Kosten T A, Miserendino M J, Haile C N, DeCaprio J L, Jatlow P I, Nestler E J
Department of Psychiatry, Yale University School of Medicine, and Connecticut Mental Health Center, New Haven 06508, USA.
Brain Res. 1997 Dec 19;778(2):418-29. doi: 10.1016/s0006-8993(97)01205-5.
Lewis and Fischer inbred rat strains differ in behavioral and biochemical responses to psychoactive drugs: Lewis rats show greater behavioral responses to psychoactive drugs than Fischer rats and they fail to show biochemical adaptations in the mesolimbic dopamine system after chronic drug exposure, in contrast to Fischer and outbred rats. This suggests that Fischer and Lewis rats may differ in the initial, reinforcing effects of psychoactive drugs, but not in responses seen after the exposure that occurs with maintenance of drug-reinforced behavior. Thus, the present study tested whether these strains differ in acquisition or maintenance of intravenous cocaine self-administration. Acquisition of cocaine self-administration was examined in separate groups that were allowed 15 days to acquire the operant at one of three cocaine doses (0.25, 0.5, or 1.0 mg/kg/infusion). Compared to Fischer rats, Lewis rats acquired cocaine self-administration after fewer training trials and at lower doses. After maintenance, both strains showed characteristic extinction responding with saline substitution and dose-related responding to cocaine, although Fischer rats tended to show higher response rates. Finally, cocaine plasma levels, obtained after an intravenous cocaine infusion (1.0 mg/kg), showed no strain differences suggesting that the strain difference in acquisition was not due to cocaine pharmacokinetics. These strain differences in acquisition of cocaine self-administration may be related to reported strain differences in the mesolimbic dopamine system. Further, because acquisition of drug self-administration is an animal model of vulnerability to drug addiction, these inbred strains may be useful to study factors underlying such vulnerability.
与费希尔大鼠和远交系大鼠相比，刘易斯大鼠对精神活性药物表现出更强的行为反应，并且在长期药物暴露后，它们在中脑边缘多巴胺系统中未表现出生化适应性变化。这表明费希尔大鼠和刘易斯大鼠在精神活性药物的初始强化作用方面可能存在差异，但在药物强化行为维持过程中出现的暴露后反应方面没有差异。因此，本研究测试了这些品系在静脉注射可卡因自我给药的习得或维持方面是否存在差异。在单独的组中检查可卡因自我给药的习得情况，这些组被给予15天时间，以三种可卡因剂量（0.25、0.5或1.0毫克/千克/输注）之一习得操作性行为。与费希尔大鼠相比，刘易斯大鼠在较少的训练试验后且在较低剂量下就习得可卡因自我给药。维持后，两个品系在盐水替代时均表现出典型的消退反应，对可卡因表现出剂量相关反应，尽管费希尔大鼠往往表现出更高的反应率。最后，静脉注射可卡因（1.0毫克/千克）后获得的可卡因血浆水平未显示出品系差异，这表明习得方面的品系差异不是由于可卡因的药代动力学。可卡因自我给药习得方面的这些品系差异可能与中脑边缘多巴胺系统中已报道的品系差异有关。此外，由于药物自我给药的习得是药物成瘾易感性的动物模型，这些近交系可能有助于研究这种易感性背后的因素。
