Published February 19, 2021
| Version v1
Journal article
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An autophagy-related protein Becn2 regulates cocaine reward behaviors in the dopaminergic system
Creators
- 1. Northwestern University
- 2. University of Chicago
- 3. University of Texas Southwestern Medical Center
- 4. The Hong Kong Polytechnic University
Description
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.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.Files
sciadv.abc8310.pdf
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(42.2 MB)
| Name | Size | Download all |
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Supplementary materials md5:5c76050759827f9c1e4204f50537bc64 |
40.2 MB | Preview Download |
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Article md5:084d657e6bd80dfe0d52992257aef93f |
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.abc8310
- Other
- oai:uchicago.tind.io:10977
Funding
- National Institutes of Health
- DK113170
- National Institutes of Health
- DA047785
- National Institutes of Health
- AA027172
- National Institutes of Health
- DA043361
- National Institutes of Health
- MH109466
- BrightFocus Foundation
- Northwestern University
- Weisman Family Foundation
- Northwestern Memorial Foundation
- Research Grants Council, University Grants Committee, Hong Kong
- PolyU 151015/17M