氟溴唑仑的奖赏效应及其神经环路机制研究  

Reward effect of flubromazolam and its underlying neural circuit mechanism

作　　者：黄为国 江炜楷 邵雨微 陈志刚 唐苏苏[1] 洪浩[1] HUANG Weiguo;JIANG Weikai;SHAO Yuwei;CHEN Zhigang;TANG Susu;HONG Hao(School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学药学院,南京210009

出　　处：《中国药科大学学报》2024年第3期390-396,共7页Journal of China Pharmaceutical University

基　　金：公安部重点实验室开放课题(No.2021-KLDMC-04);国家重点研发计划项目(No.2023YFC3304201)。

摘　　要：氟溴唑仑(Flub)是一种新型苯二氮䓬类精神活性物质,其成瘾性及其机制尚不清楚。本研究采用小鼠条件位置偏爱(CPP)模型,研究Flub的奖赏效应,以c-Fos表达评定神经元活性,采用病毒示踪技术追踪神经环路,通过化学遗传技术研究神经环路对奖赏效应的调控作用。结果显示,Flub(ip 3 mg/kg)显著增加小鼠CPP评分,增加腹侧被盖区(VTA)多巴胺(DA)能神经元c-Fos表达。抑制VTA多巴胺能神经元活性,Flub小鼠CPP评分显著降低。病毒示踪显示,VTA多巴胺能神经元接受喙内侧被盖核(RMTg)γ氨基丁酸(GABA)能神经元投射。激活RMTgGABA→VTADA环路或阻断RMTg脑区苯二氮䓬受体,Flub小鼠的CPP评分显著降低。这些结果表明,Flub通过激活RMTg脑区GABA神经元中的苯二氮䓬受体,抑制RMTgGABA→VTADA环路,产生奖赏效应。Flubromazolam(Flub)is a novel psychoactive substance of benzodiazepines and the mechanism underlying its addiction still remains elusive.This study investigated the reward effect of Flub using conditioned place preference(CPP)mouse model.The neuronal activity was evaluated by c-Fos expression,and the neural circuit was tracked by virus tracing.This study also investigated the regulatory effect of neural circuits on Flubinduced reward effects through chemogenetic approach.The results showed that,at the dose of 3 mg/kg,Flub significantly increased CPP score and c-Fos expression in dopaminergic(DA)neurons of ventral tegmental area(VTA).Inhibition of VTA dopaminergic neuron activity dramatically decreased Flub-induced CPP score.Virus tracing verified GABAergic neuronal projection of medial rostrum tegmental nucleus(RMTg)to VTA dopaminergic neurons.Activation of RMTgGABA→VTADA circuit or blockade of benzodiazepine receptors(BZR)in RMTg significantly decreased Flub-induced CPP score.These results indicate that Flub produced reward effect via BZR-mediated RMTgGABA→VTADA circuit.

关 键 词：氟溴唑仑 奖赏效应 条件性位置偏好 腹侧被盖区 喙内侧被盖核 苯二氮䓬受体 

分 类 号：R965[医药卫生—药理学]