Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens
Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens
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DOI：
10.1038/sj.npp.1300516
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发表时间：
2004-11-01
影响因子：
7.6
通讯作者：
Didriksen, M
中科院分区：
文献类型：
--
作者：
Flagstad, P;Mork, A;Didriksen, M
已经提出，神经发育的发育障碍导致类似于精神分裂症的病理生理变化。我们通过在妊娠第17天（GD 17）用甲基偶氮甲醇乙酸酯（MAM）处理妊娠大鼠母鼠来诱导这种破坏。在产前暴露于MAM的成年大鼠中，大脑总体积以及前额叶皮层和海马的体积均减小。当运动活动进行了评估，在一个开放的领域，MAM暴露的大鼠是高度反应性的一个温和的压力和安非他明（2毫克/公斤，皮下注射）。与对照组相比，他们参与的社交活动也更少。我们研究了，通过微透析，安非他明对细胞外多巴胺的影响，在自由活动的控制和MAM暴露大鼠的延髓核和内侧前额叶皮层。安非他明（2 mg/kg，s.c.）诱导的多巴胺释放的增加，是更大的MAM暴露大鼠的脑桥核比对照组，而没有差异，在内侧前额叶皮层。在对照组中，注入内侧前额叶皮质（50 μ M）的安非他明导致丘脑核细胞外多巴胺的轻微减少。这种效果是不存在的MAM暴露的大鼠，其中一个短暂的增加，在丘脑核多巴胺水平被视为安非他明输液后。这些结果表明，妊娠晚期大鼠神经发生中断导致行为变化，模仿阳性和阴性精神分裂症症状，也导致皮质下多巴胺神经传递失调。本研究有助于评估产前MAM GD 17治疗大鼠作为精神分裂症动物模型的有效性。
Gestational disruption of neurodevelopment has been proposed to lead to pathophysiological changes similar to those underlying schizophrenia. We induced such disruption by treating pregnant rat dams with methylazoxymethanol acetate (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When locomotor activity was assessed in an open field, MAM-exposed rats were hyper-responsive to a mild stress and to amphetamine (2 mg/kg, s.c,). They also engaged in less social interaction than controls. We studied, by microdialysis, the effect of amphetamine on extracellular dopamine in the nucleus accumbens and the medial prefrontal cortex of freely moving control and MAM-exposed rats. Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no difference was seen in the medial prefrontal cortex. In controls, amphetamine infused into the medial prefrontal cortex (50 muM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAM-exposed rats, where a transient increase in nucleus accumbens dopamine levels was seen after amphetamine infusion. These results show that the late gestational disruption of neurogenesis in the rat leads to behavioral changes that mimic positive and negative schizophrenia symptoms, and also to a dysregulation of subcortical dopamine neurotransmission. This study contributes to the evaluation of the validity of the prenatal MAM GD17 treatment in rats as an animal model for schizophrenia.