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

已知甲基偶氮氧基甲醇（MAM）给药于妊娠大鼠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。妊娠大鼠在GD 17以25 mg/kg的剂量腹腔内给予MAM。在PD 21时，大鼠的大脑显示海马中颗粒细胞层的阵列被破坏，皮质宽度减小。因此，我们证实了产前MAM暴露作为精神分裂症动物模型的有效性。在下一个实验中，大鼠在其产前期暴露于MAM，并从PD 7开始每天用5 mg/kg甲基苯丙胺攻击5天。这一时期被认为相当于人类的青春期。以腹侧被盖区或黑质多巴胺转运蛋白（DAT）mRNA的表达为指标，检测DAT的功能。MAM预处理未改变DAT mRNA表达。同时检测与神经元凋亡相关的Bcl-2和Bax蛋白的表达。MAM预处理对纹状体Bcl-2和Bax的表达无明显影响。这些结果表明，产前MAM暴露诱导异常发育的神经元在大脑中，但没有改变DAT的功能或凋亡相关蛋白（Bcl-2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).