Kutlu Munir Gunes, Oliver Chicora, Huang Peng, Liu-Chen Lee-Yuan, Gould Thomas J
Department of Psychology, Neuroscience Program, Weiss Hall, Temple University, Philadelphia, PA, USA.
Department of Psychology, Neuroscience Program, Weiss Hall, Temple University, Philadelphia, PA, USA.
Neuropharmacology. 2016 Oct;109:341-348. doi: 10.1016/j.neuropharm.2016.06.032. Epub 2016 Jul 1.
Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder.
慢性尼古丁摄入及从慢性尼古丁摄入状态戒断已被证明是恐惧学习行为的主要调节因素。此外，我们实验室最近的研究表明，急性尼古丁会损害小鼠的恐惧消退和安全学习。然而，慢性尼古丁及戒断对恐惧消退的影响尚不清楚。因此，开展了当前这些实验，以研究慢性尼古丁以及从慢性尼古丁摄入状态戒断对小鼠情境恐惧消退的影响。C57BL6/J小鼠在慢性尼古丁给药期间接受情境恐惧条件训练和记忆测试。然后，小鼠在慢性尼古丁给药期间或从慢性尼古丁摄入状态戒断期间接受情境恐惧消退训练。我们的结果表明，在慢性尼古丁给药期间及随后的戒断过程中，情境恐惧消退均受到损害。然而，还观察到，在戒断72小时后，先前慢性尼古丁的影响消失了，这一时间线与慢性尼古丁诱导的海马烟碱型乙酰胆碱受体（nAChR）密度上调的时间密切匹配。额外的实验发现，连续4天而非1天的尼古丁给药会上调海马nAChRs并损害情境恐惧消退。这些影响在戒断72小时后消失。总体而言，这些实验揭示了尼古丁诱导的海马nAChRs上调与焦虑症患者中观察到的恐惧消退缺陷之间的潜在联系，这可能会推动该疾病药物治疗方法的进展。
