The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes.
The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes.
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DOI：
10.1177/0269881117715598
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Steiner H
中科院分区：
文献类型：
--
作者：
Alter D;Beverley JA;Patel R;Bolaños-Guzmán CA;Steiner H
包括精神兴奋剂如哌甲酯（利他林）和选择性5-羟色胺再摄取抑制剂（SSRI）如氟西汀的药物组合适用于几种医疗条件。同时接触这些药物也发生在接受SSRIs治疗的个体使用“认知增强剂”的情况下。哌醋甲酯是一种多巴胺再摄取抑制剂，它本身在纹状体中产生一些与成瘾相关的基因调节。我们已经证明，共同管理的SSRIs加强这些哌甲酯诱导的分子效应，从而产生一个更“可卡因样”的配置文件。有证据表明，5-HT 1B 5-羟色胺受体亚型介导可卡因诱导的基因调控。因此，我们研究了5-HT 1B受体是否也修改哌甲酯诱导的基因调控，通过评估的影响，选择性5-HT 1B受体激动剂（CP 94253）对立即早期基因标记物（Zif 268，c-Fos，Homer 1a）在青春期雄性大鼠。原位杂交组织化学检测基因表达。我们的研究结果表明，CP 94253（3，10 mg/kg）产生剂量依赖性增强哌甲酯（5 mg/kg）诱导的Zif 268和c-Fos表达。这种增强作用在纹状体中广泛存在，并且在横向（感觉运动）部分中最大，因此模拟了单独使用可卡因或与氟西汀联合给药后观察到的效果。然而，与氟西汀相反，这种5-HT 1B激动剂不影响哌甲酯诱导的Homer 1a表达。CP 94253还增强了哌甲酯诱导的自发活动。这些发现表明，5-HT 1B受体的刺激可以增强哌甲酯（多巴胺）诱导的基因调控。因此，该受体可能参与氟西汀（5-羟色胺）诱导的增强作用，并可能作为药理学靶点减弱哌甲酯+SSRI诱导的“可卡因样”效应。
Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with “cognitive enhancer” use by individuals treated with SSRIs. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of SSRIs potentiates these methylphenidate-induced molecular effects, thus producing a more “cocaine-like” profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers (Zif268, c-Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c-Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate+SSRI-induced “cocaine-like” effects.
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