Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
Psychopharmacology (Berl). 2021 Nov;238(11):3335-3346. doi: 10.1007/s00213-021-05949-x. Epub 2021 Oct 14.
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.
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.
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.
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.
尼古丁使用障碍会改变与学习和记忆过程相关的突触可塑性。G 蛋白偶联受体 55（GPR55）是一种新型的大麻素受体，在中枢神经系统中高度表达，在学习和记忆中发挥着重要作用。然而，GPR55 在尼古丁使用障碍中的作用尚不清楚。
在这项研究中，我们使用条件位置偏好（CPP）范式，这是评估药物滥用奖赏效应的标准且成熟的模型，来研究小鼠中的尼古丁使用障碍行为。在行为测试后，使用 Western blot、免疫荧光染色、全细胞膜片钳记录和 ELISA 来评估 GPR55 对尼古丁反应的影响。
GPR55 的激活通过降低伏核（NAc）中自发性兴奋性突触后电流频率和血清中多巴胺的释放，显著减少了尼古丁-CPP 行为。此外，我们发现，尼古丁反应的抑制作用是由 AMPAR 的磷酸化介导的。PI3K-Akt 信号通路通过 GPR55 的激活参与了尼古丁-CPP。
我们的研究结果表明，NAc 中的 GPR55 在阻断尼古丁-CPP 行为方面发挥着特定的作用，可能是治疗尼古丁使用障碍的潜在靶点。
