Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice.
Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice.
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DOI：
10.1523/eneuro.0229-17.2018
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发表时间：
2018-01
期刊：
影响因子：
3.4
通讯作者：
Jentsch JD
中科院分区：
文献类型：
--
作者：
Linden J;James AS;McDaniel C;Jentsch JD
动物模型和人类受试者的神经影像学研究均显示，相对较低的纹状体多巴胺D2样受体结合电位与冲动控制不良和成瘾相关行为的脆弱性相关。然而，这些研究不能消除纹状体中发现的各种D2受体池的作用（例如，那些在中等多刺的纹状体-苍白球神经元上相对于在多巴胺释放神经末梢上表达的）。为了阐明后一个库，即D2自身受体的作用，我们研究了携带条件性DRD 2基因的小鼠，其具有或不具有在多巴胺转运蛋白基因座的转录控制下表达的Cre重组酶（autoDrd 2-KO，n = 19和对照，n = 21）。测试这些小鼠对可卡因的运动反应，并在操作性条件反射室中评估空间反转学习。正如所预测的，与对照小鼠相比，autoDrd 2-KO动物表现出对可卡因（10 mg/kg，i. p.）的运动刺激作用的高度敏感性，证实了之前使用类似遗传模型的研究。在空间逆转学习任务中，autoDrd 2-KO小鼠达到学习标准的速度较慢，并且难以维持长时间的鼻戳反应，测量结果在概念上与受损的反应抑制相关。学习率的初步歧视和lavelets收集奖励，启动试验，并产生反应的D2自身受体的基因缺失，丢弃可能的电机和动机因素的影响。总之，这些发现证实了D2自身受体在逆转学习中的作用，并表明更广泛地参与行为抑制机制。
Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2-KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms.