Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats

Abstract

Rationale Selective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown. Objective Our aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT 1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT 1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms. Results Perinatal FLX exposure shortened the free-running tau in response to the 5-HT 1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT 1A receptor sensitivity. No differences were found in 5-HT 1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression. Conclusions Perinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.

Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5‐HT expression in male and female adult Wistar rats

“…These results suggest that Flx exposure or 5-HT manipulation during development may promote disruption on internal circadian synchronisation between components of CTS (Kiryanova et al, 2013;Kiryanova et al, 2017;Houwing et al, 2020; see review Morrison et al, 2005) or disruption in the integrity of the SCN itself, which would induce a rearrange of the circadian cycle and gradual desynchronisation in various brain regions (Ehlers et al, 1993;Landgraf et al, 2016;reviewed by Colwell, 2021), including those related to emotional and cognitive behaviour. The integrity of brain areas may affect the parameters of circadian rhythmicity, which is related to changes in the expression of the rest-activity rhythm (Gorka et al, 1996;Tahara & Shibata, 2018;Xie et al, 2019).…”

“…Previous studies have shown the long-lasting behavioural impairments induced by early exposure to SSRIs during development in adolescent and adult offspring (for review, see Gemmel et al, 2019), mainly reporting controversial results about anxiety levels, depressivelike symptoms or impairments on memory in males and females. Concerning disruption in circadian rhythms, to the best of our knowledge, a few studies have reported circadian alterations in animals exposed to fluoxetine during development (Houwing et al, 2020;Kiryanova et al, 2013Kiryanova et al, , 2017. These authors have shown that such exposure leads to larger light-induced phase advances, smaller phase advances in response to serotonergic agonists during the midsubjective day and shorter free-running period in constant darkness in male mice.…”

“…Moreover, recent studies have suggested that perinatal Flx exposure leads to circadian alterations. These studies have shown that SSRIs induce a shorter free‐running period in total darkness (Houwing et al, 2020; Kiryanova et al, 2013) and phase advance when subjected to light pulses (Kiryanova et al, 2017). As we have hypothesised, this may be related to the alteration in the neuropeptidergic or serotonergic neurotransmission from IGL or RN, respectively, to the suprachiasmatic nuclei.…”

“…Because SSRIs can cross the placental barrier, exposure during pregnancy can lead to alterations in the brain (Hendrick et al, 2003) and behavior (Olivier et al, 2013) of developing fetuses. Preclinical and clinical studies have shown that offspring early exposed to antidepressants presented altered social behavior (Olivier et al, 2011;Houwing, Heijkoop, et al, 2019;Houwing, Staal, et al, 2019), increased risk of anxiety (Altieri et al, 2015;Ansorge et al, 2004Ansorge et al, , 2008Ko et al, 2014;Lisboa et al, 2007;Olivier et al, 2011;Silva et al, 2018), depression (Boulle et al, 2016;Ko et al, 2014;Rebello et al, 2014) or modulation of the sensitivity on the circadian timing system (Houwing et al, 2020;Kiryanova et al, 2013Kiryanova et al, , 2017McGlashan et al, 2018).…”

Female rat sexual behavior is unaffected by perinatal fluoxetine exposure

“…The dose of fluoxetine was based on previous literature comparing fluoxetine blood levels of humans and animal (Lundmark et al, 2001;Olivier et al, 2011). The same dosage was used in previous experiments (Heinla et al, 2020a;Houwing et al, 2020a;Houwing et al, 2019;Houwing et al, 2020b). Near the end of pregnancy, dams were checked twice per day (9:00 h and 15:00 h) for pup delivery.…”