The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA.
Mol Psychiatry. 2021 Feb;26(2):370-382. doi: 10.1038/s41380-020-00978-y. Epub 2021 Jan 7.
Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.
可卡因通过抑制多巴胺再摄取来发挥其刺激作用，从而增加多巴胺信号。这种作用被认为反映了可卡因与多巴胺转运体（DAT）的结合，从而抑制其功能。然而，可卡因对 DAT 的抑制作用相对较弱，并且许多 DAT 抑制剂并不具有可卡因的行为作用。我们之前表明，可卡因的毒性水平会诱导自噬性神经元细胞死亡。在这里，我们表明亚纳摩尔浓度的可卡因在体外和体内引发神经自噬。自噬抑制剂可降低可卡因在小鼠中的运动刺激作用。可卡因诱导的自噬会降解伏隔核中的多巴胺转运体，但不会降解 5-羟色胺转运体。自噬抑制会损害小鼠对可卡因的条件性位置偏好。我们的研究结果表明，DAT 的自噬降解调节可卡因的行为作用。
