Advances in research on animal models of schizophrenia established by MK-801
Schizophrenia is a severe mental illness common in psychiatry. It has a high disability rate and is one of the most serious mental disorders. Its lifetime prevalence accounts for about 1% of the entire population. The cause has not yet been elucidated. Most current studies suggest that schizophrenia is the result of brain damage caused by biological, psychological, and social environments and their interactions. Advancing the understanding of the etiology and biological mechanisms of schizophrenia, exploring the mechanism of action of antipsychotic drugs, and identifying and evaluating new treatments are inseparable from the establishment of animal models of schizophrenia. Because schizophrenia has a unique human nature, animal models cannot simulate the mental and psychological factors of patients with schizophrenia, and the development of a perfect animal model poses a daunting challenge. Therefore, this article will review the research progress in this area.
1 The status of animal model establishment
Animal models of schizophrenia can be roughly divided into three categories: pharmacologically induced animal models, developmental animal models, and transgenic animal models according to their different induction strategies [Cil. Pharmacologically induced animal models use drugs to induce schizophrenia-like symptoms. The dopamine hypothesis is the earliest hypothesis of schizophrenia, which states that the symptoms of schizophrenia are due to excess dopamine in the brain. The abnormal behavior of animals induced by mentally stimulating drugs such as amphetamine is representative of this model. Since the hypothesis that dopamine transmitter dysregulation cannot fully explain the pathogenesis of schizophrenia, the glutamate dysregulation hypothesis has attracted widespread attention in recent years. Studies have shown that injections of NMDA receptor antagonists into humans can cause behavioral symptoms similar to schizophrenia, including hallucinations, delusions, and bizarre behavior. Similarly, injecting such drugs into rodents can also result in behavioral changes similar to psychosis, such as sensorimotor gating disorders, extreme activity, social withdrawal, and learning and memory dysfunction. It is reported that these behavioral abnormalities can be restored to normal by injecting some antipsychotic drugs in the clinic. Therefore, it has become a powerful tool for elucidating the pathogenesis of schizophrenia and testing the effectiveness of new antipsychotic drugs. It is also the most commonly used model establishment method in domestic and foreign research. Its representative drugs are ketamine, PCP and MIA. -801. Among them, MIA-801 can simultaneously simulate the yin and positive symptoms of schizophrenia, so it has been widely used in model establishment research in recent years, and this article will introduce it in detail. In addition, studies have found that angiotensin is involved in the pathogenesis of schizophrenia and is involved in the mechanism of action of antipsychotics. This model is currently immature and rarely used in research.
The neurodevelopmental model is achieved by brain damage to newborn animals (especially the development of hippocampus), fetal viral infection, or normal development of animal neurons. Animals develop some behavioral and neurological disorders of schizophrenia in adulthood. Biological characteristics, which are consistent with neurodevelopmental hypotheses of schizophrenia: prenatal, perinatal, and postnatal adverse events may affect brain development to some extent, as the brain matures in twenty to thirty years Symptoms appear afterwards. This type of model can be used to screen new drugs.
It has been confirmed that schizophrenia is a highly hereditary disease, resulting in a transgenic animal model. The use of transgenic technology can selectively or comprehensively inhibit schizophrenia-related neurotransmitters and establish models to conduct related research. This model is under study and will lay the groundwork for possible gene therapy in the future.
2 MIA-801 administration method, selected dose and animal species
The existing research on the choice of experimental animals is not uniform. Domestic studies have used a single dose of high-dose (>0. Smg/kg) Sprague}awley rats in perinatal or adulthood [[A] or low dose (5. 5mg / kg) repeated administration of C9, io7 To establish the model, there are also choices for single or multiple doses of different strains of mice [D'Ichuan to conduct related research. SD rats or Wistar rats are often used in foreign studies. Some authors choose to establish models in adulthood and conduct related research, or choose to administer them shortly after birth (3-7 days), and some studies choose high doses (0. 5-1 mg/kg) single or single-dose, or low dose (0. OS0.40 mg/kg) for 2 weeks or longer. There are also some studies to establish models with mice. It is also divided into single and repeated administration. At present, there is no unified standard for animal species, dose and time of administration, so the conclusions of the study are different, and this aspect remains to be clarified.
Social behavior evaluation model
Pre-pulse suppression (PPI) sensory motion gating is an important area of ​​information processing, including proper filtering of incoming sensory information and blocking attention to outstanding stimuli by blocking irrelevant or unimportant information. Pre-pulse suppression of auditory startle reflexes is a measure of the operability of sensory motion gating. It refers to a reflex reaction caused by a sudden, intense external sensory stimulus that can be observed and measured in humans or rodents. Prepulse inhibition phenomena include the suppression of auto-shock reflex induced by fuzzy pre-stimulus. It means that when a pre-pulse that does not cause startle jump occurs 30/50 ms before a pulse that can cause startle, regardless of whether they belong to the same sensory form, the intensity of the startle reflection is reduced. A decrease in prepulse inhibition indicates that sensorimotor gating is impaired, which is particularly pronounced in patients with active psychotic symptoms. Studies have found that the use of antipsychotic drugs can normalize these defects, and the role of atypical antipsychotics is more pronounced.
So far, animals have been treated with MIA-801 shortly after birth, and there has been controversy over the long-term effects of PPI. Earlier studies indicated that a single injection of MIA-801 on day 3 postnatally in rats had no effect on basal prepulse inhibition. However, for older rats, the effect circle of the prepulse intensity can be reduced. Neonatal rats treated with MIA-801 without pre-pulse inhibition were also reported in Coleman Jr LG et al. Consistent with this, Harris L et al. Czal also did not find any change in prepulse inhibition in adult male rats after dosing on day 7 after birth. Interestingly, however, in the same study, adult female rats were treated with MIA-801 but had prepulse-inhibited lesions. Zhao YY et al. also found similar findings in the 2013 report. In contrast, in another study, female rats were injected with MIA-801 0. 25 mg / kg twice daily at 5 and 14 days after birth, and no prepulse inhibition was observed at 2 to 9 weeks of age}}} . It is therefore difficult to determine whether gender has a decisive influence on the experiment. A small number of studies have reported positive findings. Uehara T et al. were treated with MIA-801 7 to 10 days after birth, and the dose- and age-dependent effects of prepulse inhibition were found. LiM et al. studied the duration of PPI injury after NMDA receptor antagonist administration in rats for six consecutive days, a constant dose of a group, and a group of patients who were administered in a gradual increasing manner. The study found that both modes of administration can be used. Causes a stable and persistent damage to the PPI, but the latter approach works better.
Considering the problem of making reliable pre-pulse suppression changes, the latest study combines the newly-born animal MIA-801 treatment and isolated feeding to simulate the double-click hypothesis of schizophrenia. Three pre-pulse inhibition tests found that only MIA-801 treatment in neonatal rats did not produce any prepulse inhibition defects, whereas only isolated feeding produced only minor and inconsistent prepulse inhibition defects. However, the combination of the two models caused a dramatic change in prepulse inhibition, consistent with the results of the three tests, so it seems that the combination of the two methods has a more reliable prepulse inhibition change.
In recent years, many scholars have done research on the mechanism of MIA-801 causing sensory gating disorders. Bxaszczyk JW et al. believe that after treatment with different doses of MIA-801, the degree of PPI in the auditory startle reflex of mice can be used to explain the mechanism of glutamate in the shock-reflex. A recent study by Valsamis B further supports the view that over-activation of functional glutamate in the central forehead is the primary mechanism for systemic injection of MIA-801-induced sensory gating disorders. Julia Zangrand et al. pointed out that the expression of PPI in rodents is mediated by glutamate in the inferior colliculus. FijaxK et al [X330 found that 5-HT receptors are also involved in some of the mechanisms by which antipsychotics improve PPI.
3.2 Spontaneous activity MIA-801 deals with spontaneous activities with the most extensive characteristics of long-term behavioral changes induced by neonatal rats. Increased activity in schizophrenia is thought to be associated with positive symptoms and may represent an increase in the activity of the dopamine system at the midbrain margin. Most studies have shown that MIA-801 can cause an increase in rat self-release. Park SJ et al found that after acute administration of MIA-801 in mice, there may be an increase in self-release.
Similar findings were found in the study of Wilt rats by Missault S et al. Our team found that after MIA-801 was administered at 0.3 mg/kg, the spontaneous activity of the rats was lower than that of the control group, suggesting that the effect of MIA-801 on spontaneous activity may be related to the dose. Xiu Y et al found that after chronic treatment with MIA-801, the mice showed an increase in self-issue in the open field experiment, a decrease in the exploration behavior of the new environment in the well plate experiment, and an increase in anxiety in the elevated maze test. Latysheva NV et al found that rats had a decrease in spontaneous activity during the treatment phase (23 h after injection), but this change was not significant at 6 days or at 4 months after treatment, so it was concluded that the post-treatment effect could not persist for a long time. Spontaneous movements were also found in mice that did not sustain long-term changes, although their tactile behavior increased. In the gender study, Guo et al. [09] found that female rats showed an increase in self-issuance after administration, but only female subjects were used in the study and it was not possible to draw conclusions about another gender.
Schiffelholz T et al [Cool injected 0.25 mg/kg MIA-801 on day 6 of the 21st day after birth in rats, and in adulthood ((60 d) rats showed low spontaneous activity, while on day 30, activity increased. It is postulated that the high activity of juveniles may indicate abnormalities before the onset, such as impulsivity, whereas the decrease in adulthood activity may reflect mental retardation, indicating the state after the onset of the disease. Using the same treatment, Baier PC et al reported A very similar finding, MIA-801 treatment of rat spontaneous activity, by measuring the distance of action and suspension time in the elevated plus maze, was found to be significantly reduced on days 60 and 90 after birth. The spontaneous activity measured in the wilderness and elevated cross maze may vary greatly depending on the design connotation and the purpose of the device. Therefore, the results may not accurately reflect the spontaneous activity observed in the standard device (activity room or wilderness), most likely Mixed with anxiety index of mice. Low spontaneous activity of MIA-801 rats may reflect higher anxiety levels and increased immobility
3. 3 cognitive functions
3.3.1 New Object Recognition The new object recognition test routine is used to assess the re-recognition of rodents. Based on relatively familiar things, animals are more likely to explore the inherent tendencies of strange things. That is to say, animals spend more time researching new things than things they have seen before. Many studies have found that acute administration of MIA-801 can cause new object recognition disorders in animals, and antipsychotic drugs can improve this injury. After Park SJ et al. acutely administered adult mice with 0.2 mg/kg of MIA-801, mice exhibited new object recognition disorders in the test, and this disorder was significantly improved by acute injection of clozapine. The long-term effects of animals after administration of MIA-801 early in life seem to be less certain. When MIA-801 was administered at 0.1 mg/kg 7 to 10 days after birth, Caal such as Stefani MR did not find any damage in the recognition of new objects during the adult test. Similarly, whether using high-dose MK-801 or prolonging the injection time by 4 times, Baier PC et al [Ca i7 did not find any impairment of memory in the presence of any stage of life in mice. LimAL et al [29] did not find any new object recognition defects caused by MIA-801 in the evaluation of adult rats.
Despite the lack of research, the findings available so far have shown that the use of MIA-801-induced NMDA receptor antagonism in the early stages of life, after the acquisition and retention phase is 1.5 h, 2 h or Sh, there is no long-term recognition of new things. The negative impact on prisoners, however, the results outside the interval are still uncertain.
3.3.2 Spatial memory Spatial memory is the most influential in cognitive studies of rats treated with MIA-801 in early life. The water maze paradigm routine was used for rat/mouse spatial memory studies. In general, this test involves placing the animal in a circular pool of opaque water and then allowing it to find and climb a hidden platform through the help of clues outside the maze to get rid of the troubles that have been in the water. Through repeated tests, spatial learning promotes a reduction in escape latency. Even if the platform is removed from the pool, the maintenance of spatial memory can also encourage animals to have longer recreation time in the platform area. Early life MIA-801 treatment resulted in a decrease in water maze performance mainly after maturity. McLamb RL et al. did not find any change in water maze behavior in immature female rats, while Su YA et al found that female rats had slight functional impairment. Our team found that the 6-day-old pups were injected intraperitoneally with 0.3 mg/kg of MIA-801 twice a day for 2 weeks, and 1 week after the end of the drug, the mice were tested for water maze. In 801 groups, the learning ability was reduced, the learning speed was slowed down, and the long-term memory was also damaged, but still had the ability to learn. Li Jitao et al found that intraperitoneal injection of small doses of MIA-801 disrupted the reference memory, spatial working memory and inverse learning of rats, suggesting that they can mimic cognitive deficits in patients with schizophrenia in multiple cognitive dimensions. After Wang Yingli and other continuous injections of MIA-801, rats showed abnormal behaviors similar to human schizophrenia and learning and memory dysfunction, but the impairment of learning and memory was not irreversible. Therefore, the correlation between the two needs to be further studied. Domestic and foreign research news reports that rats treated with MIA-801, while causing acute psychotic attacks, also caused severe damage to synaptic plasticity, accompanied by permanent damage caused by spatial memory. Su YA and other research found that
Rats treated with MIA-801 in early life had moderate working memory impairment during puberty, whereas this injury was abnormally significant in adulthood. However, spontaneous movement and PPI were not damaged during these two stages. Studies in mice have also reported significant spatial working memory deficits. Although spatial memory is not significantly different during the learning phase, significant defects occur when the platform is transferred to another quadrant of the maze. Similarly, defects in ray maze learning are also observed in rats in a dose-dependent manner. Compared with the control group, the rats treated with 0.2 mg/kg almost took twice as long to reach the learning standard, while 0.4 mg/k; the treated rats could not reach the standard network within the prescribed time period. . In addition, in another labyrinth test for food rewards, it was also reported that the treatment group had a delay in spatial learning ability compared to the control group, although a gradual improvement was observed during the continuous training period, the MIA-801 treatment group was compared in the training phase. The control group still showed poor performance. van der Stagy FJ et al. believed that whether it was subcutaneous or intramuscular injection, the rodent administration MIA-801 should meet the criteria of cognitive impairment model as long as it does not exceed 0.1 mg / kg. Can cause sensory gating damage or toxic effects.
4 Long-term effects of MIA-801 on brain morphology and neurochemistry
4. 1 Brain Morphology The brain weight loss of rats treated with MIA-801 after birth has been reported. Facchinett F et al. recorded a significant reduction in brain weight immediately after the end of MK-801 treatment (1-12 d after birth), and this effect can persist until adulthood. More detailed studies have shown that the effects on different brain regions are not consistent. The most significant areas of weight loss are the cerebellum and striatum, with minimal impact on the hippocampus. Kawahe K et al [[52] also reported a decrease in brain weight when rats were sacrificed in adulthood, but they did not attempt to further understand the characteristics of MIA-801 affecting different brain regions.
In addition, brain weight loss may also be the result of a decrease in brain volume and number of neurons. In the study of hippocampus, Hari et al. found that the hippocampus had a decreasing capacity when the animals were sacrificed at two months of age, and the subcerebral horn was particularly prominent, accompanied by a decrease in the number of neurons in the CAl region. Similarly, studies have found that the prefrontal cortical V-cone neurons in adult rat brain tissue are reduced.
4. 2 Neurochemical neurological and functional imaging studies have found that the prefrontal cortex is one of the main cortex of the cause of schizophrenia. Blot K et al. studied the relationship between cognitive impairment and cortical function in rats. A single injection of 0.1 mg/kg of MIA-801 caused a long-term response in the hippocampal-prefrontal cortex, with long-term potentiation. The mechanism is the same. Cortically independent cognitive impairment and hippocampus-related spatial memory impairment occurred in rats after administration of MIA-801, and these effects gradually weakened within 24 h. Jia Jiao and other studies have found that blocking NMDA receptors in the neonatal period can cause the compensatory increase of NR1 and NR2A in the adult hippocampus of rats, which leads to the decrease of NGF in the prefrontal puberty. Therefore, it is believed that blocking NMDA receptors in the neonatal period will cause NGF regulation. Change, long-term compensation of glutamate system. Tang Yamei et al found that the perinatal MIA-801 repeated treatment induced schizophrenia development model in rats with mPFC and hippocampal SIT transmitter system dysfunction, hippocampal NE neurotransmitter system dysfunction. Nerve growth factor is an important neurotrophic factor, and [[54] suggests that changes in its level may be involved in the pathogenesis of schizophrenia. A study in China identified different expression patterns of brain-derived neurotrophic factors in the prefrontal and hippocampus. The increase observed in the former during the postpartum period does not last until adulthood or adolescence, while the latter has a high level of expression in adulthood and adolescence, but it was not available before.
Studies have shown that changes in adulthood of rats treated with MIA-801 early in life are mainly due to the effects of the major neurotransmitter systems. Harris L et al Czal detailed that the NR1 subtype of the NMDA receptor is lowly expressed in the dorsal region of the thalamus and in the dorsal region of the hippocampus, but overexpressed in the ventral region and the ventral CA3 region. In addition, an increase in NR1 expression was also found in the cortex. A study on the metabolism of monoamines reported that dopamine metabolism increased in the frontal and striatum, while 5-monosamine and norepinephrine increased metabolism in the frontal cortex and striatum, respectively. The qualitative effects also involve the guanidinium butyrate system. Studies have found that the treatment group lost almost half of the prefrontal cortical small albumin interneurons compared with the control group.
In addition, studies have shown that MIA-801 has a protective effect on the brain. Yuan Fenggang and other 2014 studies found that MIA-801 can inhibit the S-nitrosylation of ASIA caused by global cerebral ischemia/reperfusion in SD rats, which in turn affects ASIA apoptosis signaling pathway and protects neuronal injury. Zhou Hongxia and others have similar findings. Therefore, the mechanism of action of MK-801 remains to be further studied.
Efficacy evaluation
Schizophrenia As a complex group of diseases, it is difficult to replicate all the symptoms of an animal model, and it is almost impossible to achieve under current science and technology. Therefore, a criterion needs to be established for evaluating these models. To this end, we explored whether it is reasonable to establish an animal model of schizophrenia with MIA-801 administration. First, it is a model of the pathogenesis, based primarily on the NMDA receptor hypothesis, based on the dysregulation of dysfunction of dopaminergic neurotransmitters in schizophrenia. Second, the change in adulthood stems from the interference of adverse factors in early life, which is consistent with the neurodevelopmental model of schizophrenia. In addition, increased apoptosis is also implicated in the pathogenesis of schizophrenia because it can explain the subtle neuropathological changes observed in postmortem tissues, such as neurofibrillation and cell structure defects without glial appearance.
Although evidence suggests that behavioral behavior of animals after MIA-801 treatment in early life can mimic some of the symptoms of schizophrenia, there is still evidence that there is a difference between them, especially regarding prepulse inhibition and spontaneous activity, so this model The surface validity seems to be insufficient. Moreover, the reported changes are mainly limited to positive symptoms and cognitive impairment, and the current findings related to negative symptoms are not sufficient, so no clear conclusion can be drawn. Negative symptoms such as social dysfunction and social withdrawal are one of the early manifestations of the first episode of mental illness, and are one of the symptoms of poor response to treatment. Therefore, it is still necessary to adhere to the treatment after the relief of psychotic symptoms. Thus, we believe that the establishment of animal models plays an important role in the discovery of therapeutic drugs, and that models that can trigger behavior related to negative symptoms will have greater value.
6 summary
MIA-801 treatment of neonatal rats leads to dysfunction of NMDA receptors, which accelerates the initiation of diffuse apoptosis in immature brains, followed by cell structure and synaptic reorganization. These abnormalities may end in the presence of psychotic symptoms in later life. MIA-801 can establish a stable animal model of schizophrenia positive symptoms and cognitive impairment, with reasonable structural validity. Because of the poor reproducibility of some observations, especially in the most extensive pre-pulse inhibition and spontaneous activity in schizophrenia model behavior studies, it is controversial about the consistency of long-term behavioral effects. Moreover, the behavior associated with negative symptoms has been found to be insufficient, and further research is needed in this regard. In addition, the results of the studies often vary greatly depending on the mode of administration, the dose administered, and the type of animal. Therefore, the animal model of schizophrenia administered by MIA-801 is still
It is one of the hotspots of the discussion. In order to ensure the consistency of the research results, the model establishment method needs to be further unified. The model establishment method for improving the negative symptoms of schizophrenia needs further study.
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