Disruption of reelin signaling attenuates methamphetamine-induced hyperlocomotion
Disruption of reelin signaling attenuates methamphetamine-induced hyperlocomotion
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DOI：
10.1111/j.1460-9568.2007.05564.x
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发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
Sato, Kohji
中科院分区：
文献类型：
--
作者：
Matsuzaki, Hideo;Minabe, Yoshio;Sato, Kohji
为了阐明reelin信号是否参与成年小鼠大脑中多巴胺能神经传递，我们研究了缺乏reelin的小鼠（reeler）的多巴胺功能。我们发现甲基苯丙胺诱导的运动活动在reeler小鼠中显著减弱。为了阐明这一现象的机制，我们首先研究了突触前多巴胺释放；而在野生型、杂合子和纯合子小鼠中差异不显著。接下来，我们检查了伏隔核内注射多巴胺D1和D2受体激动剂的运动反应，发现缺乏reelin信号导致D1和D2受体介导的多巴胺能功能下降。此外，我们测量了纹状体中多巴胺受体的结合，发现纺锤鼠的D1和D2类多巴胺受体都减少了。此外，我们发现DARPP-32的磷酸化水平也会因缺乏reelin信号而改变。最后，为了区分reelin在成年小鼠中的发育作用和急性作用，我们在脑室内注入了一种针对reelin的单克隆抗体CR-50。有趣的是，注入CR-50也显著减少了野生型小鼠甲基苯丙胺诱导的过度运动，表明reelin在多巴胺能系统中具有急性作用。这些结果表明，reelin信号在成年小鼠多巴胺能系统中起着关键作用，特别是在突触后水平。
To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.