2. Academic Validation
  3. The modulation of cholecystokinin receptor 1 in the NAc core input from VTA on METH-induced CPP acquisition

The modulation of cholecystokinin receptor 1 in the NAc core input from VTA on METH-induced CPP acquisition

  • Life Sci. 2025 Jan 15:361:123290. doi: 10.1016/j.lfs.2024.123290.
Jian Wang 1,  Minglong Zhang 2,  Yufei Sun 1,  Xiaorui Su 1,  Rongji Hui 1,  Ludi Zhang 3,  Bing Xie 1,  Bin Cong 4,  Yixiao Luo 5,  Di Wen 6,  Chunling Ma 7
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 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; Department of Genetics, Qiqihar Medical University, Qiqihar, Heilongjiang Province, China.
  • 3 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; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China.
  • 4 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; Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China.
  • 5 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; The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China.
  • 6 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; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China; Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China. Electronic address: wendi01125@hebmu.edu.cn.
  • 7 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; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province, China; Hainan Tropical Forensic Medicine Academician Workstation, Haikou, Hainan Province, China. Electronic address: chunlingma@hebmu.edu.cn.
PMID: 39638282 DOI: 10.1016/j.lfs.2024.123290
Abstract

Background: Methamphetamine (METH) is a potent psychostimulant that interferes the functionality of various brain regions and nervous connections, leading to addiction. The nucleus accumbens core (NAcC), primarily composed of gamma-aminobutyric acid (GABAergic) neurons, serves as a critical nucleus intimately related to addictive behavior. Previous research has indicated the involvement of cholecystokinin (CCK) receptors in drug addiction, yet the precise function of CCK receptors within the neural circuitry mediating METH-induced addiction remains elusive.

Methods: METH-induced conditioned place preference (CPP) model was established in mice. In CCK receptor 1 conditional knockout (CCK1Rflox/flox) or CCK receptor 2 conditional knockout (CCK2Rflox/flox) mice, we then utilized the adeno-associated virus (AAV) transfection system to knock out the specific CCK receptor subtype and explore the function of the CCK receptors in the ventral tegmental area (VTA) to NAcC circuit during METH-induced CPP acquisition.

Results: During the acquisition of METH-induced CPP, the expression of CCK1R, but not CCK2R, was upregulated specifically in NAcC. Genetic disruption of either CCK1R in the NAcC effectively hindered METH-induced CPP acquisition and prevented the hyper-excitability of neurons triggered by METH. Furthermore, CCK is released by dopaminergic neurons in the VTA, projecting to the NAcC. Notably, specifically knocking out CCK1R in the VTADA → NAcCGABA circuit blocked the presynaptic release and synaptic plasticity enhancement induced by METH.

Conclusions: These discoveries highlight the critical effect of CCK1R in the VTADA → NAcCGABA circuit on METH-induced CPP acquisition and provide a more comprehensive understanding of the mechanisms underlying CCK receptors contributing to the METH-induced addictive behavior.

Keywords

Cholecystokinin receptor 1; Conditioned place preference; Methamphetamine; Neuronal excitability; Nucleus accumbens core; Synaptic plasticity.

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