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.

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review

“…Accordingly, NAC also reduced enhanced presynaptic excitatory neurotransmission to normal levels in the amygdala of valproate-exposed rats 68. NAC prevented rhythm disruption-induced anxiety in mice 69. The anxiolytic effects of NAC have also been documented in the light/dark model and in stress-induced anxiety behavior in zebrafish,70 as well as in the hole-board test, the light/dark model, the open field test, social interaction, and stress-induced hyperthermia in mice 71.…”

Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

“…In addition, it was shown that the inhibition of the activity of nNOS/cGC/PKGII input pathway components [ 36 , 37 ] delayed the circadian phase, so we could hypothesize that the phase-delays induced by GSH or NAC could be generated by a redox-dependent inhibition of the same pathway, as occurs with NOS activity and L-arginine uptake by AS treatment in the retina [ 45 ]. While Wang et al [ 5 ] evidenced the effect of GSH on resting electrical activity in SCN slices, few circadian studies were done with NAC, which had inconsistent effects [ 51 , 52 ].…”

N-acetylcysteine protects against motor, optomotor and morphological deficits induced by 6-OHDA in zebrafish larvae

“…Studies have indicated NAC effects as an anxiolytic ( Mocelin et al, 2015 ; Santos et al, 2017 ) and antidepressant drug ( Magalhães et al, 2011 ; Berk et al, 2013 ; Costa-Campos et al, 2013 ; Pilz et al, 2015 ). Therefore, NAC has advantages over the existing therapies since, besides having a potential preventive effect, it may be able to treat the non-motor aspects of PD, which include depression, anxiety, cognitive impairment and sleep disturbances ( Klockgether, 2004 ).…”