2. Academic Validation
  3. β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation

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

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: xbcen@scu.edu.cn.
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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