Continuous home cage monitoring of activity and sleep in mice during repeated paroxetine treatment and discontinuation

Abstract

Rationale: Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation.

Objectives: We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice.

Methods: Male mice received paroxetine (10 mg/kg/day, s.c.) for 12 days, then were swapped to saline injections for a 13 day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system.

Results: Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24 h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation.

Conclusions: This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.

Keywords: Circadian rhythms; Home cage monitoring; Mice; Non-invasive; Paroxetine; SSRI; Sleep.

Fig. 1

Effect of continued paroxetine and discontinuation on hourly activity. Experimental design (a). Representative actograms of a mouse in the Saline group (b) and the Paroxetine group (c). Each row of the actograms represents 24 h of activity (zeitgeist time, ZT), each spike represents activity (arbitrary units). Points represent mean ± SEM values for hourly activity comparing the in the Saline group and the Paroxetine group during the baseline period (treatment day 0) (d), at the end of paroxetine treatment (treatment day 12) (e), discontinuation day 2 (treatment day 17) (f) and discontinuation day 5 (treatment day 19) (g). Horizontal white bar represents light phase (05:00 to 17:00), black bar represents dark phase (17:00 to 05:00). Arrow represents time of daily injections. Saline group (n = 12), Paroxetine group (n = 12). Analysed with repeated measures ANOVA with post-hoc Bonferroni’s test (only the first 24 h included in analysis), * p < 0.05 between-subject comparisons (d-g)

Fig. 2

Effect of continued paroxetine and discontinuation on daily activity and sleep. Points represent mean ± SEM values of the percentage of time spent active across the whole day (a), dark phase (b) and light phase (c), and the percentage of time spent asleep across the whole day (d) dark phase (e) and light phase (f). Dotted vertical line represents discontinuation. Saline group (n = 12), Paroxetine group (n = 12), data from day 20 removed from light phase analysis due to outliers. Analysed with a mixed-effects model with Geisser-Greenhouse correction with post-hoc Bonferroni’s test, * p < 0.05 between-subject comparisons, † p < 0.05 day 0 vs 1–12, # p < 0.05 day 12 vs days 13–25 within-subject comparisons

Fig. 3

Effects of continued paroxetine and discontinuation on the stability of circadian rhythms. Bars represent mean ± SEM values of the interday stability (IS) (a) and IS by treatment period (b), and the intraday variability (IV) (c) and IV by treatment period (d). Saline group (n = 12), Paroxetine group (n = 12), dots represent individual mice. Analysed with Student’s t-tests (a, c) and repeated measures ANOVA with post-hoc Bonferroni’s test, ** p < 0.01

Fig. 4

Effect of continued paroxetine and discontinuation on sleep bout distributions. Points represent mean ± SEM values of the total number of sleep bouts in the dark phase (a) and the light phase (b), and the percentage of sleep bouts of ≤ 1 min (c), 1–10 min (d), 10–60 min (e) and > 60 min duration (f) in the dark phase. Dotted vertical line represents discontinuation. Saline group (n = 12), Paroxetine group (n = 12). Analysed with a mixed-effects model with Geisser-Greenhouse correction with post-hoc Bonferroni’s test, * p < 0.05 between-subject comparisons, † p < 0.05 day 0 vs 1–12 within-subject comparisons

Fig. 5

Effects of continued paroxetine and discontinuation on body weight. Points represent the mean ± SEM values for body weight each day (a). Dotted line represents paroxetine discontinuation. Bars represent the mean ± SEM values for weight change during paroxetine treatment (b), two days of discontinuation compared to the end of paroxetine treatment (c) and five days discontinuation compared to the end of paroxetine treatment (d). Saline group (n = 12), Paroxetine group (n = 12), dots represent individual mice. Mixed-effects model with Geisser-Greenhouse correction with post-hoc Bonferroni’s test (a) or Student’s t-test (b-d), * p < 0.05 ** p < 0.01 between-subject differences