Pre-pubertal, low-intensity exercise does not require concomitant venlafaxine to induce robust, late-life antidepressant effects in Flinders sensitive line rats

A significant number of adolescents are considered insufficiently active. This is of concern considering the negative association between physical activity and major depressive disorder (MDD). There is a lack of approved pharmacological treatment options in this population partly due to limited information on the risks associated with lasting effects during early life. Therefore, interest in non-pharmacological strategies is gaining popularity with low- to moderate-intensity exercise being especially attractive for its antidepressant-like effects and augmentation properties in combination with antidepressants. Early-life development might present a unique window of opportunity to induce long-term beneficial effects in individuals treated with central acting drugs, such as antidepressants. Therefore, we investigated the bio-behavioural effects of pre-pubertal, low-intensity exercise (EXE) and/or venlafaxine (VEN) on depressive-like behaviour in juvenile (postnatal day 35 (PND35)) and young adult (PND60) stress-sensitive Flinders sensitive line (FSL) rats. Interventions were introduced during pre-pubertal development, that is PND21-34, followed by a 26-day washout/sedentary period, when bio-behavioural analyses were performed in the early adulthood group. VEN, alone or in combination with EXE, proved ineffective in inducing any bio-behavioural changes in either age group. EXE did not induce early-life antidepressant-like effects, despite increasing frontal serotonin (5-HT) and noradrenaline (NA) levels. Later in life (PND60), pre-pubertal exercise reduced immobility and increased coping behaviours, together with increased cortical 5-HT levels, despite a significant reduction in locomotor activity. These findings emphasize a strong serotonergic basis to the observed delayed antidepressant effects of EXE later in life.