β-Arrestin-biased β-adrenergic signaling promotes extinction learning of cocaine reward memory
β-Arrestin-biased β-adrenergic signaling promotes extinction learning of cocaine reward memory
复制标题
β-抑制蛋白偏向的β-肾上腺素信号传导促进可卡因奖励记忆的消退学习
DOI：
10.1126/scisignal.aam5402
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发表时间：
2018-01-09
影响因子：
7.3
通讯作者：
Ma, Lan
中科院分区：
文献类型：
--
作者：
Huang, Bing;Li, Youxing;Ma, Lan
可卡因相关情境线索的灭绝学习可以帮助预防可卡因成瘾者复吸。在消退学习过程中对β-肾上腺素能受体（β-AR）的药理学操作正被开发为治疗药物成瘾的潜在策略。我们证明了可卡因相关记忆的消退学习是由β-arrestin 2偏向的，但不是异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）依赖的β-肾上腺素能信号传导介导的。我们发现，非偏向性β-AR拮抗剂普萘洛尔，而不是G蛋白偏向性β-AR拮抗剂卡维地洛的管理，阻断消退学习可卡因条件性位置偏爱和相关的ERK激活在边缘前额叶皮层。边缘下前额叶皮层中β-arrestin 2的过度表达促进了消退学习，而这一点被普萘洛尔阻断。敲除下边缘前额叶皮层，特别是兴奋性神经元中的β-arrestin 2，会损害可卡因条件性位置偏好的消退学习，卡维地洛无法挽救。在可卡因自我给药模型中，边缘下兴奋性神经元中的β-Arrestin 2信号传导也是消退学习所需的。我们的研究结果表明，β-arrestin偏向β-肾上腺素能信号在边缘下前额叶皮层调节可卡因相关记忆的消退学习，并可能有针对性地治疗成瘾。
Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of beta-adrenergic receptor (beta-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. We demonstrated that the extinction learning of cocaine-associated memory was mediated by beta-arrestin2-biased but not heterotrimeric guanine nucleotide-binding protein (G protein)-dependent beta-adrenergic signaling. We found that administration of the nonbiased beta-AR antagonist propranolol, but not the G protein-biased beta-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of beta-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of beta-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. beta-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Our results suggest that beta-arrestin-biased beta-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.