2. Academic Validation
  3. β2AR as a target in methamphetamine addiction: Divergent mechanisms from TAAR1

β2AR as a target in methamphetamine addiction: Divergent mechanisms from TAAR1

  • Cell Rep. 2025 Sep 23;44(10):116337. doi: 10.1016/j.celrep.2025.116337.
Yize Wang 1,  Libo Zhang 2,  Jie Li 3,  Yun Lin 1,  Ting Yuwen 2,  Jiening Wang 3,  Kexin Zhang 1,  Jie Shi 4,  Sheng Ye 5,  Shan Wu 6,  Anna Qiao 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China.
  • 2 National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China.
  • 3 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China.
  • 4 National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, Beijing 100191, China. Electronic address: shijie@bjmu.edu.cn.
  • 5 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China; Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: sye@tju.edu.cn.
  • 6 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China. Electronic address: wushan91@hubu.edu.cn.
  • 7 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China. Electronic address: anna.qiao@tju.edu.cn.
PMID: 40991929 DOI: 10.1016/j.celrep.2025.116337
Abstract

Methamphetamine (METH) abuse poses a growing global health crisis, yet the molecular mechanisms underlying its addictive effects remain poorly understood. While METH is an established agonist of trace amine-associated receptor 1 (TAAR1), our study indicates β2-adrenergic receptor (β2AR) as a METH target, demonstrating its role in Gs-mediated cAMP signaling. Using cryo-electron microscopy and mutagenesis studies, we reveal the structural basis for METH's differential ligand efficacies and stereoselectivity at β2AR and TAAR1. We further investigated synaptic plasticity of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key neural substrate for reward learning, and demonstrate that β2AR inhibition via the selective antagonist zenidolol elevates GluA1-Ser831 phosphorylation and augments excitatory inputs onto D2-MSNs in the NAc shell. In contrast, TAAR1 activation fails to elicit these synaptic modifications. Taken together, structural, behavioral, and synaptic plasticity findings highlight β2AR as a pivotal mediator of METH addiction, providing a framework for targeted therapeutic development.

Keywords

CP: Molecular biology; CP: Neuroscience; CPP; GluA1 phosphorylation; METH; TAAR1; addiction; molecular mechanism; β2AR.

Figures
Products