Increased c-Fos immunoreactivity in anxiety-related brain regions following paroxetine discontinuation

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Helen M. Collins , L. Sophie Gullino , Cara Fuller , Raquel Pinacho , David M. Bannerman , Trevor Sharp
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Abstract

Selective serotonin reuptake inhibitor (SSRI) therapy cessation often induces a disabling discontinuation syndrome, including increased anxiety. We recently reported that SSRI discontinuation induced behavioural changes in mice, which we hypothesise arose from activated anxiety circuitry. Here, we investigated the effect of discontinuation from the SSRI paroxetine on the expression of the activity-dependent gene c-fos in selected anxiety-related midbrain and forebrain regions. Male mice were injected daily with paroxetine (10 mg/kg) or saline for 12 days, then treatment was either continued or discontinued for two or five days. Mice were then tested on the elevated plus maze (EPM) and tissue collected 90 min later. Brain sections including the dorsal (DRN) and median raphe nucleus, periaqueductal grey, hippocampus, prefrontal cortex, and amygdala were processed for c-Fos immunoreactivity. Two days after paroxetine discontinuation, when mice showed elevated anxiety-like behaviour on the EPM, increased c-Fos immunoreactivity was evident in the DRN and ventral hippocampus, but not in any other region examined, compared to saline-treated controls. Increased c-Fos in the DRN was evident in TPH2-immunopositive neurons as well as neurons doubled-labelled for TPH2 and VGLUT3, suggesting activation of 5-HT-glutamate co-releasing neurons. Five days after paroxetine discontinuation, increased c-Fos immunoreactivity was evident in the DRN, but mice no longer exhibited increased anxiety. These findings suggest that, under the current conditions, paroxetine discontinuation is associated with a short-lasting activation of anxiety-promoting circuitry limited to DRN 5-HT neurons and the hippocampus. This circuitry may contribute to symptoms such as anxiety that are a feature of SSRI discontinuation syndrome.
帕罗西汀停药后焦虑相关脑区c-Fos免疫反应性增加。
选择性5 -羟色胺再摄取抑制剂(SSRI)治疗的停止经常引起致残性停药综合征,包括焦虑增加。我们最近报道,SSRI停药引起小鼠行为改变,我们假设这是由激活的焦虑回路引起的。在这里,我们研究了停止服用SSRI类药物帕罗西汀对选定的与焦虑相关的中脑和前脑区域中活动依赖基因c-fos表达的影响。雄性小鼠每天注射帕罗西汀(10 mg/kg)或生理盐水12天,然后继续或停止治疗2天或5天。然后在90分钟后对小鼠进行升高+迷宫(EPM)和组织收集测试。脑切片包括中缝背核(DRN)和中缝核、导水管周围灰质、海马、前额叶皮层和杏仁核进行c-Fos免疫反应性处理。帕罗西汀停药两天后,当小鼠在EPM上表现出焦虑样行为时,与服用盐的对照组相比,DRN和海马腹侧区明显增加了c-Fos免疫反应性,但在其他任何检查区域都没有。在TPH2免疫阳性神经元以及TPH2和VGLUT3双标记神经元中,DRN中c-Fos明显升高,提示5- ht -谷氨酸共释放神经元被激活。帕罗西汀停药5天后,DRN中c-Fos免疫反应性明显增加,但小鼠不再表现出焦虑增加。这些发现表明,在这些条件下,帕罗西汀停药与促焦虑回路的短期激活有关,该回路仅限于DRN 5-HT神经元和海马体。这种回路可能导致焦虑等症状,而焦虑是SSRI停药综合征的一个特征。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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