Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, The Netherlands. .
Addict Biol. 2013 May;18(3):434-40. doi: 10.1111/j.1369-1600.2011.00351.x. Epub 2011 Jul 25.
Cocaine dependence is associated with orbitofrontal cortex (OFC)-dependent cognitive inflexibility in both humans and laboratory animals. A critical question is whether cocaine self-administration affects pre-existing individual differences in cognitive flexibility. Serotonin transporter knockout (5-HTT(-/-) ) mice show improved cognitive flexibility in a visual reversal learning task, whereas 5-HTT(-/-) rats self-administer increased amounts of cocaine. Here we assessed: (1) whether 5-HTT(-/-) rats also show improved cognitive flexibility (next to mice); and (2) whether this is affected by cocaine self-administration, which is increased in these animals. Results confirmed that naïve 5-HTT(-/-) rats (n = 8) exhibit improved cognitive flexibility, as measured in a sucrose reinforced reversal learning task. A separate group of rats was subsequently trained to intravenously self-administer cocaine (0.5 mg/kg/infusion), and we observed that the 5-HTT(-/-) rats (n = 10) self-administered twice as much cocaine [632.7 mg/kg (±26.3)] compared with 5-HTT(+/+) rats (n = 6) [352.3 mg/kg (±62.0)] over 50 1-hour sessions. Five weeks into withdrawal the cocaine-exposed animals were tested in the sucrose-reinforced reversal learning paradigm. Interestingly, like the naïve 5-HTT(-/-) rats, the cocaine exposed 5-HTT(-/-) rats displayed improved cognitive flexibility. In conclusion, we show that improved reversal learning in 5-HTT(-/-) rats reflects a pre-existing trait that is preserved during cocaine-withdrawal. As 5-HTT(-/-) rodents model the low activity s-allele of the human serotonin transporter-linked polymorphic region, these findings may have heuristic value in the treatment of s-allele cocaine addicts.
可卡因依赖与人类和实验室动物的眶额皮层（OFC）依赖认知灵活性有关。一个关键问题是可卡因自我给药是否会影响认知灵活性的预先存在的个体差异。5-羟色胺转运体敲除（5-HTT(-/-)）小鼠在视觉反转学习任务中表现出认知灵活性提高，而 5-HTT(-/-)大鼠自我给药可卡因的量增加。在这里，我们评估了：（1）5-HTT(-/-)大鼠是否也表现出认知灵活性提高（除了老鼠）；以及（2）这是否受到这些动物中增加的可卡因自我给药的影响。结果证实，未接受处理的 5-HTT(-/-)大鼠（n = 8）在蔗糖强化反转学习任务中表现出认知灵活性提高。随后，一组大鼠被训练进行静脉内自我给药可卡因（0.5 mg/kg/剂量），我们观察到 5-HTT(-/-)大鼠（n = 10）自我给药可卡因的量是 5-HTT(+/+)大鼠（n = 6）的两倍[632.7 mg/kg（±26.3）]，超过 50 个 1 小时的疗程。在戒断 5 周后，这些可卡因暴露的动物在蔗糖强化反转学习范式中进行测试。有趣的是，与未接受处理的 5-HTT(-/-)大鼠一样，暴露于可卡因的 5-HTT(-/-)大鼠也表现出认知灵活性提高。总之，我们表明 5-HTT(-/-)大鼠的反转学习改善反映了一种预先存在的特征，这种特征在可卡因戒断期间得以保留。由于 5-HTT(-/-)啮齿动物模型是人类 5-羟色胺转运体连接多态性区域的低活性 s-等位基因，这些发现可能对 s-等位基因可卡因成瘾者的治疗具有启发价值。
