Horita A, Carino M A, Ukai Y
Department of Pharmacology, University of Washington School of Medicine, Seattle.
J Pharmacol Exp Ther. 1994 Jan;268(1):311-8.
Methamphetamine (MAP) administered in doses of 0.5 to 5 mg/kg i.p. to rats anesthetized with pentobarbital produced a shortening of the duration of loss of righting reflex. This analeptic effect of MAP was blocked by atropine but not by atropine methylbromide, indicating the central cholinergic nature of the response. This effect was also blocked by the D1 and D2 dopamine antagonists SCH 23390 (0.2 mg/kg) and raclopride (2 mg/kg), respectively. Pentobarbital decreased sodium-dependent high-affinity choline uptake (HACU) in frontal cortex and hippocampus as measured in synaptosomes from treated rats. MAP given to pentobarbital-narcotized rats restored HACU activity to nonanesthetized levels, but this restorative effect of MAP was blocked by SCH 23390 or raclopride. These data suggest that in addition to a cholinergic mechanism, the analeptic effect of MAP involves the dopamine system. alpha-Methyl-p-tyrosine, but not reserpine, pretreatment completely blocked the MAP analeptic response. In reserpinzed rats, MAP produced a markedly enhanced analeptic response. Studies of the effects of repeated administration of MAP on its analeptic activity were also undertaken in view of the well known sensitization to the locomotor and stereotypic effects of the amphetamines that occur with repeated intermittent administration. Rats pretreated daily with MAP (5 mg/kg) for 5 or 12 days showed neither tolerance nor sensitization to the analeptic effect of subsequent MAP administrations. 3H-quinuclidinyl benzilate-binding studies also showed no changes in muscarinic binding characteristics of membranes prepared from cortex or hippocampus of rats pretreated chronically with MAP. These and our earlier studies suggest that the analeptic effect of MAP is mediated via a dopaminergic-cholinergic mechanism.
以0.5至5毫克/千克的剂量腹腔注射给用戊巴比妥麻醉的大鼠的甲基苯丙胺（MAP），会缩短翻正反射消失的持续时间。MAP的这种兴奋作用被阿托品阻断，但不被甲基溴化阿托品阻断，表明该反应具有中枢胆碱能性质。这种作用也分别被D1和D2多巴胺拮抗剂SCH 23390（0.2毫克/千克）和雷氯必利（2毫克/千克）阻断。戊巴比妥降低了额叶皮质和海马中钠依赖性高亲和力胆碱摄取（HACU），这是在处理过的大鼠的突触体中测量的。给予戊巴比妥麻醉的大鼠的MAP将HACU活性恢复到未麻醉水平，但MAP的这种恢复作用被SCH 23390或雷氯必利阻断。这些数据表明，除了胆碱能机制外，MAP的兴奋作用还涉及多巴胺系统。α-甲基-p-酪氨酸预处理而非利血平预处理完全阻断了MAP的兴奋反应。在利血平化的大鼠中，MAP产生了明显增强的兴奋反应。鉴于反复间歇性给药会对苯丙胺的运动和刻板效应产生众所周知的敏感性，还进行了重复给药MAP对其兴奋活性影响的研究。每天用MAP（5毫克/千克）预处理5天或12天的大鼠对随后MAP给药的兴奋作用既没有耐受性也没有敏感性。3H-喹核醇基苯甲酸酯结合研究还表明，长期用MAP预处理的大鼠的皮质或海马制备的膜的毒蕈碱结合特性没有变化。这些以及我们早期的研究表明，MAP的兴奋作用是通过多巴胺能-胆碱能机制介导的。
