Seu Emanuele, Lang Andrew, Rivera Ronald J, Jentsch J David
Department of Psychology, University of California Los Angeles, P.O. Box 951563, Los Angeles, CA 90095-1563, USA.
Psychopharmacology (Berl). 2009 Jan;202(1-3):505-19. doi: 10.1007/s00213-008-1250-4. Epub 2008 Jul 7.
Poor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.
In the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.
Adult male Long-Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.
In accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.
Our results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.
注意力缺陷多动障碍儿童、对兴奋剂有依赖的人类以及这些疾病的动物模型中均有认知控制能力差（包括逆向学习缺陷）的报道；这些情况均与前额叶皮质内异常的儿茶酚胺能功能有关。
在当前研究中，我们试图探究通过药物抑制儿茶酚胺再摄取蛋白所产生的细胞外儿茶酚胺水平升高如何影响大鼠和猴子的行为灵活性。
分别对成年雄性Long-Evans大鼠和黑长尾猴进行四位置辨别任务或三选择视觉辨别任务训练。在全身给予多巴胺和/或去甲肾上腺素膜转运体的药物抑制剂后，让大鼠和猴子接受已习得辨别的保持或逆向训练。
与我们的先验假设一致，我们发现抑制去甲肾上腺素转运体的药物，如哌甲酯、托莫西汀和地昔帕明，可改善大鼠和猴子的逆向学习表现；这主要是由于持续性错误数量减少。有趣的是，多巴胺和去甲肾上腺素混合转运体抑制剂哌甲酯在大鼠和猴子的保持训练过程中反而损害了表现，而给予选择性多巴胺转运体抑制剂GBR-12909增加了过早反应，但未改变逆向学习表现。
我们的结果表明，对膜去甲肾上腺素而非膜多巴胺转运体进行药物抑制与行为灵活性增强有关。这些数据与早期报道相结合，可能表明去甲肾上腺素再摄取抑制继发的皮质区域细胞外儿茶酚胺水平升高可改善大鼠和猴子对反应的抑制控制的多个方面。
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