Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Ann N Y Acad Sci. 2010 Feb;1187:316-40. doi: 10.1111/j.1749-6632.2009.05148.x.
Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT membrane trafficking kinetics can rapidly regulate dopaminergic tone by altering the number of transporters present at the cell surface. Various psychostimulant DAT ligands-acting either as amphetamine-like substrates or cocaine-like nontranslocated inhibitors-affect transporter trafficking, triggering rapid insertion or removal of plasmalemmal DATs. In this review, we focus on the effects of psychostimulants of addiction (particularly D-methamphetamine and cocaine) on DAT regulation and membrane trafficking, with an emphasis on how these drugs may influence intracellular signaling cascades and transporter-associated scaffolding proteins to affect DAT regulation. In addition, we consider involvement of presynaptic receptors for dopamine and other ligands in DAT regulation. Finally, we discuss possible implications of transporter regulation to the putative toxicity of several substituted amphetamine derivatives commonly used as recreational drugs, as well as to the design of therapeutics for cocaine addiction.
大脑中的多巴胺信号主要由多巴胺转运体（DATs）调节，DATs 可将细胞外多巴胺主动转运回多巴胺能神经元内。转运蛋白具有高度的动态性，不断在质膜和内体膜之间循环运输。DAT 膜转运动力学的变化可以通过改变细胞表面存在的转运体数量来快速调节多巴胺能张力。各种致瘾性的精神兴奋剂 DAT 配体——作为类似安非他命的底物或类似可卡因的非移位抑制剂发挥作用——影响转运体的转运，触发质膜 DAT 的快速插入或去除。在这篇综述中，我们重点关注成瘾性精神兴奋剂（特别是 D-甲基苯丙胺和可卡因）对 DAT 调节和膜转运的影响，特别强调这些药物如何影响细胞内信号级联和转运体相关支架蛋白来影响 DAT 的调节。此外，我们还考虑了多巴胺和其他配体的突触前受体在 DAT 调节中的作用。最后，我们讨论了转运体调节对几种常用作娱乐性药物的取代安非他命衍生物的潜在毒性以及可卡因成瘾治疗药物设计的可能意义。
