Effects of dopamine D1-like and D2-like agonists on cocaine self-administration in rhesus monkeys:: rapid assessment of cocaine dose-effect functions
Effects of dopamine D1-like and D2-like agonists on cocaine self-administration in rhesus monkeys:: rapid assessment of cocaine dose-effect functions
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DOI：
10.1007/s002130050023
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发表时间：
2000-01-01
影响因子：
3.4
通讯作者：
Mello, NK
中科院分区：
文献类型：
--
作者：
Caine, SB;Negus, SS;Mello, NK
原理：可卡因的强化作用与它作为一种间接多巴胺激动剂的作用密切相关，这一点极具说服力。尽管人们普遍认为D1样和D2样受体机制可能都参与其中，但近期研究表明，D1样和D2样激动剂在与可卡因相关的作用方面具有不同的特性。
目的：建立一种快速评估恒河猴可卡因自身给药完整剂量 - 效应函数的方法，并使用该方法比较D1样和D2样激动剂对可卡因自身给药的影响。
方法：在2小时的实验时段内，采用多成分实验程序[固定比率（FR）30；暂停时间（TO）10秒]，通过不同剂量的可卡因或食物维持反应。在反应稳定后，评估D1样和D2样激动剂预处理（在实验前10分钟或30分钟肌肉注射）的效果。
结果：通过快速评估程序训练的所有5只恒河猴都获得了可卡因自身给药完整的倒U型剂量 - 效应函数。在重复评估中，可卡因剂量 - 效应函数的位置和形状保持稳定，反应水平由可卡因的单位剂量而非用于改变可卡因剂量的其他变量（如输注持续时间和体积）控制。D1样激动剂SKF 82958（0.32 - 1.8 mg/kg）和R - 6 - Br - APB（0.1 - 1.0 mg/kg）预处理在显著降低食物维持反应的剂量下，使可卡因剂量 - 效应函数向下移动。相比之下，D2样激动剂喹吡罗（0.001 - 0.01 mg/kg）和7 - OH - DPAT（0.01 - 0.10 mg/kg）使可卡因剂量 - 效应函数向左移动。D2样激动剂还增加了仅由与可卡因相关的提示灯维持的反应，并适度降低了食物维持的反应。
结论：结果表明，D1样和D2样激动剂对可卡因自身给药产生质的不同影响，这可能影响它们在治疗可卡因滥用和依赖方面的有效性。
Rationale: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D1-like and D2-like receptor mechanisms may be involved, recent studies suggest that D1-like and D2-like agonists have differing profiles of cocaine-related actions. Objective: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D1-like and D2-like agonists on cocaine self-administration using this procedure. Methods: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D1-like and D2-like agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. Results: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose-effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D1-like agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1.0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D2-like agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D2-like agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. Conclusions: The results suggest that D1-like and D2-like agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.