Ketamine Induces Schizophrenia-like Behavior By Blocking Neurogenesis And Neuronal Injury In Adult Mice

Objective: As a non-competitive antagonist of N-methyl-D-aspartic acid(NMDA)receptor,ketamine is highly addictive.Long-term use of ketamine can lead to persistent separation,depression,delusional thinking,cognitive impairment of working memory and other symptoms similar to schizophrenia,and long-term ketamine abuse can lead to severe brain atrophy.At present,some studies have found that there are neurogenic abnormalities in the brain of patients with schizophrenia,and its effect on neurogenesis has been found in the study of antidepressant ketamine and neonatal anesthesia.In addition,some studies have shown that dopamine receptor 1(DRD1)can regulate the transformation of self-proliferation and differentiation of neural stem cells.Our published results show that long-term exposure to ketamine can cause changes in DRD1 in the hippocampus and prefrontal cortex of mice.We hypothesized that ketamine may cause neurogenic changes in mice through DRD1,resulting in behavioral changes similar to schizophrenia in mice.Therefore,we explored the changes of neurogenesis and apoptosis in the brain of mice treated with long-term ketamine,and the effect of DRD1 on this process.Methods: 1.Four groups of mouse models were established by using normal saline,ketamine,DRD1 agonist and DRD1 antagonist,and the behavioral changes of mice in each group were observed.2.Immunofluorescence test and Westernblot test were used to detect the changes of neurons,astrocytes and microglia in prefrontal cortex and hippocampus in different survival time after ketamine injection.3.Immunofluorescence test was used to detect the changes of neural stem cells and neural progenitor cells in four groups of mice.4.The effects of different concentrations of ketamine on neuronal injury and proliferation were analyzed by cell culture in vitro.Results: The results of animal behavior showed that ketamine could induce schizophrenia-like behavioral changes such as increased spontaneous activity,increased excitement,depression-like behavior and impaired spatial learning and memory in mice;DRD1 antagonist could partially reverse the behavioral changes induced by ketamine;DRD1 agonist had the same effect as ketamine in positive symptoms of schizophrenia.The results of immunofluorescence and Western Blot experiments showed that continuous injection of 100mg/kg ketamine for 7 days could reduce the number of newborn immature neurons and newborn neurons in the hippocampus,reduce the number of neural stem cells in the prefrontal cortex,increase the number and change the morphology of astrocytes in the prefrontal cortex,but the total number of microglia and neurons did not change significantly.However,there was no significant change in DRD1 agonist group and DRD1 antagonist group.The results of immunofluorescence experiment showed that high concentration of ketamine could increase the expression of γ-H2 AX protein in neurons,inhibit the proliferation of neurons and reduce the number of neurons.Conclusions: 1.Ketamine induces schizophrenia-like behavior in adult mice through DRD1.2.Ketamine inhibits neurogenesis in adult mice.3.Ketamine can activate astrocytes in prefrontal cortex.4.High concentration of ketamine induces injury and inhibited the proliferation of HT22 cells.