A role for dopamine D2 receptors in reversal learning.
A role for dopamine D2 receptors in reversal learning.
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DOI：
10.1016/j.neuroscience.2009.04.052
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发表时间：
2009-08-04
期刊：
影响因子：
3.3
通讯作者：
Schmauss, C.
中科院分区：
文献类型：
--
作者：
Desteno, D. A.;Schmauss, C.
关键词：
逆向学习已被证明需要前脑新皮质有完整的血清素能神经支配。多巴胺通过D2受体在这一解剖区域是否起补充作用仍不清楚。在此我们表明，缺乏多巴胺D2受体的小鼠在注意力转换任务（ASST）的逆向学习阶段表现出明显受损，并且长期用D2样受体拮抗剂氟哌啶醇处理的野生型小鼠也表现出相同的认知缺陷。D2突变体和氟哌啶醇处理的小鼠在测试阶段特异性的缺陷还伴随着早期生长反应基因2（egr - 2）表达诱导的缺陷，早期生长反应基因2是一种调节性转录因子，先前已表明在接受ASST测试的小鼠的腹外侧眶额叶皮质以及前边缘和下边缘内侧前额叶皮质中被选择性诱导。然而，D2受体敲除小鼠和氟哌啶醇处理的野生型小鼠在完成需要逆向学习的ASST测试阶段后，在这些解剖区域表现出较低的egr - 2表达，但在完成无规则逆转的转换阶段后则没有。相比之下，长期用氯氮平（一种对D2受体亲和力较低且药理作用更广泛的非典型抗精神病药物）处理的小鼠在ASST的复合辨别阶段存在缺陷，而且这些缺陷也伴随着相同解剖亚区中egr - 2表达的降低。因此，这些发现表明egr - 2表达是ASST中测试阶段特异性表现的敏感指标，并且眶额叶和内侧前额叶皮质亚区中D2受体的正常功能是涉及规则逆转的测试中认知灵活性所必需的。
Reversal learning has been shown to require intact serotonergic innervation of the forebrain neocortex. Whether dopamine acting through D2 receptors plays a complementary role in this anatomic area is still unclear. Here we show that mice lacking dopamine D2 receptors exhibited significantly impaired performance in the reversal learning phase of an attention-set-shifting task (ASST) and that wild type mice treated chronically with the D2-like receptor antagonist haloperidol exhibited the same cognitive deficit. The test-phase-specific deficits of D2 mutants and haloperidol-treated mice were also accompanied by deficits in the induction of expression of early growth response gene 2 (egr-2), a regulatory transcription factor previously shown to be selectively induced in the ventrolateral orbital frontal cortex and the pre-and infralimbic medial prefrontal cortex of ASST-tested mice. D2-receptor knockout mice and haloperidol-treated wild type, however, exhibited lower egr-2 expression in these anatomic regions after completion of an ASST-test phase that required reversal learning but not after completion of set-shifting phases without rule reversals. In contrast, mice treated chronically with clozapine, an atypical neuroleptic drug with lower D2-receptor affinity and broader pharmacological effects, had deficits in compound discrimination phases of the ASST, but also these deficits were accompanied by lower egr-2 expression in the same anatomic subregions. Thus, the findings indicate that egr-2 expression is a sensitive indicator of test-phase-specific performance in the ASST and that normal function of D2 receptors in subregions of the orbital frontal and the medial prefrontal cortex is required for cognitive flexibility in tests involving rule reversals.
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