Lee Angela M, Calarco Cali A, McKee Sherry A, Mineur Yann S, Picciotto Marina R
Department of Psychiatry, Yale University, New Haven, Connecticut.
Yale Interdepartmental Neuroscience Program, New Haven, Connecticut.
Genes Brain Behav. 2020 Mar;19(3):e12601. doi: 10.1111/gbb.12601. Epub 2019 Aug 13.
Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex-specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2-adrenergic receptor agonist, may provide sex-sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress-induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress-induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress-induced reinstatement in both male and female mice, but with different nicotine dose-response patterns. In addition, we explored the variability in nicotine-dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress-induced reinstatement. In groups that showed significant stress-induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex-dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex-dependent relationships between initial chamber preference and stress-induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.
与男性相比，女性吸烟复发率更高，尤其是在压力触发时。研究表明，尼古丁奖赏与压力之间的性别特异性相互作用导致了这些性别差异。因此，针对压力途径的新型治疗选择，如α2-肾上腺素能受体激动剂胍法辛，可能会产生对性别敏感的治疗效果。临床前研究对于阐明压力诱导复发的神经生物学机制和潜在疗法至关重要，但尼古丁成瘾的啮齿动物模型往往受到行为变异性大的阻碍。在本研究中，我们使用尼古丁条件性位置偏爱来研究压力诱导的雄性和雌性小鼠尼古丁偏爱的恢复，以及胍法辛对这种行为的影响。我们的结果表明，总体而言，尼古丁在雄性和雌性小鼠中均诱导了显著的位置偏爱获得和游泳应激诱导的恢复，但具有不同的尼古丁剂量反应模式。此外，我们用中位数分割分析探讨了尼古丁依赖行为的变异性，发现每种性别的初始箱偏爱对压力诱导恢复的变异性有不同的影响。在显示出显著压力诱导恢复的组中，胍法辛预处理减弱了这种行为。最后，我们通过Arc免疫反应性评估了边缘下皮质、边缘前皮质、前脑岛、基底外侧杏仁核、外侧中央杏仁核以及伏隔核核心和壳中的神经元激活。胍法辛在边缘下皮质和前脑岛诱导了Arc免疫反应性的性别依赖性变化。本研究证明了初始箱偏爱与压力诱导的尼古丁条件性位置偏爱恢复之间的性别依赖性关系，以及胍法辛对行为和神经生物学机制的影响。
