Heal D J, Frankland A T, Buckett W R
Boots Pharmaceuticals Research Department, Nottingham, U.K.
Neuropharmacology. 1990 Dec;29(12):1141-50. doi: 10.1016/0028-3908(90)90038-s.
3-Methoxytyramine (3-MT) is a minor metabolite of dopamine which is suggested to reflect the turnover and utilization of dopamine. A novel, isocratic HPLC method has been developed which can be used to analyse 3-MT in homogenates of rat brain without the need for additional purification procedures. Furthermore, the coulometric electrochemical detection system is sensitive enough to measure 3 pg of 3-MT (equivalent to 0.6 ng/g tissue wet weight). 3-Methoxytyramine was measured in the striatum and n. accumbens after decapitation and rapid freezing, using 3-methoxy-4-hydroxybenzylamine as the internal standard. The effects of dopaminergic and other drugs on this metabolite were examined using this method. alpha-Methyl-p-tyrosine (200 mg/kg i.v.) produced parallel linear decreases in dopamine and 3-MT in naive rats, but not those pretreated with tranylcypromine (5 mg/kg i.p.). Methamphetamine (0.3-10 mg/kg i.p.) and amphetamine (0.3-10 mg/kg i.p.) both dose-dependently increased 3-MT in naive and tranylcypromine-pretreated rats. In naive animals, 3-MT was not altered by intraperitoneal injection of the dopamine reuptake inhibitors, bupropion (10 mg/kg) and nomifensine (10 mg/kg) or by sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg) and zimeldine (10 mg/kg). 3-Methoxytyramine was decreased by apomorphine (5 mg/kg i.p.) and also by large doses of the selective D2 antagonist, BRL 34778 (5 mg/kg i.p.) or L-DOPA (50 mg/kg i.p.). The selective D1 antagonist, SCH 23390 (0.1 or 5 mg/kg i.p.) was without effect. In tranylcypromine-pretreated rats, 3-MT was dose-dependently reduced and increased by apomorphine (0.01-5 mg/kg i.p.) and BRL 34778 (0.1-5 mg/kg i.p.), respectively. The drug SCH 23390 (0.1-5 mg/kg i.p.) produced much smaller increases in 3-MT which were probably mediated through the striatonigral pathway. Overall, the data suggest that measurement of 3-MT, after inhibition of monoamine oxidase, is a useful index of the release and utilization of dopamine. However, after substantial and prolonged depletion of dopamine, levels of 3-MT in naive animals are a better index. Also, the formation of 3-MT in naive rats rats provides a sensitive method for distinguishing between dopamine releasing agents and reuptake inhibitors.
3-甲氧基酪胺（3-MT）是多巴胺的一种次要代谢产物，被认为可反映多巴胺的周转和利用情况。已开发出一种新型等度高效液相色谱法，可用于分析大鼠脑匀浆中的3-MT，无需额外的纯化程序。此外，库仑电化学检测系统灵敏度足以检测3 pg的3-MT（相当于0.6 ng/g组织湿重）。断头并快速冷冻后，以3-甲氧基-4-羟基苄胺为内标，测定纹状体和伏隔核中的3-甲氧基酪胺。使用该方法研究了多巴胺能药物和其他药物对这种代谢产物的影响。在未用药的大鼠中，α-甲基对酪氨酸（200 mg/kg静脉注射）使多巴胺和3-MT呈平行线性下降，但对预先腹腔注射反苯环丙胺（5 mg/kg）的大鼠则无此作用。甲基苯丙胺（0.3 - 10 mg/kg腹腔注射）和苯丙胺（0.3 - 10 mg/kg腹腔注射）在未用药和预先用反苯环丙胺处理的大鼠中均剂量依赖性地增加3-MT。在未用药的动物中，腹腔注射多巴胺再摄取抑制剂安非他酮（10 mg/kg）、诺米芬辛（10 mg/kg）或西布曲明盐酸盐（3 mg/kg）、阿米替林（10 mg/kg）、地昔帕明（10 mg/kg）和齐美利定（10 mg/kg）不会改变3-MT。阿扑吗啡（5 mg/kg腹腔注射）以及大剂量的选择性D2拮抗剂BRL 34778（5 mg/kg腹腔注射）或左旋多巴（50 mg/kg腹腔注射）可使3-甲氧基酪胺减少。选择性D1拮抗剂SCH 23390（0.1或5 mg/kg腹腔注射）无作用。在预先用反苯环丙胺处理的大鼠中，阿扑吗啡（0.01 - 5 mg/kg腹腔注射）和BRL 34778（0.1 - 5 mg/kg腹腔注射）分别使3-MT剂量依赖性地降低和增加。药物SCH 23390（0.1 - 5 mg/kg腹腔注射）使3-MT的增加幅度小得多，这可能是通过纹状体黑质通路介导的。总体而言，数据表明，在抑制单胺氧化酶后测量3-MT是多巴胺释放和利用的有用指标。然而，在多巴胺大量且长期耗竭后，未用药动物中的3-MT水平是更好的指标。此外，未用药大鼠中3-MT的形成提供了一种区分多巴胺释放剂和再摄取抑制剂的灵敏方法。
