Implication of Rho‐associated kinase in the elevation of extracellular dopamine levels and its related behaviors induced by methamphetamine in rats
Implication of Rho‐associated kinase in the elevation of extracellular dopamine levels and its related behaviors induced by methamphetamine in rats
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DOI：
10.1046/j.1471-4159.2003.01784.x
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发表时间：
2003-07
影响因子：
4.7
通讯作者：
M. Narita;M. Takagi;K. Aoki;N. Kuzumaki;Tsutomu Suzuki
中科院分区：
文献类型：
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作者：
M. Narita;M. Takagi;K. Aoki;N. Kuzumaki;Tsutomu Suzuki
越来越多的证据表明，几种蛋白激酶参与了精神兴奋剂甲基苯丙胺诱导的药理作用的表达。本研究旨在探讨Rho/Rho相关激酶（ROCK）依赖性通路在甲基苯丙胺诱导的大鼠延髓核细胞外多巴胺水平升高及其相关行为中的作用。甲基苯丙胺（1 mg/kg，皮下注射）导致丘脑核中多巴胺的细胞外水平大幅增加，多巴胺相关行为（包括直立和嗅闻）逐渐增强。甲基苯丙胺还诱导其主要代谢物3，4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的水平下降。细胞外多巴胺水平的增加和甲基苯丙胺对多巴胺相关行为的诱导都被选择性ROCK抑制剂Y-27632的核内注射预处理显著抑制。相比之下，Y-27632对甲基苯丙胺诱导的DOPAC和HVA水平降低无影响。在这些条件下，甲基苯丙胺处理后，延髓核中膜结合RhoA的蛋白水平没有变化。值得注意的是，将Y-27632微量注射到延髓核中未能抑制由皮下注射μ阿片受体激动剂吗啡原型（10 mg/kg）诱导的延髓核中多巴胺、DOPAC和HVA细胞外水平的增加。此外，将电压依赖性Na+通道的选择性阻断剂河豚毒素（TTx）灌注到大鼠延髓核中不会影响甲基苯丙胺引起的大鼠延髓核中多巴胺细胞外水平的增加，而吗啡诱导的多巴胺升高则被TTx的应用所消除。通过在延髓核中灌注选择性多巴胺再摄取抑制剂1-[2-[双（4-氟苯基）甲氧基]-4-（3-苯基丙基）哌嗪（GBR-12909），也可增加延髓核中多巴胺的细胞外水平。这种作用不受Y-27632核内注射预处理的影响。这些研究结果提供了第一个证据，Rho/ROCK通路在延髓核可能有助于增加多巴胺的细胞外水平在延髓核引起的单次皮下注射甲基苯丙胺。与此相反，这一途径是不是必不可少的增加多巴胺在该地区诱导吗啡，提供了进一步的证据，不同的机制，多巴胺释放甲基苯丙胺和吗啡在大鼠中。
A growing body of evidence suggests that several protein kinases are involved in the expression of pharmacological actions induced by a psychostimulant methamphetamine. The present study was designed to investigate the role of the Rho/Rho‐associated kinase (ROCK)‐dependent pathway in the expression of the increase in extracellular levels of dopamine in the nucleus accumbens and its related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, subcutaneously) produced a substantial increase in extracellular levels of dopamine in the nucleus accumbens, with a progressive augmentation of dopamine‐related behaviors including rearing and sniffing. Methamphetamine also induced the decrease in levels of its major metabolites, 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA). Both the increase in extracellular levels of dopamine and the induction of dopamine‐related behaviors by methamphetamine were significantly suppressed by pretreatment with an intranucleus accumbens injection of a selective ROCK inhibitor Y‐27632. In contrast, Y‐27632 had no effect on the decrease in levels of DOPAC and HVA induced by methamphetamine. Under these conditions, there were no changes in protein levels of membrane‐bound RhoA in the nucleus accumbens following methamphetamine treatment. It is of interest to note that the microinjection of Y‐27632 into the nucleus accumbens failed to suppress the increases in extracellular levels of dopamine, DOPAC, and HVA in the nucleus accumbens induced by subcutaneous injection of a prototype of µ‐opioid receptor agonist morphine (10 mg/kg). Furthermore, perfusion of a selective blocker of voltage‐dependent Na+ channels, tetrodotoxin (TTx) into the rat nucleus accumbens did not affect the increase in extracellular levels of dopamine in the rat nucleus accumbens by methamphetamine, whereas the morphine‐induced dopamine elevation was eliminated by this application of TTx. The extracellular level of dopamine in the nucleus accumbens was also increased by perfusion of a selective dopamine re‐uptake inhibitor 1‐[2‐[bis(4‐fluorophenyl)methoxy]‐4‐(3‐phenylpropyl)piperazine (GBR‐12909) in the nucleus accumbens. This effect was not affected by pretreatment with intranucleus accumbens injection of Y‐27632. These findings provide first evidence that Rho/ROCK pathway in the nucleus accumbens may contribute to the increase in extracellular levels of dopamine in the nucleus accumbens evoked by a single subcutaneous injection of methamphetamine. In contrast, this pathway is not essential for the increased level of dopamine in this region induced by morphine, providing further evidence for the different mechanisms of dopamine release by methamphetamine and morphine in rats.