Witkin J M, Newman A H, Nowak G, Katz J L
Drug Development Group, National Institute on Drug Abuse, Baltimore, Maryland.
J Pharmacol Exp Ther. 1993 Oct;267(1):266-74.
Acute cocaine overdose can result in convulsions and death although the mechanisms associated with this toxicity are poorly understood. The role of D1 receptors in the central and peripheral actions in cocaine were investigated by comparisons of cocaine with the stable charged cocaine analog, cocaine methiodide. Both cocaine and cocaine methiodide produced dose-related increases in lethality in male, Swiss Webster mice, with cocaine methiodide being slightly more potent than cocaine; however, only cocaine produced convulsions. Several dopamine D1 antagonists ([R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine] (SCH 23390), [(-)-trans-6,7,7a,8, 9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho++ +-(2-1-b)azepin e (SCH 39166), 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline HBr (A-69024), [R-(+)-7-bromo-8-hydroxy-3- methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] (SK F83566)) produced dose-dependent protection against the lethal effects of both compounds. Protection against cocaine methiodide-induced lethality was conferred by lower doses of the D1 antagonists than those effective against cocaine. Stereoselectivity of this effect was demonstrated by the lack of activity of the inactive enantiomer of SCH 23390. The D2 antagonist haloperidol was ineffective against either cocaine- or cocaine methiodide-induced lethality. Lethal effects of the nondopaminergic local anesthetic, lidocaine, were not influenced by prior treatment with D1 antagonists. Lethal effects of cocaine were enhanced by both centrally and peripherally acting D1 agonists but not by the D2 agonist quinpirole. Cocaine methiodide-induced lethality was also enhanced by the peripherally active DA1 agonist, fenoldopam.(ABSTRACT TRUNCATED AT 250 WORDS)
急性可卡因过量可导致惊厥和死亡，尽管与这种毒性相关的机制尚不清楚。通过将可卡因与稳定的带电荷可卡因类似物甲碘可卡因进行比较，研究了D1受体在可卡因的中枢和外周作用中的作用。可卡因和甲碘可卡因在雄性瑞士韦伯斯特小鼠中均产生剂量相关的致死率增加，甲碘可卡因的效力略高于可卡因；然而，只有可卡因会引起惊厥。几种多巴胺D1拮抗剂（[R-(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓]（SCH 23390）、[(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5H-苯并[d]萘并[2,1-b]氮杂卓]（SCH 39166）、1-(2-溴-4,5-二甲氧基苄基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉HBr（A-69024）、[R-(+)-7-溴-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓]（SK F83566））产生剂量依赖性的对两种化合物致死作用的保护。与有效对抗可卡因的剂量相比，较低剂量的D1拮抗剂就能对甲碘可卡因诱导的致死率产生保护作用。SCH 23390的无活性对映体缺乏活性，证明了这种效应的立体选择性。D2拮抗剂氟哌啶醇对可卡因或甲碘可卡因诱导的致死率均无效。非多巴胺能局部麻醉药利多卡因的致死作用不受D1拮抗剂预处理的影响。中枢和外周作用的D1激动剂均可增强可卡因的致死作用，但D2激动剂喹吡罗则无此作用。外周活性DA1激动剂非诺多泮也可增强甲碘可卡因诱导的致死率。（摘要截短于250字）
