控制著神經(jīng)遞質(zhì)多巴胺活性的多巴胺轉(zhuǎn)運(yùn)蛋白(DAT)在諸如吃飯、行動和獎賞等人類的動機(jī)行為中具有關(guān)鍵的作用,。多巴胺轉(zhuǎn)運(yùn)蛋白若發(fā)生故障則可能導(dǎo)致人體出現(xiàn)問題，患上帕金森綜合癥,、毒癮,、注意力不足多動癥（ADHD）,、精神分裂癥和抑郁癥等疾病。例如,，之前的研究曾經(jīng)發(fā)現(xiàn)，注意力不足多動癥患者的多巴胺轉(zhuǎn)運(yùn)蛋白水平比普通人大約高70%。
Ali Salahpour所在的研究組深入研究了多巴胺轉(zhuǎn)運(yùn)蛋白水平對人體對安非他命反應(yīng)的影響,。安非他命是一組同多巴胺敏感性緊密相關(guān)的成癮型化學(xué)成分，被允許用于治療注意力不足多動癥和嗜睡癥及用來抑制食量過大,。但同時,，安非他命也是廣為人知的非法的“俱樂部”毒品和興奮劑,。為了深入了解高水平多巴胺轉(zhuǎn)運(yùn)蛋白的后果,，研究人員培育了具有比一般小鼠高三倍的多巴胺轉(zhuǎn)運(yùn)蛋白水平的轉(zhuǎn)基因小鼠。他們發(fā)現(xiàn),，在高水平多巴胺轉(zhuǎn)運(yùn)蛋白小鼠的身上，安非他命的效力更強(qiáng)大,。研究人員表示,，多巴胺加強(qiáng)型動物對安非他命的作用更為敏感,，變得極度亢奮,，藥物的獎賞作用也表現(xiàn)得更強(qiáng)烈,。
相關(guān)論文3月17日在線發(fā)表于美國《國家科學(xué)院院刊》（PNAS）上。（來源：EurekAlert!中文版）
生物谷推薦原始出處：
（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.
