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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1537131
This article is part of the Research Topic Psychedelic Substances and Neurological Diseases: From Basics to Clinical Application View all 3 articles
Social Hierarchy Modulates Drug Reinforcement and Protein Phosphorylation in the Nucleus Accumbens
Provisionally accepted- 1 Shenzhen University of Advanced Technology, Shenzhen, China
- 2 Sichuan University, Chengdu, Sichuan Province, China
- 3 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, Guangdong Province, China
Drug reinforcement, a form of behavioral plasticity in which behavioral changes happen in response to a reinforcing drug, would finally lead to drug addiction after chronical drug exposure. Drug reinforcement is affected by genetic and environmental factors. Social hierarchy has been reported to regulate drug reinforcement and drug-seeking behaviors (Gould et al., 2017), but the underlying molecular mechanism is almost unknown. In this study, we found that methamphetamine exhibited stronger reinforcement in the subordinate rats. Then we adopted 4-D label-free mass spectrometry to explore the complex phosphoproteome in the Nucleus Accumbens (NAc) between dominant and subordinate rats. We identified 660 sites differing between the two groups. Functional enrichment and protein-protein interaction analysis revealed that synaptic remodeling related pathways and substance use disorder related pathway are significantly characterized by social hierarchy. Motif analysis and kinase prediction showed that CaMKIIδ and its downstream proteins maybe the central hub. Specifically, we identified histone deacetylase 4 (HDAC4) which has been previously shown to play critical roles in drug addiction as a key node protein by phosbind-SDS. Finally, we forcibly altered the social hierarchy of rats through behavioral training, the differences in HDAC4 phosphorylation levels induced by social hierarchy were eliminated, correspondingly the drug reinforcement is also reversed between the two group rats. In conclusion, our research proves that protein phosphorylation in the NAc may be a vital link between social hierarchy and drug reinforcement.
Keywords: social hierarchy, drug reinforcement, phosphoproteomics, drug addiction, HDAC4
Received: 30 Nov 2024; Accepted: 05 Mar 2025.
Copyright: © 2025 Xu, Xu, Zhou, Zhong, Huang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei Xu, Shenzhen University of Advanced Technology, Shenzhen, China
Yina Huang, Sichuan University, Chengdu, 610065, Sichuan Province, China
Yingjie Zhu, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, 518055, Guangdong Province, China
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