Wang Jian, Zhang Minglong, Sun Yufei, Su Xiaorui, Hui Rongji, Zhang Ludi, Xie Bing, Cong Bin, Luo Yixiao, Wen Di, Ma Chunling
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.
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.
Life Sci. 2025 Jan 15;361:123290. doi: 10.1016/j.lfs.2024.123290. Epub 2024 Dec 3.
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.
METH-induced conditioned place preference (CPP) model was established in mice. In CCK receptor 1 conditional knockout (CCK1R) or CCK receptor 2 conditional knockout (CCK2R) 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.
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 VTA → NAcC circuit blocked the presynaptic release and synaptic plasticity enhancement induced by METH.
These discoveries highlight the critical effect of CCK1R in the VTA → NAcC 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.
甲基苯丙胺（METH）是一种强效精神兴奋剂，会干扰大脑各区域的功能和神经连接，导致成瘾。伏隔核核心区（NAcC）主要由γ-氨基丁酸（GABA能）神经元组成，是与成瘾行为密切相关的关键核团。先前的研究表明胆囊收缩素（CCK）受体参与药物成瘾，但CCK受体在介导METH诱导成瘾的神经回路中的具体功能仍不清楚。
在小鼠中建立METH诱导的条件性位置偏爱（CPP）模型。在CCK受体1条件性敲除（CCK1R）或CCK受体2条件性敲除（CCK2R）小鼠中，我们利用腺相关病毒（AAV）转染系统敲除特定的CCK受体亚型，并探讨在METH诱导的CPP获得过程中，腹侧被盖区（VTA）到NAcC回路中CCK受体的功能。
在METH诱导的CPP获得过程中，CCK1R而非CCK2R的表达在NAcC中特异性上调。NAcC中CCK1R的基因破坏有效阻碍了METH诱导的CPP获得，并防止了METH触发的神经元过度兴奋。此外，CCK由VTA中的多巴胺能神经元释放，投射到NAcC。值得注意的是，特异性敲除VTA→NAcC回路中的CCK1R可阻断METH诱导的突触前释放和突触可塑性增强。
这些发现突出了VTA→NAcC回路中CCK1R对METH诱导的CPP获得的关键作用，并为CCK受体促成METH诱导成瘾行为的潜在机制提供了更全面的理解。
