Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice

Abstract

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.

• Circadian rhythms
• corticosterone
• interleukin-6
• N-acetylcysteine

Acknowledgements

The authors thank Eliane Dallegrave, Marta Cioato, Fabíola S. Meyer, Roberta Andrejew, Adriana Simon Coitinho and Ricardo Schneider for technical support and Conselho Nacional de Desenvolvimento Científico e Tecnológico (LKP, YT, CLQ, RB, GM, MPH and EE) and CAPES (RL) for fellowships. This study was supported by FIPE/HCPA/UFRGS and PRONEX 10/0031-1.

Declaration of interest

The authors report no conflict of interest.