Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and-9-deficient mice
Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and-9-deficient mice
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DOI：
10.1111/j.1471-4159.2006.04288.x
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Nabeshima, Toshitaka
中科院分区：
文献类型：
--
作者：
Mizoguchi, Hiroyuki;Yamada, Kiyofumi;Nabeshima, Toshitaka
基质金属蛋白酶（MMP）及其抑制剂（TIMP）的功能是重塑细胞周围环境。它们的激活和调节与突触生理学和病理学有关。在这里，我们调查是否MMP-2和MMP-9参与的奖励效应和致敏甲基苯丙胺（METH）在动物中，其中神经回路的重塑可能发挥至关重要的作用。重复METH治疗诱导行为敏化，这是伴随着MMP-2和MMP-9的活性在大脑中的增加。在MMP-2-和MMP-9-缺陷小鼠[MMP-2-（-/-）和MMP-9-（-/-）]中，与野生型小鼠相比，MET诱导的行为敏化和条件性位置偏爱（奖励效应的测量）以及MET增加的丘脑核（NAc）中多巴胺释放减弱。与此相反，注入纯化的人MMP-2到NAc显着增强的MET增加多巴胺的释放。重复METH治疗后，野生型小鼠纹状体突触体的[H-3]多巴胺摄取减少，但MMP-2-（-/-）和MMP-9-（-/-）小鼠中[H-3]多巴胺摄取的METH诱导变化显著减弱。这些结果表明，MMP-2和MMP-9发挥了至关重要的作用，在METH诱导的行为敏化和奖励，通过调节METH诱导的多巴胺释放和摄取的NAC。
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) function to remodel the pericellular environment. Their activation and regulation are associated with synaptic physiology and pathology. Here, we investigated whether MMP-2 and MMP-9 are involved in the rewarding effects of and sensitization to methamphetamine (METH) in animals, in which the remodelling of neural circuits may play a crucial role. Repeated METH treatment induced behavioural sensitization, which was accompanied by an increase in MMP-2 and MMP-9 activity in the brain. In MMP-2- and MMP-9-deficient mice [MMP-2-(-/-) and MMP-9-(-/-)], METH-induced behavioural sensitization and conditioned place preference, a measure of the rewarding effect, as well as METH-increased dopamine release in the nucleus accumbens (NAc) were attenuated compared with those in wild-type mice. In contrast, infusion of purified human MMP-2 into the NAc significantly potentiated the METH-increased dopamine release. The [H-3]dopamine uptake into striatal synaptosomes was reduced in wild-type mice after repeated METH treatment, but METH-induced changes in [H-3]dopamine uptake were significantly attenuated in MMP-2-(-/-) and MMP-9-(-/-) mice. These results suggest that both MMP-2 and MMP-9 play a crucial role in METH-induced behavioural sensitization and reward by regulating METH-induced dopamine release and uptake in the NAc.