Lasting effects of chronic fluoxetine treatment on the late developing rat brain: Age-dependent changes in the serotonergic neurotransmitter system assessed by pharmacological MRI

Abstract

With the growing prevalence of psychotropic drug prescriptions among children and adolescents, the need for studies on lasting effects of drug exposure on the developing brain rises. Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) officially registered to treat major depressive disorder in children. Although various (pre)clinical studies have assessed the (long-term) effects of fluoxetine exposure in the perinatal period and in adulthood, limited data is available on its effects on the developing brain later in life, i.e. during adolescence. The present study aimed at investigating the effects of age following chronic SSRI treatment on the central serotonin (5-HT) system. To this end, pharmacological MRI (phMRI) was performed in chronic fluoxetine-treated (5 mg/kg, oral gavage for 3 weeks) juvenile (PND25) and adult rats (PND65) after a 1-week washout period, using an acute fluoxetine challenge (5 mg/kg, i.v.) to trigger the 5-HT system. We observed a diminished brain response to the acute challenge in adult treated animals when compared to control animals, whereas this response was increased in juvenile treated rats. As a result, a significant age by treatment interaction effect was seen in several (subcortical) 5-HT related brain regions. An opposite effect of chronic fluoxetine treatment was seen in the developing brain compared to that in matured brain, as assessed non-invasively using phMRI. These findings most likely reflect neuronal imprinting effects of juvenile SSRI treatment and may underlie emotional disturbances seen in animals and children treated with this drug. Also, our findings suggest that phMRI might be ideally suited to study this important issue in the pediatric population.