The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania.
The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania.
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DOI：
10.1016/j.neuropharm.2016.07.030
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发表时间：
2017-02
影响因子：
4.7
通讯作者：
Young JW
中科院分区：
文献类型：
--
作者：
Milienne-Petiot M;Kesby JP;Graves M;van Enkhuizen J;Semenova S;Minassian A;Markou A;Geyer MA;Young JW
双相情感障碍（BD）躁狂患者表现出认知能力差和寻求奖励/过度动机，对患者的生活质量产生负面影响。目前的治疗方法（例如，锂），不要治疗这种缺陷。由于对这些行为背后的神经机制缺乏了解，治疗方法的发展受到限制。在这里，我们调查了假定的认知和奖励寻求/动机的变化相关的BD躁狂症患者使用两个验证的小鼠模型和神经化学分析的机制。在水或长期锂处理期间，在概率逆转学习任务（PRLT）和渐进比率断点（PRB）测试中评估了通过遗传（敲低vs.野生型同窝小鼠）或药理学（GBR 12909 vs.溶剂处理的C57 BL/6 J小鼠）平均值降低多巴胺转运蛋白（DAT）功能的影响。这些任务分别量化了奖励学习和努力动机。使用高效液相色谱法对DAT突变体±慢性锂的脑样品进行神经化学。减少DAT功能增加逆转的PRLT，效果部分衰减慢性锂。慢性锂单独减缓PRLT收购。减少DAT功能增加动机（PRB），锂在GBR 12909治疗的小鼠中减弱的作用。神经化学分析显示，DAT敲除小鼠表现出高香草酸水平升高，但锂对这些升高的水平没有影响。减少DAT功能重现BD躁狂症的许多方面，包括过度动机和改善的逆转学习（转换），以及高香草酸水平升高。慢性锂只发挥主要作用，损害学习和提高小鼠的去甲肾上腺素和血清素水平，而不是专门治疗这些模型中确定的潜在机制。
Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient’s quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses. The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography. Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels. Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.
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