Molecular genetic and experimental studies on abnormalities of glutamatergic transmission in schizophrenia

以下研究被用来研究精神分裂症谷氨酸能传递异常的病理生理学基础。首先，研究精神分裂症患者N-乙酰化α-连锁酸性二肽酶(NAALADase)基因的分子遗传学异常。其次，使用几种可能的精神分裂症动物模型进行了实验研究。双侧内嗅皮层注射NAALADase基因反义寡核苷酸后，大鼠的自发活动和甲基苯丙胺诱导的运动活动均未见改变。体外放射自显影显示，N-甲基-D-天冬氨酸(N-甲基-D-天冬氨酸)R1亚基反义寡核苷酸作用于大鼠，黑质多巴胺D2受体密度显著降低，Northern印迹分析显示纹状体多巴胺D2mRNA显著增加。在长期接受非竞争性NMDA拮抗剂苯环利定或MK-801治疗的大鼠中，与社交相关的行为显著减少。

Following studies were undertaken to investigate the pathophysiology underlying abnormalities of glutamatergic transmission in schizophrenia. First, a molecular genetic abnormality in gene encoding N-acetylated alpha-linked acidic dipeptidase (NAALADase) was investigated in patients with schizophrenia. Second, experimental studies were performed using several possible animal models of schizophrenia. Rats administered with antisense oligonucleotide complementary to mRNA of NAALADase into the bilateral entorhinal cortex did not show changes in spontaneous locomotor activity or metamphetamine-induced locomotor activity. Intracerebroventricular administration to rats with antisense oligonucleotide complementary to mRNA of N-methyl-D aspartate (NMDA) R1 subunit induced a significant reduction in dopamine D2 receptor density in the substantia nigra using in vitro [3H] YM-09151-2 autoradiography as well as a significant increase in dopamine D2 mRNA in the striatum using northern blot analysis. In rats treated chronically with non-competitive NMDA antagonist, phencyclidine or MK-801, behaviors related social interaction were significantly decreased.