A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex
A developmentally regulated and psychostimulant-inducible novel rat gene mrt1 encoding PDZ-PX proteins isolated in the neocortex
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DOI：
10.1038/sj.mp.4001258
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发表时间：
2003-01-01
影响因子：
11
通讯作者：
Nishikawa, T
中科院分区：
文献类型：
--
作者：
Kajii, Y;Muraoka, S;Nishikawa, T
出生后第 3 周后，单次或重复接触安非他明和可卡因等精神兴奋剂会导致啮齿动物随后受到兴奋剂挑战而引起的拟精神病反应持久增强。这种行为敏化现象被认为是出生后发育关键期后兴奋剂引起的大脑基因表达改变的神经后果。使用差异克隆技术、RNA 任意引物 PCR，我们现在从大鼠新皮质中鉴定出一种新型的发育调节甲基苯丙胺 (MAP) 诱导基因 mrtl1（MAP 响应转录本 1）。 mrt1 编码两种主要类型的 PDZ 和 PX 结构域，包含大小约为 62 kDa 且具有不同羧基末端的蛋白质：Mrt1a 和 Mrt1b。 Mrt1a、mrt1a 和 Mrt1b、mrt1b 的 mrt1 mRNA 分别主要在不同的大脑区域和睾丸中表达。出生后第 3 周，急性 MAP 注射以 D1 受体拮抗剂敏感的方式上调新皮质中 mrt1b 的表达，而不影响 mrt1a 的表达。另一种兴奋剂可卡因模仿了这种上调，而戊巴比妥和 D1 拮抗剂未能改变 mrt1b 转录水平。此外，每天重复使用 MAP（而非 MAP 加 D1 拮抗剂）治疗 5 天，导致停药后 2 周和 3 周 mrt1b 基础表达增加。 MAP 对 mrt1b 的这些晚期发展、可卡因交叉反应、1311 拮抗剂敏感和长期调节与兴奋剂诱导的行为敏化的药理学特征相似，因此可能与长期神经元适应的启动和/或维持有关。
Single or repeated exposure to psychostimulants such as amphetamines and cocaine after postnatal week 3 leads to an enduring enhancement in the psychotomimetic responses elicited by a subsequent challenge of a stimulant in rodents. This behavioral sensitization phenomenon has been considered to be the neural consequences of stimulant-induced alterations in gene expression in the brain after a critical period of postnatal development. Using a differential cloning technique, RNA arbitrarily primed PCR, we have now identified from the rat neocortex a novel and developmentally regulated methamphetamine (MAP)inducible gene mrtl1 (MAP responsive transcript 1). mrt1 encodes two major types of PDZ- and PX-domains containing proteins of approximately 62 kDa in size with different carboxy termini, Mrt1a and Mrt1b. The mrt1 mRNAs for Mrt1a, mrt1a, and for Mrt1b, mrt1b, are predominantly expressed in various brain regions and the testes, respectively. Acute MAP injection upregulated mrt1b expression in the neocortex after postnatal week 3 in a D1 receptor antagonist-sensitive manner without affecting mrt1a expression. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to change the mrt1b transcript levels. Moreover, repeated daily treatment of MAP, but not MAP plus D1 antagonist, for 5 days caused an augmentation of the basal expression of mrt1b 2 and 3 weeks after the drug discontinuation. These late-developing, cocaine-crossreactive, 1311 antagonist-sensitive and long-term regulations of mrt1b by MAP are similar to the pharmacological profiles of stimulant-induced behavioral sensitization, and therefore may be associated with the initiation and/or maintenance of the long-term neuronal adaptation.