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, Junghong Hwa, Tong Xiao, Beth Levine, Xianxiu Qiu, Yanxiang Zhao, Richard J. Miller, Hongxin Dong, Herbert Y. Meltzer, Ming Xu, Congcong He*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Drug abuse is a foremost public health problem. Cocaine is a widely abused drug worldwide that produces various reward-related behaviors. The mechanisms that underlie cocaine-induced disorders are unresolved, and effective treatments are lacking. Here, we found that an autophagy-related protein Becn2 is a previously unidentified regulator of cocaine reward behaviors. Becn2 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.

Original languageEnglish (US)
Article numbereabc8310
JournalScience Advances
Issue number8
StatePublished - Feb 19 2021

ASJC Scopus subject areas

  • General


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