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首页> 外文期刊>Addiction biology >Methylphenidate and cocaine self-administration produce distinct dopamine terminal alterations
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Methylphenidate and cocaine self-administration produce distinct dopamine terminal alterations

机译：哌醋甲酯和可卡因的自我给药会产生明显的多巴胺末端改变

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Methylphenidate (MPH) is a commonly abused psychostimulant prescribed for the treatment of attention deficit hyperactivity disorder. MPH has a mechanism of action similar to cocaine (COC) and is commonly characterized as a dopamine transporter (DAT) blocker. While there has been extensive work aimed at understanding dopamine (DA) nerve terminal changes following COC self-administration, very little is known about the effects of MPH self-administration on the DA system. We used fast scan cyclic voltammetry in nucleus accumbens core slices from animals with a 5-day self-administration history of 40 injections/day of either MPH (0.56 mg/kg) or COC (1.5 mg/kg) to explore alterations in baseline DA release and uptake kinetics as well as alterations in the interaction of each compound with the DAT. Although MPH and COC have similar behavioral effects, the consequences of self-administration on DA system parameters were found to be divergent. We show that COC self-administration reduced DAT levels and maximal rates of DA uptake, as well as reducing electrically stimulated release, suggesting decreased DA terminal function. In contrast, MPH self-administration increased DAT levels, DA uptake rates and DA release, suggesting enhanced terminal function, which was supported by findings of increased metabolite/DA tissue content ratios. Tyrosine hydroxylase messenger RNA, protein and phosphorylation levels were also assessed in both groups. Additionally, COC self-administration reduced COC-induced DAT inhibition, while MPH self-administration increased MPH-induced DAT inhibition, suggesting opposite pharmacodynamic effects of these two drugs. These findings suggest that the factors governing DA system adaptations are more complicated than simple DA uptake blockade.
机译：哌醋甲酯（MPH）是处方药，通常用于治疗注意力不足过动症。 MPH具有类似于可卡因（COC）的作用机制，通常被称为多巴胺转运蛋白（DAT）阻滞剂。尽管已经进行了大量旨在了解COC自我给药后多巴胺（DA）神经末梢变化的工作，但关于MPH自我给药对DA系统的影响知之甚少。我们使用来自动物的伏隔核核心切片中的快速扫描循环伏安法进行了5天的自给药历史，每天有40次注射MPH（0.56 mg / kg）或COC（1.5 mg / kg），以探讨基线DA的变化释放和吸收动力学以及每种化合物与DAT相互作用的改变。尽管MPH和COC具有类似的行为效果，但发现自我管理对DA系统参数的后果是不同的。我们表明，COC自我管理降低了DAT水平和DA摄取的最大速率，以及减少了电刺激释放，提示DA终末功能降低。相反，MPH自我给药可增加DAT水平，DA吸收率和DA释放，提示终末功能增强，这被代谢物/ DA组织含量比增加的结果所支持。两组还评估了酪氨酸羟化酶信使RNA，蛋白质和磷酸化水平。另外，COC自我给药可降低COC诱导的DAT抑制，而MPH自我给药可提高MPH诱导的DAT抑制，表明这两种药物的药效相反。这些发现表明，控制DA系统适应性的因素比简单的DA吸收阻滞更为复杂。

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