Postnatal and Juvenile Fluoxetine Treatment Evokes Sex-Specific, Opposing Effects on Mood-Related Behavior, Gene Expression, Mitochondrial Function, and Dendritic Architecture in the Rat Medial Prefrontal Cortex.

Background: Serotonin shapes emotional neurocircuit development, and serotonergic neurotransmission is implicated in both the pathophysiology and treatment of neuropsychiatric disorders. The selective serotonin reuptake inhibitor fluoxetine is a common first-line treatment for childhood and adolescent mood disorders due to a favorable risk-benefit profile. Using a rodent model, we addressed specific long-term behavioral, molecular, bioenergetic, and cytoarchitectural consequences of postnatal fluoxetine (PNFlx) and juvenile fluoxetine (JFlx) treatment.

Methods: Rat pups received PNFlx (postnatal day 2 [P2]-P21) or JFlx (P28-P48) treatment with the impact on anxiety- and despair-like behavior examined in adulthood, along with assessing global gene expression, mitochondrial function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC).

Results: PNFlx and JFlx evoked long-lasting, opposing changes in anxiety- and despair-like behavior in male, but not female, rats. The PNFlx- and JFlx-evoked increase and decrease in anxiety- and despair-like behavior, respectively, were accompanied by distinctive, minimally overlapping, transcriptional changes in the mPFC in adulthood. Furthermore, we noted starkly differing outcomes of PNFlx and JFlx on mitochondrial function and dendritic cytoarchitecture in the mPFC. The PNFlx-evoked despair-like behavior was reversed by adult-onset treatment with nicotinamide, a NAD⁺ (oxidized nicotinamide adenosine dinucleotide) precursor that enhances mitochondrial bioenergetics.

Conclusions: Collectively, our findings highlight distinct developmental epochs wherein fluoxetine exposure can program long-term, sex-specific, opposing outcomes on mood-related behavior, accompanied by persistent changes in gene expression, mitochondrial function, and neuronal cytoarchitecture in the mPFC in adulthood. These findings provide motivation for future studies to examine a potential role for altered bioenergetics in shaping the differential impact of early fluoxetine treatment on emotionality.