Chronic Antidepressant Treatment in Normal Mice Induces Anxiety and Impairs Stress-coping Ability

Antidepressants are clinically used for patients with major depression. Antidepressant treatments in certain groups of patients are effective for relieving depression as well as anxiety disorder. However, it is not clearly known whether the use of current antidepressants in healthy persons is beneficial for upcoming depression- and anxiety-inducing life events. To address this question, normal mice were intraperitoneally administered with imipramine or fluoxetine for more than 2 weeks, and behaviors related to anxiety and depression were evaluated. Mice treated with imipramine or fluoxetine for more than 14 days exhibited significantly decreased immobility time in the forced swim test and tail suspension test, but these mice exhibited enhanced anxiety in several behavioral tests. Furthermore, chronic antidepressant treatments followed by sub-threshold level of stress in normal mice profoundly aggravated antidepressant-induced anxiety-like behaviors without further affecting depression-related behaviors. Chronic antidepressant treatments followed by sub-threshold level of stress produced swollen vesicles and ulcerations on the lips as well as a watery and inflammatory nose. Mice given chronic antidepressant treatments displayed intestinal abnormalities evidenced by a highly enlarged and inflamed small intestine full of defecation materials. These results suggest that chronic antidepressant treatment in normal mice provokes anxiety-like behaviors and impairs their stress-coping ability.

AAD-2004 Attenuates Progressive Neuronal Loss in the Brain of Tg-betaCTF99/B6 Mouse Model of Alzheimer Disease

Alzheimer's disease (AD) is a neurodegenerative disease that proceeds with the age-dependent neuronal loss, an irreversible event which causes severe cognitive and psychiatric devastations. In the present study, we investigated whether the compound, AAD-2004 [2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] which has anti-oxidant and anti-inflammatory properties, is beneficial for the brain of Tg-betaCTF99/B6 mice, a murine AD model that was recently developed to display age-dependent neuronal loss and neuritic atrophy in the brain. Administration of AAD-2004 in Tg-betaCTF99/B6 mice from 10 months to 18 months of age completely repressed the accumulation of lipid peroxidation in the brain. AAD-2004 markedly suppressed neuronal loss and neuritic atrophy, and partially reversed depleted expression of calbindin in the brain of Tg-beta-CTF99/B6. These results suggest that AAD-2004 affords neurodegeneration in the brain of AD mouse model.

Repeated Short-term (2hx14d) Emotional Stress Induces Lasting Depression-like Behavior in Mice

Chronic behavioral stress is a risk factor for depression. To understand chronic stress effects and the mechanism underlying stress-induced emotional changes, various animals model have been developed. We recently reported that mice treated with restraints for 2 h daily for 14 consecutive days (2h-14d or 2hx14d) show lasting depression-like behavior. Restraint provokes emotional stress in the body, but the nature of stress induced by restraints is presumably more complex than emotional stress. So a question remains unsolved whether a similar procedure with "emotional" stress is sufficient to cause depression-like behavior. To address this, we examined whether "emotional" constraints in mice treated for 2hx14d by enforcing them to individually stand on a small stepping platform placed in a water bucket with a quarter full of water, and the stress evoked by this procedure was termed "water-bucket stress". The water-bucket stress activated the hypothalamus-pituitary-adrenal gland (HPA) system in a manner similar to restraint as evidenced by elevation of serum glucocorticoids. After the 2hx14d water-bucket stress, mice showed behavioral changes that were attributed to depression-like behavior, which was stably detected >3 weeks after last water-bucket stress endorsement. Administration of the anti-depressant, imipramine, for 20 days from time after the last emotional constraint completely reversed the stress-induced depression-like behavior. These results suggest that emotional stress evokes for 2hx14d in mice stably induces depression-like behavior in mice, as does the 2hx14d restraint.