Long-term effects of pre-pubertal fluoxetine on behaviour and monoaminergic stress response in stress-sensitive rats.
OBJECTIVE
Although prescription rates of antidepressants for children and adolescents have increased, concerns have been raised regarding effects on neurodevelopment and long-term outcome. Using a genetic animal model of depression, this study investigated the long-term effects of pre-pubertal administration of fluoxetine (FLX) on depressive-like behaviour in early adulthood, as well as on central monoaminergic response to an acute stressor. We postulated that pre-pubertal FLX will have lasting effects on animal behaviour and monoaminergic stress responses in early adulthood.


METHODS
Flinders sensitive line (FSL) rats received 10 mg/kg/day FLX subcutaneously from postnatal day 21 (PnD21) to PnD34 (pre-pubertal). Thereafter, following normal housing, rats were either subjected to locomotor testing and the forced swim test (FST) on PnD60 (early adulthood), or underwent surgery for microdialysis, followed on PnD60 by exposure to acute swim stress and measurement of stressor-induced changes in plasma corticosterone and pre-frontal cortical monoamine concentrations.


RESULTS
Pre-pubertal FLX did not induce a late emergent effect on immobility in FSL rats on PnD60, whereas locomotor activity was significantly decreased. Acute swim stress on PnD60 significantly increased plasma corticosterone levels, and increased pre-frontal cortical norepinephrine (NE) and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations. Pre-pubertal FLX significantly blunted the pre-frontal cortical NE and 5-HIAA response following swim stress on PnD60. Baseline dopamine levels were significantly enhanced by pre-pubertal FLX, but no further changes were induced by swim stress.


CONCLUSIONS
Pre-pubertal FLX did not have lasting antidepressant-like behavioural effects in genetically susceptible, stress-sensitive FSL rats. However, such treatment reduced locomotor activity, abrogated noradrenergic and serotonergic stressor responses and elevated dopaminergic baseline levels in adulthood.
1Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Nico Johan
NJ
Badenhorst
1Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Linda
L
Brand
1Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Brian Herbert
BH
Harvey
3Statistical Consultation Services,Centre for Business Mathematics and Informatics,North-West University,Potchefstroom,2520,South Africa.
Susanna Maria
SM
Ellis
1Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Christiaan Beyers
CB
Brink
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D013315:Stress, Psychological / Q000188:drug therapy*
D005473:Fluoxetine; D006897:Hydroxyindoleacetic Acid; D009638:Norepinephrine
animal; antidepressive agents; child; fluoxetine; models