State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain Science, and Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200032, China.
Sci Signal. 2018 Jan 9;11(512):eaam5402. doi: 10.1126/scisignal.aam5402.
Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-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 β-arrestin2-biased but not heterotrimeric guanine nucleotide-binding protein (G protein)-dependent β-adrenergic signaling. We found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein-biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of β-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of β-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. β-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Our results suggest that β-arrestin-biased β-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.
可卡因相关环境线索的灭绝学习可以帮助预防可卡因成瘾者复发。在灭绝学习过程中对β肾上腺素能受体（β-AR）进行药理学操作，被开发为治疗药物成瘾的潜在策略。我们证明，可卡因相关记忆的灭绝学习是由β-arrestin2 偏向但不是异三聚体鸟苷酸结合蛋白（G 蛋白）依赖性β-肾上腺素能信号介导的。我们发现，给予非偏向性β-AR 拮抗剂普萘洛尔，但不是 G 蛋白偏向性β-AR 拮抗剂卡维地洛，阻断可卡因条件性位置偏好的灭绝学习和相关 ERK 在额下回前额皮质中的激活。在额下回前额皮质中过度表达β-arrestin2 促进了灭绝学习，而普萘洛尔则阻断了这种学习。特异性在兴奋性神经元中敲除额下回前额皮质中的β-arrestin2 会损害可卡因条件性位置偏好的灭绝学习，而卡维地洛并不能挽救这种学习。额下回兴奋性神经元中的β-arrestin2 信号也需要可卡因自我给药模型中的灭绝学习。我们的结果表明，额下回前额皮质中的β-arrestin 偏向β-肾上腺素能信号调节可卡因相关记忆的灭绝学习，并且可以作为治疗靶点来治疗成瘾。
