Oh Ji-eun, Zupan Bojana, Gross Steven, Toth Miklos
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Neuropsychopharmacology. 2009 Sep;34(10):2197-207. doi: 10.1038/npp.2009.47. Epub 2009 May 13.
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, as well as open-field and elevated plus maze tests, we show that both Swiss Webster and C57Bl/6 mice, receiving fluoxetine in a clinically relevant dose and during their juvenile age corresponding to child-adolescent periods in humans, 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.
抑郁症、焦虑症和品行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）常被用于治疗这些病症。氟西汀（百忧解）是首个被批准用于治疗该人群抑郁症的SSRI。尽管总体上认为氟西汀在儿童和青少年精神病学中是有效的，但已有关于特定药物不良反应的报告，最显著的是自杀倾向以及诸如激越、抑郁加重和焦虑等精神症状。长期使用氟西汀会大幅增加大脑细胞外5-羟色胺浓度，而处于发育阶段的幼龄大脑可能会对超生理水平的5-羟色胺产生特定的不良反应，这些反应在成人大脑中未见或不那么显著。通过新奇诱导性摄食减少试验以及旷场试验和高架十字迷宫试验，我们发现，给予临床相关剂量氟西汀的瑞士韦伯斯特小鼠和C57Bl/6小鼠，在相当于人类儿童青少年时期的幼龄阶段，均表现出矛盾的致焦虑反应。幼龄期使用氟西汀的不良反应在停药后消失，且未出现长期行为后果。成年小鼠未出现对长期使用氟西汀的不良反应，反而产生了剂量依赖性的抗焦虑作用。这些数据表明，小鼠的年龄，与本研究中使用的品系和试验无关，是决定对长期使用氟西汀的反应是抗焦虑还是致焦虑的决定因素。综上所述，幼龄和成年大脑对氟西汀的反应可能存在根本差异，此处描述的幼龄期给予氟西汀的小鼠模型可能有助于确定这种差异背后的机制。
