Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats
Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats
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DOI：
10.1124/jpet.301.3.1097
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发表时间：
2002-06-01
影响因子：
3.5
通讯作者：
Baldessarini, RJ
中科院分区：
文献类型：
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作者：
Davids, E;Zhang, KH;Baldessarini, RJ
与其在注意力缺陷多动障碍（ADHD）中的临床作用一致，兴奋剂哌甲酯和安非他明可减少患有新生儿6-羟基多巴胺（6-OHDA）前脑多巴胺（DA）系统损伤的幼年雄性大鼠的运动多动。由于兴奋剂作用于几种胺能神经传递系统，我们通过比较d-哌甲酯（DA神经元转运的选择性抑制剂）的行为作用研究了相关的潜在机制[GBR-12909（1-[2-[双（4-氟苯基）甲氧基]乙基] 4-[ 3-苯基丙基]哌嗪二盐酸盐），氨醛酸]，血清素[5-羟色胺（5-HT），西酞普兰，氟伏沙明]，和去甲肾上腺素（NE;地昔帕明，尼索西汀）。在出生后第5天（PD），在地昔帕明预处理（25 mg/kg，s.c.）保护去甲肾上腺素能神经元在新环境中记录PD 25时的运动活动90 min之前，腹膜内给予大鼠测试试剂或载体。d-哌甲酯刺激假手术对照组的运动活动，拮抗损伤大鼠的多动。选择性DA转运抑制剂GBR-12909和amfonelic酸大大刺激运动活动在假对照组，但没有拮抗多动损伤大鼠。与此相反，所有选择性5-HT和NE转运体拮抗剂测试大大降低运动过度活跃6-OHDA损伤大鼠，但不改变假手术对照组的运动活动。研究结果表明，在新生儿6-OHDA损伤的年轻大鼠中，兴奋剂的行为效应可能是通过NE或5-HT的释放介导的，并支持使用增加去甲肾上腺素或5-羟色胺活性的药物治疗ADHD。
Consistent with their clinical effects in attention deficit-hyperactivity disorder (ADHD), the stimulants methylphenidate and amphetamine reduce motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of the forebrain dopamine (DA) system. Since stimulants act on several aminergic neurotransmission systems, we investigated underlying mechanisms involved by comparing behavioral actions of d-methylphenidate, selective inhibitors of the neuronal transport of DA[GBR-12909 (1-[2-[bis(4-fluorophenyl) methoxy] ethyl] 4-[ 3-phenylpropyl] piperazine dihydrochloride), amfonelic acid], serotonin [5-hydroxytryptamine (5-HT), citalopram, fluvoxamine], and norepinephrine (NE; desipramine, nisoxetine) in 6-OHDA lesioned rats. Selective dopamine lesions were made using 6-OHDA (100 mug, intracisternal) on postnatal day (PD) 5 after desipramine pretreatment (25 mg/kg, s.c.) to protect noradrenergic neurons. Rats were given test agents or vehicle, intraperitoneally, before recording motor activity for 90 min at PD 25 in a novel environment. d-Methylphenidate stimulated motor activity in sham controls and antagonized hyperactivity in lesioned rats. Selective DA transport inhibitors GBR-12909 and amfonelic acid greatly stimulated motor activity in sham control subjects, too, but did not antagonize hyperactivity in lesioned rats. In contrast, all selective 5-HT and NE transporter antagonists tested greatly reduced motor hyperactivity in 6-OHDA lesioned rats but did not alter motor activity in sham controls. The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD.