Juvenile Fluoxetine Treatment Mediates an Anxiogenic Phenotype That Is Ameliorated by Its Re-exposure in Adulthood

Accumulating preclinical evidence indicates that early-life exposure to psychotropic medications induce an anxiogenic-like behavioral profile in later life. However, these preclinical approaches have been conducted primarily using male subjects. This is problematic since clinical data indicates that women are more likely to be diagnosed with anxiety disorders than their male counterparts, and thus, women are prescribed with psychotropic medications like fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), at significantly higher rates. Therefore, the goal of this Dissertation is to examine whether alterations in behavioral responses to anxiety-eliciting stimuli are exhibited in adulthood, as a result of early-life FLX exposure. To do this, female C57BL/6 mice were forced to consume FLX (250 mg/L in their drinking water) during adolescence (postnatal days [PD] 35-49). After a 21-day washout period, at PD 70, they were assessed for baseline shifts in anxiety-like behavior using the open field test (OFT), light/dark box (LDB), and elevated plus maze (EPM) â?? tasks traditionally implemented to evaluate anxiogenic responses in rodents. Since SSRIâ??s are prescribed long-term, and throughout the lifespan for the management of anxiety disorders, we further evaluated if FLX re-exposure in adulthood (PD70-84) would reverse such behavioral alteration (PD85). Lastly, because FLX mediates its therapeutic effects by its ability to block the serotonin transporter (5-HTT), thus increasing global serotonin and brain derived neurotropic factor (BDNF), the enduring effects of FLX on the 5HTT, as well as the BDNF TrkB receptor and its downstream-related signaling molecules, were assessed within the hippocampus and prefrontal cortex â?? brain regions implicated in mood-related disorders. We found that adolescent exposure to FLX mediated a persistent anxiogenic profile per the OFT, LDB and EPM, without changes in hippocampal or prefrontal cortex 5-HTT or TrkB receptor levels. However, decreases in BDNF-related signaling markers, within both brain regions assessed, were evident in adulthood, as a function of adolescent FLX pretreatment. Also, as hypothesized, FLX re-exposure in adulthood ameliorated the enduring SSRI-induced anxiety-related responses across all behavioral tasks. Interestingly, FLX re-exposure, in adult female mice with juvenile FLX history, normalized the decrease in BDNF-related signaling markers observed within the prefrontal cortex, but not the hippocampus. Collectively, these data suggest that adolescent exposure to FLX mediates neurobehavioral adaptations that endure into adulthood, which are indicative of a generalized anxiogenic-like phenotype, and that this persistent effect is ameliorated by re-exposure to FLX, in female C57BL/6 mice