The Effects Of Quetiapine On Dysmyelination And Schizophrenia-like Behaviors In Rats Induced By PCP Injection

Objectives:This study was designed to explore whether the rats receiving phencyclidine(PCP, a kind of NMDA receptor antagonist) injections on postnatal days canexhibit schizophrenia-like behaviors and abnormalities of brain myelination whenthey are in puberty, so as to develop a new animal model which can be used tostudy the mechanisms related to the dysmyelination hypothesis of schizophrenia.At the same time, we also investigated the effects of quetiapine, an atypicalantipsychotic drug with protective effect against myelin impairments, on the PCPinduced schizophrenia-like behaviors and myelin abnormalities in the rats.Methods:In this study, all the experiments were performed in animals, and were divided into two parts. In the first part we proposed to observe the myelin changesand behavioral abnormalities in the rats receiving phencyclidine on postnatal days.In the second part we intended to find out if quetiapine can reverse thePCP-induced schizophrenia-like behaviors and myelin abnormalities.For the first part, the rats were randomly divided into two groups:(1) Salinegroup (Con group) in which the animals were injected subcutaneously in theirneck with saline once daily for14consecutive days (from PND2to PND15). Thedose of saline was1ml/kg.(2) PCP group in which the animals were injectedsubcutaneously in their neck with PCP once daily for14consecutive days (fromPND2to PND15). The concentration of PCP was1mg/ml and the dose of PCPwas10mg/kg.For the second part, the rats were randomly divided into four groups:(1)“Saline+Saline” group (Con group) in which the animals were injectedsubcutaneously with saline twice daily for14consecutive days (from PND2toPND15). The interval between2injection was30minutes. From PND16toPND20, the animals in this group was injected with saline once dailysubcutaneously. The dose of saline was1ml/kg.(2)“Saline+PCP” group (PCPgroup) in which the animals were injected subcutaneously with saline prior toPCP for14consecutive days (from PND2to PND15). The interval between salineinjection and PCP injection was30minutes. From PND16to PND20, the animalsin this group was injected with saline once daily subcutaneously. The dose ofsaline was1ml/kg. The concentration of PCP was1mg/ml and the dose of PCPwas10mg/kg.(3)“Quetiapine+Saline” group (QUE group) in which the animalswere injected subcutaneously with quetiapine prior to saline for14consecutivedays (from PND2to PND15). The interval between quetiapine injection andsaline injection was30minutes. From PND16to PND20, the animals in this group was injected with quetiapine once daily subcutaneously. The dose of salinewas1ml/kg. The concentration of quetiapine was1mg/ml and the dose ofquetiapine was10mg/kg.(4)“Quetiapine+PCP” group (QUE+PCP group) inwhich the animals were injected subcutaneously with quetiapine prior to PCP for14consecutive days (from PND2to PND15). The interval between quetiapineinjection and PCP injection was30minutes. From PND16to PND20, the animalsin this group was injected with quetiapine once daily subcutaneously. Theconcentration of quetiapine and PCP both were1mg/ml and the dose both were10mg/kg.Schizophrenia-like behaviors were measured by locomotion (for assessinglocomotion hyperactivity) and prepulse inhibition tests (for measuring the sensorygating function) in rats. In addition, Cerebral myelination and matureoligodendrocytes were evaluated by measuring the expressions of myelin basicprotein (MBP) and glutathione S-transferase (GST)-π, respectively.Ultra-structure of myelin was observed with transmission electronic microscope.Results:In the first part of the study, we found that PCP caused obvious myelindevelopmental defects on PND16, PND22and PND32, such as reduced numberof mature oligodendrocytes, reduced distribution of myelin and decreasedexpression of MBP. And we also found the ultra-structural pathological changesof white matter. Moreover, The schizophrenia-like behaviors were also found inPCP group on PND30and PND31. The detail of the results was written asfollows:1. We investigated the myelin changes in the rats on PND16. First, comparedwith Con group, the number of mature oligodendrocytes (GST-π positive cells) was reduced significantly in the PFC area of the rat brains in PCPgroup (P <0.05, t-test). Second, the sections from rat brains showed compactmyelin marked by anti-MBP antibody in the PFC area of Con group but notin PCP group, and the distribution range of myelin in PCP group wasdecreased. The optical density value showed that the myelin density in thePFC area of PCP group was significantly reduced compared with Con group(P <0.05, t-test). Finally, the MBP expression was significantly lower in thePFC area of PCP group compared with Con group (P <0.05, t-test).2. We investigated the myelin changes in the rats on PND22. The results showedthat the number of the GST-π positive cells, the myelin density and the MBPexpression were significantly decreased in PCP group compared with Congroup (P <0.05, t-test). But compared with the rat brains on PND16, themyelin was more compact in the rat brains on PND22both in Con group andPCP group. This indicated the myelin/oligodensrocytes developed quicklyduring the period.3. We investigated the myelin changes in the rats on PND32. In contrast to theresults on PND16and PND22, we found that only the MBP expression wasdecreased significantly in PCP group compared with Con group(P <0.05,t-test). The number of the GST-π positive cells and the myelin density wasnot significant different between Con group and PCP group (P>0.05). Andwe found focal lysis of myelin sheath lamellae with the formation ofconcentric lamellar bodies by electronic microscope.4. In order to evaluate the PCP-induced schizophrenia-like behaviors, thelocomotion and PPI tests were performed. Results showed that there wassignificant locomotion hyperactivity in PCP group (P <0.05, t-test). PCP administration also caused significant influence on PPI [F(1,34)=13.48, P=0.0008], and Post-hoc analysis showed the PPI was decreased at both PP8andPP16levels in PCP group compared with Con group (P <0.05).In the second part of the study, we found that quetiapine at the dose of10mg/kg couldn’t reverse the PCP-induced myelin defects and the PPIimpairments which is related to cognitive symptoms, but could alleviate thelocomotion hyperactivity which is related to positive symptoms. The detail ofthe results was written as follows:1. We investigated the myelin changes in the rats of4groups on PND16. One-wayANOVA analysis showed that the number of the GST-π positive cells[F(3,12)=5.493, P=0.0131], the myelin density [F(3,12)=30.93, P <0.0001]and the MBP expression [F(3,12)=37.77, P <0.0001] were significant differentamong4groups. Post-hoc analysis showed that PCP injection causedsignificant decrease of the number of the GST-π positive cells, the myelindensity and the MBP expression compared with Con group, but quetiapineadministration at the dose of10mg/kg couldn’t reverse these changes (P <0.05).2. We investigated the myelin changes in the rats of4groups on PND32. One-wayANOVA analysis showed that only the MBP expression were significantdifferent among4groups [F(3,12)=23.30, P <0.0001]. The number of theGST-π positive cells [F(3,12)=0.6297, P=0.6097] and the myelin density[F(3,12)=0.3711, P=0.7754] was not significant different among4groups.Post-hoc analysis showed that PCP injection caused significant decrease of theMBP expression compared with Con group, but quetiapine administration atthe dose of10mg/kg couldn’t reverse these changes (P <0.05). 3. The locomotion and PPI tests were performed in the rats of4groups on PND30and PND31. The results showed that the locomotion was significant differentamong4groups [F(3,34)=3.625, P=0.0226]. PCP and/or quetiapine injectioncaused significant influence on PPI [F(3,64)=8.235, P=0.0001]. Post-hocanalysis showed that PCP injection caused significant locomotion hyperactivityand PPI decrease compared with Con group. Quetiapine at the dose of10mg/kgcould alleviate PCP-induced locomotion hyperactivity, but couldn’t reverse thePPI impairment (P <0.05).Conclusions:The rats receiving PCP injections on postnatal days exhibitedschizophrenia-like behaviors and abnormalities of brain myelination when theywere in puberty, and the increase in PPI impairment was correlated to a decreasein MBP expression in the frontal cortex. This indicated dysmyelination mightplay important roles in the pathogenesis of schizophrenia, and this model mightbe used for the study about the dysmyelination hypothesis in schizophrenia.Meanwhile, quetiapine administration at the dose of10mg/kg couldn’t reverse thedysmyelination and PPI impairment induced by PCP injections, but couldalleviate PCP-induced locomotion hyperactivity.