Department of Psychology and Neuroscience, Genome Sciences Research Building II - 3rd Floor, 572 Research Drive - Box 91050, Duke University, Durham, NC 27708, USA.
Neuropharmacology. 2012 Mar;62(3):1221-9. doi: 10.1016/j.neuropharm.2011.01.042. Epub 2011 Feb 4.
The dopamine transporter (DAT) is the major regulator of the spatial and temporal resolution of dopaminergic neurotransmission in the brain. Hyperdopaminergic mice with DAT gene deletions were evaluated for their ability to perform duration discriminations in the seconds-to-minutes range. DAT -/- mice were unable to demonstrate temporal control of behavior in either fixed-interval or peak-interval timing procedures, whereas DAT +/- mice were similar to DAT +/+ mice under normal conditions. Low to moderate-dose methamphetamine (MAP) challenges indicated that DAT +/- mice were less sensitive to the clock-speed enhancing effects of MAP compared with DAT +/+ mice. In contrast, DAT +/- mice were more vulnerable than DAT +/+ mice to the disruptive effects of MAP at high doses as revealed by the elevation of response rate in the right hand tail of the Gaussian-shaped timing functions. Moreover, this treatment made DAT +/- mice functionally equivalent to DAT -/- mice in terms of the loss of temporal control. Taken together, these results demonstrate the importance of dopaminergic control of interval timing in cortico-striatal circuits and the potential link of timing dysfunctions to schizophrenia and drug abuse.
多巴胺转运体（DAT）是大脑中多巴胺能神经传递的空间和时间分辨率的主要调节者。具有 DAT 基因缺失的高多巴胺能小鼠被评估其在秒到分钟范围内进行持续时间区分的能力。DAT -/- 小鼠在固定间隔或峰值间隔定时程序中均无法表现出行为的时间控制，而 DAT +/- 小鼠在正常条件下与 DAT +/+ 小鼠相似。低至中等剂量的甲基苯丙胺（MAP）挑战表明，与 DAT +/+ 小鼠相比，DAT +/- 小鼠对 MAP 增强时钟速度的作用的敏感性较低。相比之下，DAT +/- 小鼠比 DAT +/+ 小鼠更容易受到 MAP 的高剂量的破坏作用的影响，这反映在高斯形状定时函数的右手尾部的反应率升高。此外，这种治疗使 DAT +/- 小鼠在时间控制丧失方面与 DAT -/- 小鼠具有功能等效性。总之，这些结果表明皮质纹状体回路中多巴胺能控制对间隔计时的重要性，以及计时功能障碍与精神分裂症和药物滥用的潜在联系。
