Pilz Luísa K, Trojan Yasmine, Quiles Caroline L, Benvenutti Radharani, Melo Gabriela, Levandovski Rosa, Hidalgo Maria Paz L, Elisabetsky Elaine
Laboratório de Etnofarmacologia, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul. Rua Sarmento Leite , Porto Alegre, RS , Brazil .
Chronobiol Int. 2015 Mar;32(2):248-54. doi: 10.3109/07420528.2014.965315. Epub 2014 Oct 6.
Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.
昼夜节律紊乱是抑郁症的风险因素之一，但缺乏特定的动物模型。本研究旨在描述小鼠急性节律紊乱的影响，并研究丙咪嗪和N-乙酰半胱氨酸（NAC）对节律紊乱诱导变化的影响。将小鼠暴露于12:12小时随后10:10小时的光照：黑暗周期（LD）；在后者条件下，小鼠分别接受生理盐水、丙咪嗪或NAC治疗。分别用活动记录仪和温度记录器评估休息/活动节律和体温。在实验开始时以及第8个10:10 LD时再次进行旷场试验和社交偏好试验，同时评估血浆皮质酮和IL-6水平。活动记录图显示，10:10 LD时间表至少在13个周期内阻止了体温和活动节律的同步。随后光照方案的改变使活动和体温振幅呈现出类似的下降模式，随后是恢复尝试。在10:10 LD时间表期间，活动和体温振幅显著降低（配对t检验），丙咪嗪加剧了这种效应（方差分析/Student-Newman-Keuls检验）。10:10 LD时间表增加了焦虑（配对t检验），NAC（30mg/kg）可预防这种效应。本研究确定了光照方案改变后特定时间点出现的轻微但显著的行为变化。我们认为，如果长期反复出现，这些细微变化可能会导致与焦虑和情绪障碍相关的持续性行为障碍。数据表明，丙咪嗪可能导致持续的节律紊乱，而NAC似乎可以预防节律紊乱引起的焦虑。睡眠/昼夜节律紊乱与抑郁发作复发之间的关联强调了潜在药物导致节律紊乱持续存在的相关性。
