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

Published:3 December 2024 DOI: 10.1016/j.lfs.2024.123290 PMID: 39638282
Jian Wang,?Minglong Zhang,?Yufei Sun,?Xiaorui Su,?Rongji Hui,?Ludi Zhang,?Bing Xie,?Bin Cong,?Yixiao Luo,?Di Wen,?Chunling Ma

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.

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Triton X-100 9002-93-1 (C2H4O)nC14H22O 844 suppliers $16.00-$5950.00
Paraformaldehyde 30525-89-4 (CH2O)x 768 suppliers $16.00-$2985.50

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