Haile Colin N, Zhang Xiang Yang, Carroll F Ivy, Kosten Therese A
Department of Psychiatry, Division of Substance Abuse, Yale University School of Medicine, VA-CT Hospital System, 950 Campbell Avenue, Building 5; 3rd Floor, West Haven CT 06516, USA.
Brain Res. 2005 Sep 7;1055(1-2):186-95. doi: 10.1016/j.brainres.2005.07.012.
Lewis and Fischer 344 (F344) rats differ in responses to cocaine and characteristics of the mesolimbic dopamine system. Compared to F344 rats, Lewis rats have lower D2 receptor and dopamine transporter (DAT) levels in nucleus accumbens (NAc). We showed previously that altering D1 and D2 receptor levels pharmacologically had strain-dependent effects on cocaine self-administration. This study tests whether the phenyltropane analog, 3beta-(4-Chlorophenyl) tropane-2beta-[3-(4'-methylphenyl) isoxazol-5-yl] Hydrochloride (RTI 336), a potent and selective DAT inhibitor, differentially alters reinforcing, discriminative, and locomotor effects of cocaine in these strains. The effects of RTI 336 pretreatment on cocaine self-administration were assessed under a fixed-ratio (FR) schedule of reinforcement. Its effects on cocaine discrimination were conducted using a two-lever food-reinforced task. Finally, the effects of RTI 336 pretreatment on cocaine-induced locomotor activity were examined. RTI 336 increased cocaine self-administration in F344 rats, while Lewis rats showed reduced intake under the FR schedule. RTI 336 reduced cocaine-induced locomotor activity in Lewis rats but not in F344 rats. RTI 336 did not substitute for or antagonize cocaine's discriminative stimulus effects in either strain. Results show that a DAT inhibitor alters cocaine-induced behaviors in a strain-dependent manner. These effects may relate to inherent differences in NAc DAT levels between Lewis and F344 rats.
刘易斯大鼠和费希尔344（F344）大鼠对可卡因的反应以及中脑边缘多巴胺系统的特征存在差异。与F344大鼠相比，刘易斯大鼠伏隔核（NAc）中的D2受体和多巴胺转运体（DAT）水平较低。我们之前表明，通过药理学方法改变D1和D2受体水平对可卡因自我给药具有品系依赖性效应。本研究测试了苯基托烷类似物3β-(4-氯苯基)托烷-2β-[3-(4'-甲基苯基)异恶唑-5-基]盐酸盐（RTI 336），一种强效且选择性的DAT抑制剂，是否会在这些品系中对可卡因的强化、辨别和运动效应产生不同影响。在固定比率（FR）强化程序下评估了RTI 336预处理对可卡因自我给药的影响。使用双杠杆食物强化任务研究了其对可卡因辨别能力的影响。最后，检测了RTI 336预处理对可卡因诱导的运动活动的影响。RTI 336增加了F344大鼠的可卡因自我给药量，而刘易斯大鼠在FR程序下的摄入量减少。RTI 336降低了刘易斯大鼠中可卡因诱导的运动活动，但对F344大鼠没有影响。RTI 336在两种品系中均不能替代或拮抗可卡因的辨别刺激效应。结果表明，DAT抑制剂以品系依赖性方式改变可卡因诱导的行为。这些效应可能与刘易斯大鼠和F344大鼠伏隔核DAT水平的固有差异有关。
