β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation

  • Cell Rep. 2022 Nov 29;41(9):111724. doi: 10.1016/j.celrep.2022.111724.
Hongchun Li  1 ,  Xuemei Wan  1 ,  Zhixiang Wu  2 ,  Yuanyi Zhou  1 ,  Rong Chen  1 ,  Wei Xu  3 ,  Jiamei Zhang  1 ,  Zhen Yang  4 ,  Lin Bai  4 ,  Jie Zhang  4 ,  Feng Qin  1 ,  Liang Wang  1 ,  Yaxing Chen  1 ,  Linhong Jiang  1 ,  Yuman He  1 ,  Xiaojie Wang  1 ,  Qingfan Wei  1 ,  Shu Li  1 ,  Yanping Dai  1 ,  Yuanyuan Chen  1 ,  Yonghai Wang  5 ,  Hongbo Wang  5 ,  Jingwei Tian  5 ,  Yinglan Zhao  1 ,  Xiaobo Cen  6
Affiliations
  • 1. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Faculty of Environmental and Life Science, Beijing University of Technology, Beijing 100124, China.
  • 3. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Shenzhen Key Laboratory of Drug Addiction, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen 518055, China.
  • 4. Histology and Imaging Platform, Core Facilities of West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5. Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 6. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 36450263 DOI: 10.1016/j.celrep.2022.111724
Abstract

Studies have shown the therapeutic effects of a ketogenic diet (KD) on Epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of β-hydroxybutyrate (β-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that β-OHB posttranslationally modifies CaMKII-α with β-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that β-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.

Keywords
CP: Neuroscience; CaMKII-α; cocaine relapse; hippocampus; ketogenic diet; β-hydroxybutyrate; β-hydroxybutyrylation.
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