Shippenberg T S, Heidbreder C
Behavioral Pharmacology and Genetics Section, Addiction Research Center/NIDA, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1995 May;273(2):808-15.
An unbiased place preference conditioning procedure was used to determine whether the repeated administration of cocaine results in sensitization to its conditioned rewarding effects. Rats received noncontingent injections of saline or cocaine (10 mg/kg i.p.) for 5 days. Place preference conditioning commenced 72 hr later. A minimum of three drug conditioning sessions was necessary for the establishment of cocaine-induced conditioned place preferences (CPP) in saline-pretreated rats. The minimum dose producing this effect was 10.0 mg/kg. In contrast, pre-exposure to cocaine resulted in significant place preferences occurring after only two drug conditioning sessions. Furthermore, CPP was observed in response to doses as low as 5.0 mg/kg. This shift in the cocaine dose-response curve was apparent when conditioning commenced either 3 or 7, but not 14, days after the cessation of cocaine pretreatment. An increased sensitivity to cocaine was also observed in rats which received only two cocaine (25.0 mg/kg) injections before conditioning and in those which had received either d-amphetamine (0.5 mg/kg) or morphine (5.0 mg/kg) for 5 days. Repeated administration of the D1 dopamine (DA) receptor antagonist, SCH-23390 (0.01-0.05 mg/kg), or the D2 antagonist, raclopride (0.1-1.0 mg/kg), for 5 days did not modify cocaine-induced place conditioning. Administration of SCH-23390 (0.05 mg/kg) in combination with cocaine, however, prevented the sensitized response to cocaine. In contrast, raclopride did not influence the sensitized response to cocaine. These data demonstrate that sensitization occurs to the conditioned rewarding effects of cocaine and suggest an involvement of D1 DA receptors in the development of this phenomenon.
采用无偏性位置偏爱条件反射程序来确定可卡因的反复给药是否会导致对其条件性奖赏效应的敏感化。大鼠连续5天接受非条件性的生理盐水或可卡因（10毫克/千克，腹腔注射）注射。72小时后开始位置偏爱条件反射。对于生理盐水预处理的大鼠，建立可卡因诱导的条件性位置偏爱（CPP）至少需要三次药物条件反射实验。产生这种效应的最小剂量为10.0毫克/千克。相比之下，预先接触可卡因会导致仅在两次药物条件反射实验后就出现显著的位置偏爱。此外，在低至5.0毫克/千克的剂量下也观察到了CPP。当在停止可卡因预处理后3天或7天（而非14天）开始条件反射时，可卡因剂量-反应曲线的这种变化很明显。在条件反射前仅接受两次可卡因（25.0毫克/千克）注射的大鼠以及接受d-苯丙胺（0.5毫克/千克）或吗啡（5.0毫克/千克）5天的大鼠中，也观察到了对可卡因的敏感性增加。连续5天反复给予D1多巴胺（DA）受体拮抗剂SCH-23390（0.01 - 0.05毫克/千克）或D2拮抗剂雷氯必利（0.1 - 1.0毫克/千克），并不会改变可卡因诱导的位置条件反射。然而，将SCH-23390（0.05毫克/千克）与可卡因联合给药可防止对可卡因的敏感化反应。相比之下，雷氯必利并不影响对可卡因的敏感化反应。这些数据表明，对可卡因的条件性奖赏效应会发生敏感化，并提示D1 DA受体参与了这一现象的发展。
