An autophagy-related protein Becn2 regulates cocaine reward behaviors in the dopaminergic system
Yoon-Jin Kim, Qingyao Kong, Soh Yamamoto, Kenta Kuramoto, Mei Huang, Nan Wang, Jung Hwa Hong, Tong Xiao, Beth Levine, Xianxiu Qiu, Yanxiang Zhao, Richard J. Miller, Hongxin Dong, Herbert Y. Meltzer, Ming Xu, Congcong He
Abstract
deletion protects mice from cocaine-stimulated locomotion and reward behaviors, as well as cocaine-induced dopamine accumulation and signaling, by increasing presynaptic dopamine receptor 2 (D2R) autoreceptors in dopamine neurons. Becn2 regulates D2R endolysosomal trafficking, degradation, and cocaine-induced behaviors via interacting with a D2R-bound adaptor GASP1. Inactivating Becn2 by upstream autophagy inhibitors stabilizes striatal presynaptic D2R, reduces dopamine release and signaling, and prevents cocaine reward in normal mice. Thus, the autophagy protein Becn2 is essential for cocaine psychomotor stimulation and reward through regulating dopamine neurotransmission, and targeting Becn2 by autophagy inhibitors is a potential strategy to prevent cocaine-induced behaviors.