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.

中文翻译：

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尼古丁条件性位置偏好和小鼠应激诱导恢复的变异性：性别、初始腔室偏好和胍法辛的影响。

与男性相比，女性吸烟的复发率更高，尤其是在压力引发的情况下。研究表明，尼古丁奖励和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，针对压力途径的新治疗方案，例如胍法辛，一种 α2-肾上腺素能受体激动剂，可能会提供性别敏感的治疗效果。临床前研究对于阐明压力诱发的复发和潜在疗法的神经生物学机制至关重要，但尼古丁成瘾的啮齿动物模型往往受到巨大的行为变异性的阻碍。在这项研究中，我们使用尼古丁条件位置偏好来研究压力诱导的雄性和雌性小鼠尼古丁偏好的恢复，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诱导显着的位置偏好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，我们通过中位数拆分分析探索了尼古丁依赖行为的变异性，发现每个性别的初始腔室偏好不同地解释了压力引起的恢复的变异性。在表现出显着压力诱导恢复的组中，用胍法辛预处理减弱了这种行为。最后，我们通过下边缘皮层、前边缘皮层、前岛叶、基底外侧杏仁核、外侧中央杏仁核和伏隔核核和壳中的 Arc 免疫反应性评估了神经元激活。胍法辛在边缘下皮层和前岛叶中诱导 Arc 免疫反应性的性别依赖性变化。