Early-life exposure to fluoxetine and/or exercise on bio-behavioural markers of depression in early adulthood in stress sensitive rats
Schoeman, Jacobus Christiaan
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Juvenile depression is a major concern worldwide, with only the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram approved for treatment. The effects of early-life exposure to SSRIs on neurodevelopment and subsequent lasting effects are not well understood. Exercise positively affects neuroplasticity, rendering exercise a potential augmentation strategy for drug therapy in juvenile depression. The current study investigated long-lasting behavioural and neurochemical effects of juvenile fluoxetine treatment and the potential role of exercise as treatment augmentation strategy in stress sensitive rats. Male Flinders Sensitive Line (FSL) rats (n = 12 -16 per group), a well described, validated genetic animal model of depression, received either fluoxetine (5 mg/kg/day or 10 mg/kg/day subcutaneous) or vehicle control from postnatal day 21 (PostND21) to PostND34 (i.e. phase of pre-adolescence), together with simultaneous exposure to no, low or moderate intensity exercise (ethics approval no. NWU-00148-14-A5). Thereafter rats were housed normally and subjected to the open field test (OFT) and the forced swim test (FST) on PostND35 or PostND60 (early adulthood) to assess locomotor activity and depressive-like behaviour, respectively. Furthermore, euthanasia was applied to rats of the main study on PostND61, to assess hippocampal levels of brain-derived neurotrophic factor (BDNF), plasma levels of corticosterone, malondealdehyde (MDA) and superoxide dismutase (SOD). On PostND35, 5 mg/kg/day fluoxetine, but not 10 mg/kg/day, significantly decreased immobility in the FST vs. vehicle control. This effect of 5 mg/kg fluoxetine was associated with enhanced climbing but no change in swimming behaviour in the FST, suggesting enhanced adrenergic but not serotonergic neurotransmission following early-life exposure. Neither low nor moderate intensity exercise altered immobility in the FST on PostND35 with also no changes in locomotor activity observed in the OFT. This effect of low intensity exercise was however associated with enhanced swimming behaviour, suggesting enhanced serotonergic neurotransmission following early-life exposure. The combination of fluoxetine 5 mg/kg/day and low intensity exercise significantly decreased immobility when compared to the sedentary plus vehicle control group on PostND35. This was associated with enhanced swimming behaviour. No changes were observed in locomotor activity. On PostND60, following 26 days treatment-free housing, fluoxetine 5 mg/kg/day significantly decreased immobility vs. the vehicle plus sedentary control group, associated with increased climbing behaviour, again suggesting enhanced adrenergic neurotransmission. Locomotor activity, as measured in the OFT, was unaffected. Pre-pubertal low intensity exercise significantly decreased immobility in the FST on PostND60, also as a result of increased climbing behaviour. Fluoxetine plus exercise did not affect behaviour in the FST on PostND60, but did significantly decrease locomotor activity in the OFT when compared to the vehicle plus sedentary control group. Further, only SOD was significantly increased in all treatment groups when compared to the vehicle plus sedentary group. BDNF was significantly decreased in the fluoxetine plus exercise group when compared to the vehicle plus exercise group. No differences were observed in lipid peroxidation (MDA) and plasma corticosterone levels in early adulthood. The pre-adolescent period in rats therefore presents a window of opportunity during which neurodevelopment is highly plastic and can therefore be manipulated to result in detrimental or beneficial lasting effects. These lasting effects are dependent upon the neurodevelopmental age at the time of exposure, the dose of drug as well as the intensity of exercise. Furthermore the exercise intensity should be adapted according to age, in order to ensure training at the targeted intensity (% VO2max). The current data further suggest, as a working hypothesis, that treatment of depression during pre-adolescence in humans should be tailored individually, in order to optimise early-life treatment and ensure lasting beneficial neurodevelopmental effects.
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