Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists
Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists
复制标题
DOI：
10.1007/s002130100872
复制
发表时间：
2001-11-01
影响因子：
3.4
通讯作者：
Terry, P
中科院分区：
文献类型：
--
作者：
Costanza, RM;Barber, DJ;Terry, P
基本原理：不同多巴胺受体亚型对可卡因辨别性刺激效应的相对贡献可能受到可卡因训练剂量的影响。多巴胺受体激动剂的替代试验表明，与10 mg/kg的训练剂量相比，3 mg/kg可卡因的训练剂量下多巴胺D2样受体的作用相对于D1样受体的作用减弱。目的：为了测试多巴胺D2样受体拮抗剂是否在不同训练剂量下对减弱可卡因的辨别性刺激效应具有差异有效性，并首次测试对D2样受体亚家族内的多巴胺D2受体具有选择性的拮抗剂。研究方法：训练大鼠在接受可卡因后按压一个杠杆，在接受盐水后按压另一个杠杆（保持>95%的药物适当反应）。在以3 mg/kg或10 mg/kg可卡因训练的大鼠中测试了三种多巴胺D2样受体拮抗剂（氟哌啶醇、雷氯必利和L-741，626）。在较低的训练剂量下，还检测了D1样受体拮抗剂SCH 39166。结果如下：拮抗剂在训练组之间的效果没有差异：它们都在可卡因的剂量效应函数中产生了平行的，快速的变化。表示可以克服的对抗。结论：结果表明，具有不同亲和力的各种D2样受体的D2样受体拮抗剂可以拮抗可卡因在两个训练剂量的辨别刺激效应。重要的是，L-741，626的拮抗作用意味着单独刺激D2受体（而不是D3或D4受体）足以介导可卡因的区别性刺激效应。最后，声称D1样受体优先参与低训练剂量的可卡因是唯一符合目前的研究结果，如果间接刺激D2受体的低剂量的可卡因仍然是必要的D1样受体介导的效果的表达。
Rationale: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. Objectives: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. Methods: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. Results: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function. indicating surmountable antagonism. Conclusions: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.