控制着神经递质多巴胺活性的多巴胺转运蛋白(DAT)在诸如吃饭、行动和奖赏等人类的动机行为中具有关键的作用。多巴胺转运蛋白若发生故障则可能导致人体出现问题，患上帕金森综合症、毒瘾、注意力不足多动症（ADHD）、精神分裂症和抑郁症等疾病。例如，之前的研究曾经发现，注意力不足多动症患者的多巴胺转运蛋白水平比普通人大约高70%。
Ali Salahpour所在的研究组深入研究了多巴胺转运蛋白水平对人体对安非他命反应的影响。安非他命是一组同多巴胺敏感性紧密相关的成瘾型化学成分，被允许用于治疗注意力不足多动症和嗜睡症及用来抑制食量过大。但同时，安非他命也是广为人知的非法的“俱乐部”毒品和兴奋剂。为了深入了解高水平多巴胺转运蛋白的后果，研究人员培育了具有比一般小鼠高三倍的多巴胺转运蛋白水平的转基因小鼠。他们发现，在高水平多巴胺转运蛋白小鼠的身上，安非他命的效力更强大。研究人员表示，多巴胺加强型动物对安非他命的作用更为敏感，变得极度亢奋，药物的奖赏作用也表现得更强烈。
相关论文3月17日在线发表于美国《国家科学院院刊》（PNAS）上。（来源：EurekAlert!中文版）
生物谷推荐原始出处：
（PNAS），doi：10.1073/pnas.0707646105，Ali Salahpour，Marc G. Caron
Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter
Ali Salahpour*, Amy J. Ramsey*, Ivan O. Medvedev*, Brian Kile, Tatyana D. Sotnikova*, Ericka Holmstrand, Valentina Ghisi*, Peter J. Nicholls*, Ling Wong, Karen Murphy*, Susan R. Sesack, R. Mark Wightman, Raul R. Gainetdinov*, and Marc G. Caron*,
*Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Chemistry and Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599-3290; and Departments of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260
Edited by Susan G. Amara, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved January 22, 2008 (received for review August 13, 2007)
Abstract
The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic signaling wherein it controls both the spatial and temporal actions of dopamine. Here we evaluated the behavioral and neurochemical consequences of increased DAT function by generating DAT transgenic mice (DAT-tg) that overexpress the transporter. These mice were generated by pronuclear injection of a bacterial artificial chromosome containing the mouse DAT locus, yielding an anatomical expression pattern of DAT-tg identical to WT. In DAT-tg mice there is a 3-fold increase in the levels of total and membrane-expressed DAT, but synaptic plasma membrane fractions of DAT-tg mice show only a 30% increase in transporter levels. Functional studies reveal that in the DAT-tg animals there is a 50% increase in the rate of dopamine (DA) uptake resulting in extracellular levels of DA that are decreased by 40%. Behaviorally, DAT-tg animals display similar locomotor stimulation when treated with DAT blockers such as GBR12909, methylphenidate, and cocaine. However, these mice demonstrate markedly increased locomotor responses to amphetamine compared with WT animals. Furthermore, compared with controls, there is a 3-fold greater increase in the amount of DA released by amphetamine in DAT-tg mice that correlates with the 3-fold increase in protein expression. Finally, DAT-tg animals show reduced operant responding for natural reward while displaying preference for amphetamine at much lower doses (0.2 and 0.5 mg/kg) than WT mice (2 mg/kg). These results suggest that overexpression of DAT leads to a marked increase in sensitivity to psychomotor and rewarding properties of amphetamine.
