Bergman J, Spealman R D, Madras B K, Rosenzweig-Lipson S
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts, USA.
J Pharmacol Exp Ther. 1996 Mar;276(3):942-50.
Dopamine agonists that reportedly differ in intrinsic activity at dopamine D1 receptors were compared for their behavioral effects in squirrel monkeys responding under a fixed-ration schedule of reinforcement. When administered alone, all drugs produced dose-related decreases in fixed-ratio response rates. Pretreatment with the dopamine D1 receptor blocker SCH 39166, but not the dopamine D2 receptor blocker eticlopride, produced rightward shifts in the dose-effect functions for the high-efficacy dopamine D1 agonists SKF 82958 (R,S-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine) SKF 81297 (R,S-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ) and dihydrexidine, indicative of surmountable antagonism at dopamine D1 receptors. Pretreatment with SCH 39166, however, did not antagonize the effects of the low-efficacy dopamine D1 agonists SKF 75670 (R,S-7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ), SKF 77434 (R,S-7,8-dihydroxy-3-allyl-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) or R-SKF 38393 (R-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine); instead, dose-effect functions for each of these drugs were shifted downward and to the left. In additional experiments, pretreatment with SKF 75670 produced overall rightward shifts in the dose-effect functions for dihydrexidine and SKF 81297; pretreatment with R-SKF 38393 produced an overall rightward shift in the dose-effect function for dihydrexidine, but not SKF 81297; and pretreatment with SKF 81297 failed to produce a rightward shift in the dose-effect function for dihydrexidine. These findings provide further evidence that the behavioral effects of dopamine D1 agonists in monkeys are mediated primarily by their actions at dopamine D1 receptors. The differing susceptibility of dopamine D1 agonists to antagonism by SCH 39166 and their differing interactions provide functional evidence for differences in their dopamine D1 agonist efficacy.
据报道，在多巴胺D1受体上内在活性不同的多巴胺激动剂，在松鼠猴按照固定比率强化程序做出反应时，对它们的行为效应进行了比较。单独给药时，所有药物都会使固定比率反应率出现剂量相关的下降。用多巴胺D1受体阻断剂SCH 39166预处理，但不用多巴胺D2受体阻断剂依替必利预处理，会使高效能多巴胺D1激动剂SKF 82958（R,S-6-氯-7,8-二羟基-3-烯丙基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓）、SKF 81297（R,S-6-氯-7,8-二羟基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓）和二氢麦角隐亭的剂量效应函数向右移动，这表明在多巴胺D1受体上存在可克服的拮抗作用。然而，用SCH 39166预处理并不能拮抗低效能多巴胺D1激动剂SKF 75670（R,S-7,8-二羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓）、SKF 77434（R,S-7,8-二羟基-3-烯丙基-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓）或R-SKF 38393（R-7,8-二羟基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓）的效应；相反，这些药物各自的剂量效应函数向下并向左移动。在另外的实验中，用SKF 75670预处理会使二氢麦角隐亭和SKF 81297的剂量效应函数整体向右移动；用R-SKF 38393预处理会使二氢麦角隐亭的剂量效应函数整体向右移动，但不会使SKF 81297的剂量效应函数向右移动；用SKF 81297预处理未能使二氢麦角隐亭的剂量效应函数向右移动。这些发现进一步证明，多巴胺D1激动剂在猴子身上的行为效应主要是由它们在多巴胺D1受体上的作用介导的。多巴胺D1激动剂对SCH 39166拮抗作用的不同敏感性以及它们不同的相互作用，为它们多巴胺D1激动剂效能的差异提供了功能证据。
