Weissenborn R, Deroche V, Koob G F, Weiss F
Department of neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA.
Psychopharmacology (Berl). 1996 Aug;126(4):311-22. doi: 10.1007/BF02247382.
The present study examined the effects of receptor subtype-selective dopamine agonists and antagonists on (i) cocaine-induced responding for a cocaine-associated stimulus and (ii) on responding for food and cocaine reinforcement. Rats implanted with intravenous catheters were trained to lever-press for food or cocaine reinforcers on an FR5-FR5 multiple schedule, which was preceded by a 5-min component during which only stimuli previously associated with the primary reinforcers were available response-contingently. (i) Non-contingent delivery of cocaine at the beginning of the stimulus component significantly increased responding for the cocaine-associated stimulus, compared to responding for the food-associated cue. Changes in the dose of cocaine administered non-contingently before the stimulus component resulted in an inverted U-shaped dose-effect curve in responding for the cocaine-associated cue. In subsequent experiments, pretreatment with the dopamine D2 receptor agonist bromocriptine (4.0-16.0 mg/kg IP) attenuated the cocaine-induced increase in responding for the cocaine-associated cue. In contrast, pretreatment with low doses of SDZ 208-911, a dopamine D2 partial agonist (0.025-0.1 mg/kg SC), further potentiated the cocaine-induced response. Pretreatment with low and medium doses of the dopamine D1 and D2 receptor subtype-selective antagonists SCH 23390 (D1; 5-10 micrograms/kg SC) and raclopride (D2; 100-200 micrograms/kg SC) blocked responding for cocaine-associated cues, with SCH 23390 acting more selectively than raclopride. At higher doses (SCH 23390: 20 micrograms/kg SC; raclopride: 400 micrograms/kg SC), both drugs produced non-selective effects by inhibiting responses for the food-associated cue. (ii) Varying the dose of cocaine self-administered during the multiple schedule resulted in an inverted U-shaped dose-effect curve during the cocaine components, while the number of food pellets earned remained unchanged. Pretreatment with bromocriptine selectively reduced the number of cocaine infusions obtained. The compensatory increases in responding for cocaine typically associated with SCH 23390, raclopride or SDZ 208-911 pretreatment were also observed under the present schedule conditions, although the effect did not reach statistical significance in the case of SCH 23390 and raclopride, possibly due to methodological constraints. The results indicate that the present rat model of cocaine-seeking behavior is sensitive to pharmacological manipulations and may yield important information regarding the neurobiological mechanisms underlying conditioned and unconditioned reinforcing aspects of cocaine addiction.
（i）可卡因诱发的对与可卡因相关刺激的反应，以及（ii）对食物和可卡因强化物的反应。给植入静脉导管的大鼠在FR5-FR5多重强化程序下训练，使其按压杠杆以获取食物或可卡因强化物，在该程序之前有一个5分钟的成分期，在此期间只有先前与主要强化物相关的刺激可根据反应情况获得。（i）在刺激成分期开始时非条件性给予可卡因，与对食物相关线索的反应相比，显著增加了对可卡因相关刺激的反应。在刺激成分期之前非条件性给予的可卡因剂量变化导致对可卡因相关线索的反应呈倒U形剂量效应曲线。在随后的实验中，用多巴胺D2受体激动剂溴隐亭（4.0 - 16.0 mg/kg腹腔注射）预处理减弱了可卡因诱发的对可卡因相关线索反应的增加。相反，用低剂量的多巴胺D2部分激动剂SDZ 208 - 911（0.025 - 0.1 mg/kg皮下注射）预处理进一步增强了可卡因诱发的反应。用低剂量和中等剂量的多巴胺D1和D2受体亚型选择性拮抗剂SCH 23390（D1；5 - 10微克/千克皮下注射）和雷氯必利（D2；100 - 200微克/千克皮下注射）预处理阻断了对可卡因相关线索的反应，其中SCH 23390的作用比雷氯必利更具选择性。在较高剂量下（SCH 23390：20微克/千克皮下注射；雷氯必利：400微克/千克皮下注射），两种药物通过抑制对食物相关线索的反应产生非选择性作用。（ii）在多重强化程序中改变自我给药的可卡因剂量，在可卡因成分期产生了倒U形剂量效应曲线，而获得的食物颗粒数量保持不变。用溴隐亭预处理选择性地减少了获得的可卡因注射次数。在当前强化程序条件下，也观察到了通常与SCH 23390、雷氯必利或SDZ 208 - 911预处理相关的对可卡因反应的代偿性增加，尽管在SCH 23390和雷氯必利的情况下该效应未达到统计学显著意义，可能是由于方法学限制。结果表明，当前的可卡因寻求行为大鼠模型对药物操作敏感，可能会产生有关可卡因成瘾的条件性和非条件性强化方面潜在神经生物学机制的重要信息。
