Biological mechanisms of pubertal onset of schizophrenia in animal model of rats based on neurodevelopmental hypothesis.

已知甲氧基甲醇(MAM)在给怀孕大鼠服用时会导致大脑神经发育异常。我们评估了产前暴露MAM作为精神分裂症动物模型的有效性。GD17孕鼠按25 mg/kg剂量给孕鼠灌胃给药。PD 21时大鼠大脑海马区颗粒细胞层排列紊乱，皮质宽度变窄。因此，我们证实了产前暴露MAM作为精神分裂症动物模型的有效性。在接下来的实验中，大鼠在出生前暴露于MAM，并从PD 7开始每天给予5 mg/kg的甲基苯丙胺，连续5天。这段时间被认为相当于人类青春期。以腹侧被盖区或黑质多巴胺转运体(DAT)mRNA的表达为指标，检测DAT的功能。经MAM处理后，DAT基因表达无明显变化。同时检测与神经元凋亡相关的Bcl2和Bax蛋白的表达。MAM预处理不影响纹状体内Bcl2和Bax的表达。这些结果表明，产前暴露于MAM可导致脑神经元发育异常，但并未改变DAT的功能或凋亡相关蛋白(Bcl2和Bax)的表达。

Methylazoxymethanol (MAM) is known to cause neurodeveolpmental abnormalities in the brain when administered to pregnant rats. We assessed the validity of prenatal exposure of MAM as an animal model of schizophrenia. MAM was administered to pregnant rats at GD 17 at a dose of 25 mg/kg intraperitoneally. The brain of rats at PD 21 showed an disrupted array of granular cell layer in the hippocampus and reduced width of the cortex. Thus, we confirmed the validity of prenatal MAM exposure as an animal model for schizophrenia. In next experiment, rats were exposed with MAM in their prenatal period and were challenged with 5 mg/kg methamphetamine daily for 5 days from PD 7. This period is considered to be equivalent with human pubertal period. The function of dopamine transporter (DAT) was examined by the expression of DAT mRNA in the ventral tegmental area or substantia nigra as a measure. DAT mRNA expression was not altered by MAM pretreatment. At the same time, the expressions of Bcl-2 and Bax protein, both of which are related to apoptosis of the neurons, were also examined. The expressions of Bcl-2 and Bax in the striatum were not changed by MAM pretreatment. These findings suggest that prenatal MAM exposure induce an abnormal development of neurons in the brain, but did not change either the function of DAT or the expression of apoptosis-related proteins (Bcl-2 and Bax).