Dopamine transporters govern diurnal variation in extracellular dopamine tone
Dopamine transporters govern diurnal variation in extracellular dopamine tone
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DOI：
10.1073/pnas.1407935111
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发表时间：
2014-07-01
影响因子：
11.1
通讯作者：
Jones, Sara R.
中科院分区：
文献类型：
--
作者：
Ferris, Mark J.;Espana, Rodrigo A.;Jones, Sara R.
大多数神经递质系统显示出状态依赖性细胞放电率的变化，这些变化与其各自神经递质的细胞外水平或音调的变化机械地相关。纹状体内多巴胺浓度的昼夜变化也已得到证实，但这种神经递质是独特的，因为多巴胺浓度的变化可能与多巴胺细胞放电无关;这主要是因为观察到中脑多巴胺神经元的放电率不显示昼夜波动。因此，我们对细胞外多巴胺张力变化的可能机制进行了系统研究。使用微透析和快速扫描循环伏安法在大鼠，以及野生型和多巴胺转运蛋白（DAT）基因敲除小鼠，我们表明，多巴胺摄取通过DAT和亚秒多巴胺释放的幅度是负相关的细胞外多巴胺的大小。我们研究了多巴胺的代谢，摄取，释放，D2自身受体的敏感性，酪氨酸羟化酶的表达和活性作为这种变化的机制。使用这种方法，我们已经确定了DAT作为细胞外多巴胺张力昼夜变化的关键总督，因此，影响电刺激多巴胺释放的幅度。了解多巴胺张力的昼夜变化对于理解和治疗源于多巴胺系统扰动的多种精神疾病至关重要。
The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system.