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Cannabinoid receptor GPR55 activation blocks nicotine use disorder by regulation of AMPAR phosphorylation

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Abstract

Rationale

Nicotine use disorder can alter synaptic plasticity correlated with learning and memory process. G protein–coupled receptor 55 (GPR55), a novel cannabinoid receptor, which is highly expressed in the central nervous system, plays a prominent role in learning and memory. However, the role of GPR55 in nicotine use disorder remains unclear.

Methods

In this study, we used the conditioned place preference (CPP) paradigm, a standard and well-established model for evaluating the rewarding effect of drug abuse, to investigate nicotine use disorder behavior in mice. After behavioral tests, the effect of GPR55 on nicotine response was evaluated using Western blotting, immunofluorescence staining, whole-cell patch-clamp recordings, and ELISA.

Results

GPR55 activation significantly reduced nicotine-CPP behavior by decreasing the spontaneous excitatory postsynaptic currents frequency in the nucleus accumbens (NAc) and the release of dopamine in serum. Furthermore, we found that the inhibition effects of nicotine response were mediated by phosphorylation of AMPAR. The PI3K-Akt signaling was involved in nicotine-CPP via GPR55 activation.

Conclusion

Our findings showed that GPR55 in the NAc plays a specific role in blocking nicotine-CPP behavior and might be a potential target for the treatment of nicotine use disorder.

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Funding

This research was supported by the National Natural Science Foundation Grant No. 81870893 (to QY) and the National Postdoctoral Program for Innovative Talents No. BX20160025 (to QY).

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Author notes

  1. Qingqing Liu, Jiaoyan Yu and Xi Li contributed equally to this work.

Authors and Affiliations

  1. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi’an, 710038, China

    Qingqing Liu, Jiaoyan Yu, Xi Li, Yanyan Guo, Ting Sun, Li Luo, Jing Ren, Wei Jiang, Ruitao Zhang, Peng Yang & Qi Yang

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  1. Qingqing Liu
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  2. Jiaoyan Yu
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  3. Xi Li
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  6. Li Luo
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  10. Peng Yang
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Correspondence to Qi Yang.

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Liu, Q., Yu, J., Li, X. et al. Cannabinoid receptor GPR55 activation blocks nicotine use disorder by regulation of AMPAR phosphorylation. Psychopharmacology 238, 3335–3346 (2021). https://doi.org/10.1007/s00213-021-05949-x

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  • DOI: https://doi.org/10.1007/s00213-021-05949-x

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