in the control and MK-801group received ddH2O(1ml/kg i.g qd); the rats in the rest groups respectively received Quetiapine (25mg/kg i.g qd), Quetiapine (25mg/kg i.g qd)+Tandospirone (0.6mg/kg i.g qd) or Quetiapine (25mg/kg i.g qd)+WAY100635(0.1mg/kg i.g qd). Morris water maze test and PepTag PKA kit were applied to assess spatial memory and PKA activity in hippocampus.Results:In the present study, cognitive function of the rats in quetiapine group and tandospirone group was significantly higher than that of the rats in MK-801group. Cognitive function of the rats in WAY100635group was significantly lower than those of the rats in quetiapine group. However, tandospirone group was similar with quetiapine group on cognitive function. The analysis results on PKA activities in hippocampus indicated that quetiapine group and tandospirone group were significantly higher than control group and MK-801group. Compared with quetiapine group, PKA activity of tandospirone group was significantly higher and PKA activity of WAY100635group was significantly lower.Conclusion:Upregulation of PKA activity in hippocampus by activating5-HT1a presynaptic receptor plays a key role in the reverse effect of quetiapine on cognitive impairments induced by MK-801. These results provide a new idea for the treatment of cognitive deficits in schizophrenia.