Katz J L, Kopajtic T A, Myers K A, Mitkus R J, Chider M
Psychobiology Section, National Institute of Drug Abuse, Intramural Research Program, Baltimore, Maryland.
J Pharmacol Exp Ther. 1999 Oct;291(1):265-79.
The present study compared interactions among dopamine D1-like agonists and partial agonists with cocaine on the locomotor stimulant effects of cocaine, as well as the discriminative-stimulus effects of cocaine, and effects of cocaine on rates of responding. Cocaine alone produced a dose-related stimulation of locomotor activity in Swiss-Webster mice and a dose-related increase in the proportion of responses on the cocaine-appropriate response key in squirrel monkeys (Saimiri sciureus) trained to discriminate cocaine (0.3 mg/kg i.m.) from saline. None of the D1 dopaminergic agents fully reproduced these effects, with SKF 77434 producing marginal stimulation of locomotor activity and SCH 23390, SCH 39166, and SKF 77434 producing some, although incomplete substitution for cocaine in monkeys discriminating cocaine. The D1 dopamine antagonists SCH 23390, SCH 39166, and A-69024 dose-dependently shifted the cocaine dose-effect curve for locomotor activity to the right and decreased the efficacy of cocaine. The same compounds shifted the discriminative-stimulus effects of cocaine to the right without altering efficacy of cocaine. In contrast to the effects on locomotor activity, the maximal shift to the right in the discriminative-stimulus effects of cocaine was approximately 3-fold, with higher doses of the antagonists producing no greater shifts in the cocaine dose-effect curve than with intermediate doses. The partial D1 agonists (+/-)-SKF 38393, (+)-SKF 38393, and SKF 77434 also dose-dependently shifted the dose-effect curve for locomotor stimulant effects to the right and decreased the maximal effect of cocaine. These compounds only shifted the discriminative-stimulus effects of cocaine to a 2-fold maximum. In general, cocaine effects on rates of responding in the subjects discriminating cocaine from saline were only minimally antagonized by coadministration of the D1 dopaminergic agents. Both potency for producing behavioral effects alone and in antagonizing the effects of cocaine were related to binding affinities assessed by displacement of [(3)H]SCH 23390 from rat striatum. These results suggest that actions mediated by D1-like receptors contribute to the behavioral effects of cocaine. However, the various limitations to the degree of antagonism accomplished indicate that D1-like dopaminergic actions appear to be more involved in the effects of cocaine on locomotor activity, relatively less involved in the discriminative-stimulus effects of cocaine, and least involved in the effects of cocaine on operant response rates. This differential involvement of D1 dopamine receptors in these various behavioral effects of cocaine suggests problems in predicting clinical efficacy of at least D1 receptor antagonists as potential treatments for cocaine abuse. Additional studies are necessary to determine whether the antagonism of cocaine can predict therapeutic efficacy at all, and, if so, which effects when antagonized are the best predictors.
本研究比较了多巴胺D1样激动剂和部分激动剂与可卡因在可卡因运动刺激作用、辨别刺激作用以及可卡因对反应率的影响方面的相互作用。单独使用可卡因可使瑞士-韦伯斯特小鼠的运动活动产生剂量相关的刺激，并使受过训练以区分可卡因（0.3毫克/千克，肌肉注射）和生理盐水的松鼠猴（松鼠猴属）在可卡因合适反应键上的反应比例产生剂量相关的增加。没有一种D1多巴胺能药物能完全重现这些效应，SKF 77434对运动活动产生轻微刺激，而SCH 23390、SCH 39166和SKF 77434在辨别可卡因的猴子中能产生一定程度的替代可卡因的作用，尽管并不完全。D1多巴胺拮抗剂SCH 23390、SCH 39166和A-69024剂量依赖性地将可卡因运动活动剂量效应曲线向右移动，并降低了可卡因的效力。相同的化合物将可卡因的辨别刺激效应向右移动，而不改变可卡因的效力。与对运动活动的影响相反，可卡因辨别刺激效应向右的最大移动约为3倍，较高剂量的拮抗剂在可卡因剂量效应曲线上产生的移动并不比中等剂量时更大。部分D1激动剂（±）-SKF 38393、（+）-SKF 38393和SKF 77434也剂量依赖性地将运动刺激效应的剂量效应曲线向右移动，并降低了可卡因的最大效应。这些化合物仅将可卡因的辨别刺激效应最大向右移动两倍。一般来说，在辨别可卡因和生理盐水的受试者中，可卡因对反应率的影响仅被D1多巴胺能药物的共同给药轻微拮抗。单独产生行为效应以及拮抗可卡因效应的效力均与通过从大鼠纹状体中置换[（3）H]SCH 23390评估的结合亲和力相关。这些结果表明，由D1样受体介导的作用有助于可卡因的行为效应。然而，拮抗程度的各种局限性表明，D1样多巴胺能作用似乎更多地参与可卡因对运动活动的影响，相对较少地参与可卡因的辨别刺激效应，而最少地参与可卡因对操作性反应率的影响。D1多巴胺受体在可卡因这些不同行为效应中的这种不同参与表明，预测至少D1受体拮抗剂作为可卡因滥用潜在治疗方法的临床疗效存在问题。需要进行更多研究来确定可卡因的拮抗作用是否根本能预测治疗效果，如果可以，拮抗哪些效应是最佳预测指标。
