Cagniard Barbara, Sotnikova Tatyana D, Gainetdinov Raul R, Zhuang Xiaoxi
Department of Neurobiology, the University of Chicago , Chicago, Illinois , USA.
J Neurogenet. 2014 Mar-Jun;28(1-2):112-21. doi: 10.3109/01677063.2014.908191.
Although both cocaine and amphetamine mainly target the dopamine transporter (DAT) and cause psychomotor effects, they have very different mechanisms of actions. The authors examined whether responses to cocaine and amphetamine were affected differentially by changes in DAT expression levels using transgenic mice with different DAT expression levels. In the constitutive DAT knockdown mice, reduced DAT expression enhanced cocaine's locomotor stimulatory effects and at the same time diminished amphetamine's locomotor stimulatory effects. Similar effects were observed in the inducible DAT knockdown mice, ruling out the contribution of developmental compensations in DAT knockdown mice. Extracellular dopamine levels in response to psychostimulants were assessed by in vivo microdialysis. Whereas amphetamine-induced increase in extracellular dopamine was drastically diminished in constitutive DAT knockdown mice, cocaine-induced increase in extracellular dopamine had a faster onset in knockdown mice compared with wild-type controls. Postsynaptically, D1 agonist-stimulated c-fos expression was significantly attenuated in constitutive DAT knockdown mice compared with wild-type controls. The authors propose that responses to cocaine and amphetamine depend on psychostimulant drug type, drug dose, as well as DAT expression level. DAT expression level affects presynaptic responses to psychostimulants directly and postsynaptic responses to psychostimulants indirectly via changes in receptor signaling. These data imply that individual differences in DAT expression (either genetically or pharmacologically induced) may affect susceptibility to addiction of different types of psychostimulants.
虽然可卡因和苯丙胺主要作用于多巴胺转运体（DAT）并产生精神运动效应，但它们的作用机制却大不相同。作者使用具有不同DAT表达水平的转基因小鼠，研究了DAT表达水平的变化是否会对可卡因和苯丙胺的反应产生不同影响。在组成型DAT基因敲低小鼠中，DAT表达的降低增强了可卡因的运动刺激作用，同时减弱了苯丙胺的运动刺激作用。在诱导型DAT基因敲低小鼠中也观察到了类似的效果，排除了DAT基因敲低小鼠中发育补偿的作用。通过体内微透析评估精神兴奋剂引起的细胞外多巴胺水平。在组成型DAT基因敲低小鼠中，苯丙胺诱导的细胞外多巴胺增加显著减少，而与野生型对照相比，可卡因诱导的细胞外多巴胺增加在基因敲低小鼠中的起效更快。在突触后，与野生型对照相比，组成型DAT基因敲低小鼠中D1激动剂刺激的c-fos表达显著减弱。作者提出，对可卡因和苯丙胺的反应取决于精神兴奋剂的药物类型、药物剂量以及DAT表达水平。DAT表达水平直接影响对精神兴奋剂的突触前反应，并通过受体信号的变化间接影响对精神兴奋剂的突触后反应。这些数据表明，DAT表达的个体差异（无论是遗传诱导还是药物诱导）可能会影响对不同类型精神兴奋剂成瘾的易感性。
