Sinnott R S, Mach R H, Nader M A
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
Drug Alcohol Depend. 1999 Apr 1;54(2):97-110. doi: 10.1016/s0376-8716(98)00162-8.
Numerous studies have suggested that dopamine (DA) D2 and D3 receptors are involved in the behavioral effects of cocaine. The present experiments evaluated the reinforcing and cocaine-like discriminative stimulus effects of several D2/D3 agonists in rhesus monkeys. In the first experiment, animals (n = 4) were trained to self-administer 0.03 mg/kg/inj cocaine under a fixed-interval (FI) 5-min schedule. When substituted for cocaine, the D2/D3 agonist quinpirole (0.003-0.03 mg/kg/inj) functioned as a reinforcer in all monkeys. In two cocaine-naive monkeys trained to respond under an FI 3-min schedule of food presentation, quinpirole maintained low rates of responding in one subject, while at the highest dose (0.03 mg/kg/inj) it functioned as a reinforcer in the second monkey. In this animal, increased activity was observed at this dose, which may have contributed to the overall rate of responding. In the second experiment, monkeys (n = 4) were trained to discriminate cocaine from saline using a two-lever, food-reinforced, drug discrimination procedure. The D2/D3 agonists quinpirole, (+/-)-7-OH-DPAT, and R-( + )-7-OH-DPAT fully substituted for cocaine. However, the time-course of substitution differed between quinpirole, which substituted for cocaine 10 min after administration, and (+/-)- and R-(+)-7-OH-DPAT, which required 60-min pretreatments. The behavioral potencies, as determined from ED50, values, correlated with previously reported in vitro binding affinity and functional activity at the D3 receptor [R-(+ )-7-OH-DPAT > (+/-)-7-OH-DPAT > quinpirole]. These results further indicate that direct-acting D2/D3 agonists can function as reinforcers and produce cocaine-like discriminative stimulus effects, and support the idea that D3 receptors should continue to be a valuable target for future behavioral studies evaluating cocaine's mechanisms of action.
众多研究表明，多巴胺（DA）D2和D3受体参与了可卡因的行为效应。本实验评估了几种D2/D3激动剂对恒河猴的强化作用及可卡因样辨别刺激效应。在第一个实验中，动物（n = 4）接受训练，在固定间隔（FI）5分钟的时间表下自我注射0.03毫克/千克/注射剂量的可卡因。当用D2/D3激动剂喹吡罗（0.003 - 0.03毫克/千克/注射）替代可卡因时，在所有猴子中它都起到了强化物的作用。在两只未接触过可卡因且接受训练在FI 3分钟食物呈现时间表下做出反应的猴子中，喹吡罗在一只猴子中维持了较低的反应率，而在最高剂量（0.03毫克/千克/注射）时，它在第二只猴子中起到了强化物的作用。在这只动物中，在该剂量下观察到活动增加，这可能对总体反应率有贡献。在第二个实验中，猴子（n = 4）接受训练，使用双杠杆、食物强化的药物辨别程序来区分可卡因和生理盐水。D2/D3激动剂喹吡罗、（±）-7-羟基-DPAT和R-（+）-7-羟基-DPAT完全替代了可卡因。然而，喹吡罗在给药后10分钟替代可卡因，而（±）-和R-（+）-7-羟基-DPAT需要60分钟预处理，它们的替代时间进程有所不同。从ED50值确定的行为效力与先前报道的D3受体体外结合亲和力和功能活性相关[R-（+）-7-羟基-DPAT > （±）-7-羟基-DPAT > 喹吡罗]。这些结果进一步表明，直接作用的D2/D3激动剂可以起到强化物的作用，并产生可卡因样辨别刺激效应，支持了D3受体应继续作为未来评估可卡因作用机制的行为研究的重要靶点这一观点。
