Breese G R, Cooper B R, Hollister A S
Psychopharmacologia. 1975 Oct 14;44(1):5-10. doi: 10.1007/BF00421175.
The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with alpha-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-beta-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by alpha-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.
在大鼠中研究了中枢去甲肾上腺素能、多巴胺能和5-羟色胺能神经系统对哌甲酯运动兴奋作用的意义。为了研究脑儿茶酚胺的作用，给大鼠预先注射利血平（2.5毫克/千克），24小时后再用α-甲基酪氨酸（25毫克/千克）或多巴胺-β-羟化酶抑制剂U-14,624（75毫克/千克）进行处理。在这些实验中，α-甲基酪氨酸拮抗了哌甲酯刺激的运动活性，而U-14,624处理后运动活性增强，这表明新合成的多巴胺的释放对哌甲酯的运动兴奋作用很重要。在用帕吉林或对氯苯丙氨酸（PCPA）预处理的大鼠中获得了涉及脑5-羟色胺在哌甲酯作用中的证据。发现在哌甲酯给药前1小时给予帕吉林可降低哌甲酯诱导的运动活性，而低剂量的PCPA预处理可拮抗这种作用。高剂量的PCPA导致哌甲酯诱导的活性显著升高，而5-羟色氨酸可降低这种升高。用5,7-二羟色胺破坏5-羟色胺能神经元也增强了哌甲酯诱导的运动。后一发现表明5-羟色胺能纤维在脑中具有抑制功能。结合哌甲酯在多动症中可能起作用的机制对这些结果进行了讨论。
