The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats
The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats
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DOI：
10.1016/j.brainres.2007.09.072
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发表时间：
2007-12-12
期刊：
影响因子：
2.9
通讯作者：
Hasegawa, Takaaki
中科院分区：
文献类型：
--
作者：
Nakayama, Hironao;Kitaichi, Kiyoyuki;Hasegawa, Takaaki
有机阳离子转运蛋白-3(Oct3)在包括脑在内的多种组织中表达。我们先前已经证明，对甲基苯丙胺(METH)行为敏化的大鼠增加了甲基苯丙胺(METH)的脑渗透率，并减少了Oct3在脑中的表达。考虑到早期的体外研究表明：1)Oct3可以转运多巴胺(DA)；2)通过Oct3的特异性转运可以被冰毒抑制，这些结果表明，Oct3的减少可能减少了冰毒和/或DA从脑中的外流，从而导致行为敏化的发展。因此，本研究利用Oct3反义核酸(Oct3-AS)处理大鼠进行了与DA相关的行为任务和药代动力学实验，因为尚无Oct3的特异性配体。持续注入Oct3-AS可显著降低脉络膜神经丛(CP)上皮细胞Oct3的表达。冰毒诱导的大鼠多动症和冰毒诱导的伏隔核和前额叶皮质细胞外多巴胺水平均显著升高。此外，Oct3 AS处理组大鼠脑脊液和伏隔核胞外区的冰毒浓度显著增加。这些结果表明，Oct3的减少增加了脑内冰毒和/或多巴胺的浓度，从而增强了多巴胺能神经元的传递，增加了冰毒所致的超速运动。综上所述，Cp的Oct3可以通过控制脑内冰毒和/或DA的水平来调节冰毒的作用。因此，这些结果表明Oct3可能是治疗药物滥用和精神分裂症等冰毒相关疾病的新分子靶点。(C)2007 Elsevier B.V.保留所有权利。
Organic cation transporter-3 (OCT3) is expressed in several tissues including the brain. We have previously demonstrated that rats with behavioral sensitization to methamphetamine (METH) increased the brain penetration of METH with decreased expression of OCT3 in brain. Considering the earlier in vitro studies demonstrating that 1) OCT3 could transport dopamine (DA) and 2) the specific transport via OCT3 could be inhibited by METH, these results suggest that decreased OCT3 might decrease the efflux of METH and/or DA from brain, subsequently causing the development of behavioral sensitization. Thus, in the present study, behavioral task related to DA and pharmacokinetic experiment were performed using rats treated with antisense against OCT3 (OCT3-AS) since no specific ligands for OCT3 are still available. The continuous infusion of OCT3-AS into the third ventricle significantly decreased the expression of OCT3 in choroid plexus (CP) epithelial cells. Both METH-induced hyperlocomotion and METH-induced extracellular DA levels in nucleus accumbens and prefrontal cortex were significantly increased in OCT3-AS-treated rats. Moreover, the concentrations of METH were significantly increased in cerebrospinal fluid as well as extracellular areas at the nucleus accumbens in OCT3-AS-treated rats. These results suggested that decreased OCT3 elevated the concentration of METH and/or DA in brain, subsequently enhancing doparninergic neuronal transmission and increasing METH-induced hyperlocomotion. In summary, OCT3 at the CP could regulate the effect of METH by controlling the levels of METH and/or DA in brain. Thus, these results suggest that OCT3 may be a new molecular target to treat METH-related disorders such as drug abuse and schizophrenia. (c) 2007 Elsevier B.V. All rights reserved.