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  3. CCK2R regulates METH-induced CPP acquisition within VTA-BLA-BNST circuit in male mice

CCK2R regulates METH-induced CPP acquisition within VTA-BLA-BNST circuit in male mice

  • Transl Psychiatry. 2026 Mar 27;16(1):210. doi: 10.1038/s41398-026-03982-y.
Jian Wang 1 2,  Minglong Zhang 1 3,  Linyi Qiao 1,  Yeneng Pu 1,  Yufei Sun 1,  Xiaorui Su 1,  Rongji Hui 1,  Ludi Zhang 1 4,  Bing Xie 1,  Bin Cong 1 5,  Yixiao Luo 6 7,  Chunling Ma 8 9 10,  Di Wen 11 12 13
Affiliations

Affiliations

  • 1 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province, China.
  • 2 Department of Forensic Medicine, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, Jiangxi Province, China.
  • 3 Department of Genetics, Qiqihar Medical University, Qiqihar, Heilongjiang Province, China.
  • 4 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China.
  • 5 Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China.
  • 6 NHC Key Laboratory of Birth Defect for Research and Prevention (Hunan Provincial Maternal and Child Health Care Hospital), Hunan Province People's Hospital, Changsha, Hunan Province, China. [email protected].
  • 7 The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China. [email protected].
  • 8 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province, China. [email protected].
  • 9 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China. [email protected].
  • 10 Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China. [email protected].
  • 11 College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province, China. [email protected].
  • 12 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China. [email protected].
  • 13 Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China. [email protected].
PMID: 41888094 DOI: 10.1038/s41398-026-03982-y
Abstract

Methamphetamine (METH) addiction is a severe public health issue driven by maladaptive neuroplasticity in reward circuits. Cholecystokinin (CCK), a neuropeptide abundant in the ventral tegmental area (VTA), modulates addiction-related behaviors through its receptors (CCK1R/CCK2R), yet its role in METH-induced conditioned place preference (CPP) remains unclear. Here, we investigated the involvement of CCK2R in the VTA→basolateral amygdala (BLA)→bed nucleus of the stria terminalis (BNST) circuit during METH CPP acquisition. Using CCKflox/flox male mice, we selectively knocked out CCK in VTA dopaminergic neurons, which attenuated METH CPP and reduced neuronal excitability. Optogenetic and chemogenetic manipulations revealed that METH enhanced CCK release from VTA → BLA projections, while CCK2R knockout in BLA glutamatergic neurons abolished CPP and normalized synaptic plasticity. Further, chemogenetic inhibition of the VTA → BLA → BNST pathway disrupted METH reward encoding, and CCK2R deletion in this circuit reversed METH-induced increases in AMPA/NMDA ratios, paired-pulse facilitation, and dendritic spine density in BNST. Electrophysiological and Golgi staining analyses confirmed CCK2R's critical role in regulating neuronal excitability and structural plasticity. Our findings demonstrate that CCK2R in the VTADA→BLAGlu → BNST circuit is essential for METH CPP acquisition, highlighting its potential as a therapeutic target for addiction.

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