Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction
Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction
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DOI：
10.1038/s41386-020-00879-2
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发表时间：
2020-10-08
影响因子：
7.6
通讯作者：
Espana, R. A.
中科院分区：
文献类型：
--
作者：
Alonso, I. P.;Pino, J. A.;Espana, R. A.
多巴胺转运蛋白（DAT）与多种与觉醒相关的过程有关，包括运动活动、学习、动机行为、精神兴奋剂滥用以及最近的睡眠/觉醒状态的调节。我们之前证明，DAT 的摄取调节纹状体中细胞外多巴胺 (DA) 的波动，在整个光/暗周期中，DA 水平在暗阶段最高，在亮阶段最低。尽管有这些证据，但光/暗周期中 DA 摄取的波动是否与睡眠/觉醒的变化相关尚未得到测试。为了解决这个问题，我们结合使用睡眠/觉醒记录、快速扫描循环伏安法和蛋白质印迹法来检查睡眠/觉醒状态和/或亮/暗相是否影响雄性大鼠的 DA 末端神经传递。此外，我们评估了质膜 DAT 水平的变化和/或 DAT 上苏氨酸 53 位点的磷酸化是否会导致 DA 神经传递的波动。鉴于大量证据表明精神兴奋剂通过与 DAT 相互作用来增加 DA，我们还研究了可卡因抑制 DAT 的效果在睡眠/清醒状态下的变化程度。结果表明，个体睡眠/清醒状态与 DA 末端神经传递之间存在显着关联，睡眠后观察到 DA 摄取率较高、DAT 磷酸化增加以及可卡因效力增强。这些发现表明，睡眠/清醒状态影响 DA 神经传递的方式可能会影响许多 DA 依赖性过程，包括各种神经精神疾病。
The dopamine transporter (DAT) has been implicated in a variety of arousal-related processes including the regulation of motor activity, learning, motivated behavior, psychostimulant abuse, and, more recently, sleep/wake state. We previously demonstrated that DAT uptake regulates fluctuations in extracellular dopamine (DA) in the striatum across the light/dark cycle with DA levels at their highest during the dark phase and lowest during the light phase. Despite this evidence, whether fluctuations in DA uptake across the light/dark cycle are associated with changes in sleep/wake has not been tested. To address this, we employed a combination of sleep/wake recordings, fast scan cyclic voltammetry, and western blotting to examine whether sleep/wake state and/or light/dark phase impact DA terminal neurotransmission in male rats. Further, we assessed whether variations in plasma membrane DAT levels and/or phosphorylation of the threonine 53 site on the DAT accounts for fluctuations in DA neurotransmission. Given the extensive evidence indicating that psychostimulants increase DA through interactions with the DAT, we also examined to what degree the effects of cocaine at inhibiting the DAT vary across sleep/wake state. Results demonstrated a significant association between individual sleep/wake states and DA terminal neurotransmission, with higher DA uptake rate, increased phosphorylation of the DAT, and enhanced cocaine potency observed after periods of sleep. These findings suggest that sleep/wake state influences DA neurotransmission in a manner that is likely to impact a host of DA-dependent processes including a variety of neuropsychiatric disorders.