5-HT1B receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats
5-HT1B receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats
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DOI：
10.1038/sj.npp.1301445
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发表时间：
2008-02-01
影响因子：
7.6
通讯作者：
Ferre, Sergi
中科院分区：
文献类型：
--
作者：
Borycz, Janusz;Zapata, Agustin;Ferre, Sergi
先前的研究表明，多巴胺（DA）摄取阻滞剂哌甲酯，一种广泛用于治疗注意力缺陷多动障碍（ADHD）的精神兴奋剂，可以防止高度滥用的DA抑制剂甲基苯丙胺的神经毒性作用。然而，缺乏关于这两种药物在行为水平上的药理学相互作用的信息。当在2h间隔内全身给药时，先前给予哌醋甲酯（10mg/kg，腹膜内（i.p.））并不改变甲基苯丙胺诱导的自发激活。另一方面，先前给予甲基苯丙胺（lmg/kg，i.p.）显著增强哌甲酯诱导的运动激活。在体内微透析实验中，甲基苯丙胺和哌甲酯被发现增加多巴胺细胞外水平在延髓核（NAs）。甲基苯丙胺，但不是哌甲酯，显着增加细胞外的5-羟色胺（5-HT）的NAs的水平。甲基苯丙胺诱导的5-HT释放在给药后2h仍显著升高，表明5-HT的增加可能是增强哌甲酯诱导的运动激活的原因。事实上，先前给予5-HT摄取阻断剂氟西汀（10mg/kg，i.p.）还增强哌醋甲酯诱导的运动激活。选择性5-HT 1B受体拮抗剂（GR 55562; 1mg/kg），但不是5-HT 2受体拮抗剂（利坦色林; 2mg/kg，i.p.），抵消了甲基苯丙胺和氟西汀对哌醋甲酯引起的运动激活的影响。此外，5-HT 1B受体激动剂（CP 94253; 1 - 10mg/kg，i.p.）强烈和剂量依赖性地增强哌甲酯诱导的运动激活。5-HT1B受体介导的对哌甲酯诱导的大鼠运动激活的调节可能对ADHD的治疗有意义。
Previous studies have shown that the dopamine (DA) uptake blocker methylphenidate, a psychostimulant widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), prevents the neurotoxic effects of the highly abused DA releaser methamphetamine. However, there is a lack of information about the pharmacological interactions of these two drugs at the behavioral level. When systemically administered within an interval of 2h, previous administration of methylphenidate (10mg/kg, intraperitoneal (i.p.)) did not modify locomotor activation induced by methamphetamine. On the other hand, previous administration of methamphetamine (1mg/kg,i.p.) markedly potentiated methylphenidate-induced motor activation. With in vivo microdialysis experiments, methamphetamine and methylphenidate were found to increase DA extracellular levels in the nucleus accumbens (NAs). Methamphetamine, but not methylphenidate, significantly increased the extracellular levels of serotonin (5-HT) in the NAs. Methamphetamine-induced 5-HT release remained significantly elevated for more than 2h after its administration, suggesting that the increased 5-HT could be responsible for the potentiation of methylphenidate-induced locomotor activation. In fact, previous administration of the 5-HT uptake blocker fluoxetine (10mg/kg,i.p.) also potentiated the motor activation induced by methylphenidate. A selective 5-HT1B receptor antagonist (GR 55562; 1mg/kg), but not a 5-HT2 receptor antagonist (ritanserin;2mg/kg,i.p.), counteracted the effects of methamphetamine and fluoxetine on the motor activation induced by methylphenidate. Furthermore, a 5-HT1B receptor agonist (CP94253;1-10mg/kg,i.p.) strongly and dose-dependently potentiated methylphenidate-induced locomotor activation. The 5-HT1B receptor-mediated modulation of methylphenidate-induced locomotor activation in rat could have implications for the treatment of ADHD.