National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Peking University Sixth Hospital and Institute of Mental Health, Peking University, Beijing, China; National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Biol Psychiatry. 2017 Dec 1;82(11):781-793. doi: 10.1016/j.biopsych.2017.04.017. Epub 2017 May 11.
Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms.
In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry-fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles.
Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking.
Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse.
尼古丁成瘾和复吸常常发生在尼古丁奖赏记忆重新激活之后。我们最近开发了一种记忆检索-再巩固干扰程序，通过急性暴露于尼古丁（非条件刺激 [UCS]）重新激活尼古丁奖赏记忆，然后用药物干扰记忆再巩固，从而减少了大鼠对尼古丁的觅药和吸烟者对尼古丁的渴望。在这里，我们研究了潜在的机制。
在一系列实验中，我们对大鼠进行尼古丁诱导的条件位置偏好（CPP）或尼古丁自我给药训练，然后在 UCS 诱导的记忆检索后立即向脑室中注射蛋白合成抑制剂放线菌酮。在第二系列实验中，我们使用酪胺酶放大免疫组织化学-荧光原位杂交技术，检测由尼古丁条件刺激或 UCS 诱导的记忆检索重新激活的外侧杏仁核（BLA）中的神经团。然后，我们使用 Daun02 化学遗传失活程序选择性抑制尼古丁 UCS 重新激活的 BLA 神经元团。
在尼古丁 UCS 记忆检索后立即向脑室注射放线菌酮，可抑制随后的尼古丁 CPP 和长期或短期戒断后对操作性觅药的复吸。更重要的是，在 BLA 中，不同的神经元团编码了巴甫洛夫式 CPP 和操作性自我给药奖励记忆，而在笼内注射尼古丁则重新激活了这两个神经元团。Daun02 化学遗传失活尼古丁重新激活的神经元团，抑制了尼古丁 CPP 和对尼古丁寻求的复吸。
结果表明，尼古丁 UCS 诱导的记忆检索操作重新激活了多个由不同 BLA 神经元团编码的尼古丁奖赏记忆，这些记忆在尼古丁偏好和复吸中发挥作用。
