Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice
Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice
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DOI：
10.1038/sj.npp.1301301
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发表时间：
2007-08-01
影响因子：
7.6
通讯作者：
Wang, Jia Bei
中科院分区：
文献类型：
--
作者：
Barbier, Elisabeth;Zapata, Agustin;Wang, Jia Bei
蛋白激酶C相互作用蛋白/组氨酸三联体核苷酸结合蛋白1（PKC 1/HINT 1）是组氨酸三联体蛋白家族的成员。虽然这种蛋白质广泛表达于哺乳动物的大脑中，包括中皮质边缘和中纹状体区域，但其在中枢神经系统中的生理功能仍然未知。最近的微阵列研究报告减少PKC 1/HINT 1的mRNA表达在额叶皮质的个人精神分裂症，这表明这种蛋白质可能参与疾病的病理生理。鉴于多巴胺（DA）传递和精神分裂症之间的联系，本研究采用行为和神经化学方法来研究组成性PKC 1/HINT 1缺失对以下活动的影响：（i）基础和苯丙胺（AMPH）诱发的运动活动;（ii）背侧纹状体中的DA动力学;（iii）突触后DA受体功能。相对于野生型（WT）对照，PKC 1/HINT 1（-/-）（KO）小鼠显示出较低的自发运动。急性AMPH给药显著增加了WT小鼠的自发活动;尽管如此，KO小鼠的效果得到了增强。定量微透析研究显示KO小鼠纹状体或中脑核中的基础DA动力学没有改变。急性AMPH增加DA水平的能力没有改变，表明这些区域的突触前DA神经传递功能并不构成KO小鼠行为表型的基础。与WT小鼠相反，全身给予直接作用的DA受体激动剂阿扑吗啡（10 mg/kg）显著增加KO小鼠的运动活动，表明这些动物的突触后DA功能发生了改变。这些结果表明PKC 1/HINT 1在调节AMPH的行为反应中起重要作用。此外，他们指出，这种蛋白质的缺乏可能与突触后DA传递的失调。
Protein kinase C interacting protein/histidine triad nucleotide binding protein 1 (PKC1/HINT1) is a member of the histidine triad protein family. Although this protein is widely expressed in the mammalian brain including mesocorticolimbic and mesostriatal regions, its physiological function in CNS remains unknown. Recent microarray studies reported decreased mRNA expression of PKC1/HINT1 in the frontal cortex of individuals with schizophrenia, suggesting the possible involvement of this protein in the pathophysiology of the disease. In view of the documented link between dopamine (DA) transmission and schizophrenia, the present study used behavioral and neurochemical approaches to examine the influence of constitutive PKC1/HINT1 deletion upon: (i) basal and amphetamine (AMPH)evoked locomotor activity; (ii) DA dynamics in the dorsal striatum, and (iii) postsynaptic DA receptor function. PKC1/HINT1(-/-) (KO) mice displayed lower spontaneous locomotion relative to wild-type (WT) controls. Acute AMPH administration significantly increased locomotor activity in WT mice; nonetheless, the effect was enhanced in KO mice. Quantitative microdialysis studies revealed no alteration in basal DA dynamics in the striatum or nucleus accumbens of KO mice. The ability of acute AMPH to increase DA levels was unaltered indicating that function in presynaptic DA neurotransmission in these regions do not underlie the behavioral phenotype of KO mice. In contrast to WT mice, systemic administration of the direct-acting DA receptor agonist apomorphine (10 mg/kg) significantly increased locomotor activity in KO mice suggesting that postsynaptic DA function is altered in these animals. These results demonstrate an important role of PKC1/HINT1 in modulating the behavioral response to AMPH. Furthermore, they indicate that the absence of this protein may be associated with dysregulation of postsynaptic DA transmission.