Long-lasting effects of fluoxetine and/or exercise augmentation on bio-behavioural markers of depression in pre-pubertal stress sensitive rats

- Maximal exercise intensity (as estimated by VO2max) in rats increases with age and should be adapted accordingly.
- Pre-pubertal fluoxetine and fluoxetine plus low intensity exercise exerts early antidepressant-like effects.
- Pre-pubertal low intensity exercise or low dose fluoxetine exerts lasting antidepressant-like effects into early adulthood.
- The combination of fluoxetine with low intensity exercise does not exert any lasting effects on depressive-like behaviour.
- Exercise, fluoxetine and the combination thereof increased hippocampal superoxide dismutase in early-adulthood.

Juvenile depression is of great concern with only limited treatment currently approved. Delayed onset of action, low remission and high relapse rates, and potential long-lasting consequences further complicates treatment and highlights the need for new treatment options. Studies reporting on long-lasting effects of early-life treatment have reported conflicting results, with the pre-adolescent period mostly overlooked. The anti-depressive effect of exercise, as a possible treatment option or augmentation strategy, is dependent on age and exercise intensity. We investigated the immediate (i.e. postnatal day 35 (PND35)) and lasting (PND60 to PND61) effects of pre-pubertal (PND21 to PND34) fluoxetine and/or exercise on bio-behavioural markers of depression and oxidative stress in stress sensitive Flinders Sensitive Line rats. Low, but not moderate, intensity exercise or 5, but not 10, mg/kg/day fluoxetine displayed anti-depressant-like properties at PND35. Pre-pubertal treatment with 5 mg/kg/day fluoxetine or low intensity exercise exerted lasting anti-depressive-like effects into adulthood, whereas the combination of these two treatments did not. Furthermore, the combination of fluoxetine plus exercise reduced hippocampal BDNF levels as compared to exercise alone, which may explain the latter findings. In all treatment groups hippocampal SOD activity was significantly increased at PND61, suggesting an increased anti-oxidant capacity in adulthood. In conclusion, the data confirm the anti-depressant-like properties of both early-life fluoxetine and exercise in a genetic animal model of depression. However, optimal lasting effects of early-life interventions may require adjustment of antidepressant dose and/or exercise intensity to developmental age, and that a combination of antidepressant and exercise may not necessarily be augmentative.