Long-lasting bio-behavioural effects of early-life sildenafil administration in stress-sensitive versus healthy control rats

Abstract

Major depressive disorder (MDD) in children and adolescents is prevalent, serious and of great concern globally. Yet, only two selective serotonin reuptake inhibitors (SSRIs) are approved for the treatment of juvenile MDD, namely fluoxetine and escitalopram. In addition, the effects of early-life exposure to psychotropic drugs on neurodevelopment and the potential long-lasting effects thereof into adulthood are poorly understood. This study investigated the later-in-life bio-behavioural effects of early-life exposure to the psychotropic drug, sildenafil, in stress-sensitive versus healthy control rats. Male Flinders Sensitive Line (FSL) rats (n = 12 per group), a validated genetic animal model of MDD, and behavioural control male Sprague-Dawley (SD) rats (n = 12 per group) received either saline or sildenafil (3 mg/kg/day) subcutaneously from postnatal day (PnD) 21 to 34 (for the pre-pubertal groups) or from PnD 35 to 48 (for the pubertal groups) (ethics approval no. NWU-00277-17-S5). The rats were subsequently housed under standard laboratory conditions until PnD 60 (i.e. adulthood), representing a wash-out period following sildenafil treatment, leading to only later-in-life, and not immediate, bio-behavioural effects being observed. On PnD 60, a battery of behavioural tests was conducted, consisting of the novel object recognition test (nORT) to assess cognition, the open field test (OFT) to assess general locomotor activity and anxiety-like behaviour, and the forced swim test (FST) to assess depressive-like behaviour. Rats were subsequently euthanized on PnD 60 and hippocampal concentrations of brain-derived neurotrophic factor (BDNF) were measured. Juvenile sildenafil treatment had no later-in-life effect on cognition, general locomotor activity or anxiety-like behaviour into adulthood in both strains and regardless of treatment initiation age (i.e. pre-pubertal or pubertal). In the FST, saline-treated FSL rats displayed a greater immobility (i.e. enhanced depressive-like behaviour) compared to saline-treated SD rats. Sildenafil treatment reduced the immobility (i.e. reduced depressive-like behaviour) and increased struggling (i.e. enhanced noradrenergic neurotransmission) in the FSL but not in the SD rats (i.e. only in rats genetically susceptible to develop MDD), regardless of treatment initiation age. In addition, sildenafil increased swimming behaviour (i.e. enhanced serotonergic neurotransmission) in the pre-pubertal but not pubertal treated groups (i.e. treatment age susceptibility differences), regardless of the strain. Juvenile sildenafil treatment had no later-in-life effect on hippocampal BDNF concentrations into adulthood in both strains and regardless of treatment initiation age (i.e. pre-pubertal or pubertal). Our data suggest that both pre-pubertal and pubertal neurodevelopment in rats may be putatively manipulated by sildenafil treatment to bring about long-lasting effects into adulthood. It can therefore be concluded that early-life sub-chronic sildenafil treatment has later-in-life antidepressant-like effects into adulthood, with no observed later-in-life effect on cognition and anxiety-like behaviour