Irifune M, Nomoto M, Fukuda T
Department of Pharmacology, Faculty of Medicine, Kagoshima University, Japan.
Eur J Pharmacol. 1995 Jan 5;272(1):79-85. doi: 10.1016/0014-2999(94)00620-m.
The effects of GBR 12909 1-[2-[bis(4-fluorophenyl)methoxy]-ethyl]-4- [3-phenylpropyl]piperazine, a very potent and selective dopamine uptake inhibitor, and apomorphine, a dopamine receptor agonist, alone and in combination were investigated on locomotor activity and dopamine turnover in discrete brain regions of mice. The levels of dopamine and its metabolites were examined 40 min after the administration of GBR 12909 and/or apomorphine, when the effects of the drugs on locomotor activity were approximately at a peak. GBR 12909 (10 mg/kg i.p.) reversed a low dose of apomorphine (0.05 mg/kg s.c.)-induced suppression in locomotor activity and significantly increased this activity. Despite the dramatic change in the behavior, GBR 12909 did not influence the decrease in 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio (which is one of the indications of transmitter turnover) induced by a low dose of apomorphine in the nucleus accumbens and striatum. In contrast, GBR 12909 did not enhance the high-dose apomorphine (2 mg/kg s.c.)-induced hyperlocomotion, and did not modify the larger decrease in dopamine turnover produced by the high dose of apomorphine in the frontal cortex, nucleus accumbens and striatum. This suggests that postsynaptic dopamine receptors may reach maximum stimulation at a high dose of apomorphine. These results indicate that a behavioral change induced via stimulation of postsynaptic dopamine receptors does not necessarily lead to an alteration in dopamine turnover.
研究了强效选择性多巴胺摄取抑制剂GBR 12909（1-[2-[双(4-氟苯基)甲氧基]-乙基]-4-[3-苯基丙基]哌嗪）和多巴胺受体激动剂阿扑吗啡单独及联合应用对小鼠离散脑区运动活性和多巴胺周转的影响。在给予GBR 12909和/或阿扑吗啡40分钟后，检测多巴胺及其代谢产物的水平，此时药物对运动活性的影响大致达到峰值。GBR 12909（腹腔注射10 mg/kg）逆转了低剂量阿扑吗啡（皮下注射0.05 mg/kg）诱导的运动活性抑制，并显著增加了该活性。尽管行为发生了显著变化，但GBR 12909并未影响低剂量阿扑吗啡在伏隔核和纹状体中诱导的3,4-二羟基苯乙酸（DOPAC）/多巴胺比值下降（这是递质周转的指标之一）。相反，GBR 12909并未增强高剂量阿扑吗啡（皮下注射2 mg/kg）诱导的运动亢进，也未改变高剂量阿扑吗啡在额叶皮质、伏隔核和纹状体中引起的多巴胺周转更大幅度下降。这表明，高剂量阿扑吗啡可能使突触后多巴胺受体达到最大刺激。这些结果表明，通过刺激突触后多巴胺受体诱导的行为变化不一定会导致多巴胺周转改变。
