Paradoxical anxiogenic response of juvenile mice to fluoxetine.
Paradoxical anxiogenic response of juvenile mice to fluoxetine.
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DOI：
10.1038/npp.2009.47
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发表时间：
2009-09
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抑郁、焦虑和行为障碍在儿童和青少年中很常见，选择性5-羟色胺再摄取抑制剂（SSRIs）通常用于治疗这些疾病。氟西汀（百忧解）是第一个被批准用于治疗抑郁症的SSRI。尽管总体上认为氟西汀在儿童和青少年精神病学中有效，但也有特定药物不良反应的报告;最突出的是自杀倾向和精神症状，如激越、抑郁和焦虑恶化。慢性氟西汀可显著增加脑细胞外5-HT浓度，青少年发育中的大脑可能对超生理5-HT水平产生反应，在成人大脑中未观察到或不太突出的特定不良反应。使用新奇诱导的食欲减退（NIH），以及开放领域（OF）和高架十字迷宫（ESTA）测试，我们表明，瑞士韦伯斯特（SW）和C57 B1/6（B6）小鼠，接受氟西汀在临床相关剂量和在其青少年年龄对应的儿童-青少年时期的人类，表现出矛盾的焦虑反应。青少年氟西汀的不良反应在停药后消失，没有明显的长期行为后果。在成年小鼠中未观察到慢性氟西汀的不良反应，并产生了剂量依赖性抗焦虑作用。这些数据表明，小鼠的年龄，独立于本研究中使用的品系和试验，是慢性氟西汀反应是抗焦虑还是致焦虑的决定因素。总之，幼年和成年大脑对氟西汀的反应可能根本不同，本文描述的幼年氟西汀给药小鼠模型可能有助于确定这种差异的机制。
Depression, anxiety and conduct disorders are common in children and adolescents and selective serotonin reuptake inhibitors (SSRIs) are often used to treat these conditions. Fluoxetine (Prozac) is the first approved SSRI for the treatment of depression in this population. Although it is believed that overall, fluoxetine is effective in child and adolescent psychiatry, there have been reports of specific adverse drug effects; most prominently suicidality and psychiatric symptoms such as agitation, worsening of depression and anxiety. Chronic fluoxetine substantially increases brain extracellular 5-HT concentrations and the juvenile developing brain may respond to supraphysiological 5-HT levels with specific adverse effects not seen or less prominent in adult brain. Using novelty induced hypophagia (NIH), as well as open field (OF) and elevated plus maze (EPM) tests, we show that both Swiss Webster (SW) and C57Bl/6 (B6) mice, receiving fluoxetine in a clinically relevant dose and during their juvenile age corresponding to child-adolescent period in human, exhibit a paradoxical anxiogenic response. The adverse effects of juvenile fluoxetine disappeared upon drug discontinuation and no long term behavioral consequences were apparent. No adverse effect to chronic fluoxetine was seen in adult mice and a dose dependent anxiolytic effect developed. These data show that the age of the mice, independently of the strains and tests used in this study, is the determining factor of whether the response to chronic fluoxetine is anxiolytic or anxiogenic. Taken together, the response of the juvenile and adult brain to fluoxetine could be fundamentally different and the juvenile fluoxetine administration mouse model described here may help to identify the mechanism underlying this difference.
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