Chronic Treatment of Anti-Depressants Causes Emotion-Related Behavioral Impairments in Mice

Abstract

Depression is one of the most prevalent forms of psychiatric disorders that presents with depressed mood, loss of interest, low self-worth, and diminished ability to experience pleasure. Epidemiological studies showed that 12% of men and 20-25% of women are likely to become significantly depressed at some time in their lives. Antidepressants are usually prescribed for treatment of depression. Despite the fact that numerous studies have been carried out, the action mechanism of anti-depressants developed thus far is not clear yet. Current anti-depressants need to be taken for 2-4 weeks to achieve therapeutic effects, but it can not be explained why it takes so long. Various side effects such as dizziness, nausea, lethargy, headache, anxiety, and agitation, sexual dysfunction, weight gain and sleep disturbance are other problems faced with current anti-depressants. Thus, currently available anti-depressants including fluoxetine are not satisfactory. In the present study, it was assessed whether chronic anti-depressant treatments affect emotion related behavior, with focusing on anxiety and stress. Anxiety-like behavior was assessed by the elevated plus maze test, novelty suppressed feeding test and social interaction test. It was examined whether chronic treatments (for 14-16 days) with the tricyclic antidepressant imipramine(20 mg/kg) or the selective serotonin reuptake inhibitor fluoxetine(20 mg/kg) in C57BL/6 mice induced anxiety, and that chronic treatments of the drugs made animals more vulnerable to stress. Assessment by the three anxiety test models, including the elevated plus maze test, social interaction test, and novelty-suppressed feeding test consistently suggests that chronic imipramine treatment enhances anxiety. Although it was found that stress can have an influence on behavior, stress-induced effect on imipramine-induced anxiety was negligible. Imipramine also suppressed locomotor activity in the open field test. Despite the negative effects on behavior, imiprmine certainly confers an antidepressant property as examined by the tail suspension test and the forced swimming test. Chronic fluoxetine treatment increased antidepreesnat-like behavior in the tail suppressed test. However, chronic fluoxetine treatment also enhanced anxiety in the elevated plus maze test. When fluoxetine-treated mice were exposed to restraints for 6h-3d, they showed less percentage of entries and of time spent in open arms than the vehicle treatment animals, and fluoxetine-treated mice with restraints for 6h-3d showed a tendency to enhance the reduction in open arm entries and time, and statistical significance for stress effects was assigned. In summary, chronic treatment of imipramine and fluoxetine produces side effects related to emotion, which includes an induction of anxiety, despite of the fact that long-term treatment of these antidepressants still confers s an anti-depressant effect. ;우울증이란 우울한 감정상태, 자아-정체성 상실, 흥미나 의욕저하 증상 등을 동반하는 정신질환중의 하나로 여자가 남자보다 거의 2배 비율로 발병한다고 알려져 있다. 우울증의 치료제로는 항우울제를 널리 사용하고 있으며, 최근에는 기존 항우울제가 지닌 부작용을 최소화시킨 선택적으로 세로토닌(serotonin)의 재흡수를 차단하는 약물을 많이 사용하고 있으며 항우울제 역할뿐만 아니라 불안장애 치료제로도 사용되고 있지만 명확한 기전은 아직 밝혀지지 않았다. 최근 FDA에서는 항우울제를 25세보다 젊은 사람이 복용할 경우 자살할 확률이 높아짐을 알아냈으며, 통계학적으로 어린이와 청소년기에 항우울제복용은 자살생각과 자살행위를 2배수 증가시키며, 18~24연령 집단에서의 자살경향성은 1.5배수 증가시키는 것을 밝혔다. 본 연구에서는 항우울제를 장기적으로 정상 쥐에 투여했을 경우 emotion-related behaviors에 영향을 미치는지를 확인하였으며, 이러한 영향이 스트레스에 의해 악화되는지를 확인하였다. 고가미로실험, 사회적 상호작용실험, 억제된 섭취 실험을 포함한 세 가지의 불안반응실험을 통해 imipramine(20 mg/kg)의 장기적인 투여로 불안감을 유도시켰으나, 유도된 불안감이 스트레스에 의해서 약간 증가하는 경향은 있었지만 큰 영향은 없었다. Fluoxetine(20 mg/kg)을 장기적으로 투여 한 뒤, 고가미로실험을 통해 불안감이 증가되었다. 그리고 스트레스에 의해 불안감이 더 증가됨을 확인하였다. 본 연구는 imipramine, fluoxetine과 같은 항우울제를 장기적으로 투여하면 일반적인 항우울제의 성질은 지니고 있으나, 불안장애와 같은 emotion과 관련되어 부작용이 일어나며 스트레스에 취약함을 밝혔다.