The effect of sertraline and voluntary exercise during pregnancy on litter characteristics and postpartum affective behaviour in rat dams.

Introduction: Sertraline is the frontline pharmacotherapy for the treatment of depression and anxiety during pregnancy. However, there is little evidence regarding the effects of sertraline on maternal behaviour or the maternal brain. Furthermore, the efficacy of non-pharmacological approaches to treatment in pregnancy, such as exercise, are unclear. Therefore, the aim of this study was to examine the effects of sertraline and exercise during pregnancy on maternal postpartum depressive-like, anxiety-like and associated behaviours, as well as litter characteristics, in a rat model of depression. We also investigated the effects of these treatments on the maternal brain, focusing initially on DNA methylation and glutamatergic markers, which have been implicated in depression.

Method: Twenty-four female Wistar-Kyoto (WKY; strain that models depression and anxiety) rats were divided into three groups: 1. WKY-Sertraline; 2. WKY-Exercise, 3. WKY-Vehicle; Six female Wistar (WIS) rats were included as controls. Rats were treated with sertraline (10 mg/kg) or vehicle (33 % propylene glycol) twice/day, from gestational day (GD) 1 to postpartum day 14. The WKY-Exercise group were provided access to a running wheel during pregnancy for 3 h/day from GD1-18. Dam and litter characteristics, as well as pup ultrasonic vocalisations (USVs), were measured. Dams underwent behavioural testing at 5-weeks postpartum to assess depressive-, anxiety- and cognitive-like behaviours. Gene expression of DNA methylation markers (Dnmt1, Dnmt3a) and glutamate receptors (Grin1, Grin2a, Grin2b) were measured in the prefrontal cortex (PFC), using RT-qPCR.

Result: The WKY-Sertraline group gained 39 % less weight in their first pregnancy week compared to all other groups (p < 0.05) and produced smaller litters compared to WIS controls (-43 %; p = 0.003) and WKY-Exercise (-38 %; p = 0.012); WKY-Sertraline pups had slightly smaller brain weights compared to WKY-Vehicle (p = 0.031). WKY-Vehicle pups showed reduced number of USV calls, call amplitude and call duration compared to WIS control (p < 0.001). The WKY-Exercise pups produced increased number of USVs, with increased call amplitude of USVs, at postnatal day (PN)7 compared to WKY-Vehicle (p < 0.01). Maternal sertraline treatment did not significantly affect dam behavioural measures, or maternal cortical gene expression. The WKY-Exercise group however showed reduced anxiety-like behaviours, spending more time in the open arms (620 %; p = 0.027) and less time in the closed arms (-22 %; p = 0.047) of the elevated plus maze (EPM) compared to WKY-Vehicle, and more time in the centre of the open field test (OFT) compared to WKY-Vehicle (132 %; p = 0.057). Furthermore, WKY-Exercise dams showed a 64 % increase in Dnmt3a mRNA levels in the PFC compared to WKY-Vehicle (p = 0.019), effectively reversing the 44 % reduction observed in WKY-Veh relative to WIS controls (p = 0.009).

Conclusion: Voluntary exercise during pregnancy in the WKY rat model, reduced postpartum anxiety-like behaviour. This was accompanied by elevated DNMT3a gene expression in the PFC, suggesting this region may be sensitive to DNA methylation changes following maternal exercise. In contrast, maternal sertraline did not impact these behaviours or genes. Maintaining sertraline treatment beyond postpartum day 14, or trialling different doses, may have resulted in broader effects on postpartum behaviour, which should be explored further. Maternal sertraline did appear to have some adverse effects on the in-utero environment, evidenced by smaller litters, with slightly smaller pup brain weights, which should be investigated further. Our findings suggest a long-term beneficial effect of exercise during pregnancy and support future studies examining the effects of exercise in antenatal depression in the human population.