Peripubertal PTSD-like stress in rats induces transient behavioral but lasting metabolic and inflammatory alterations: Limited fluoxetine efficacy

Abstract

Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder, with neuroendocrine, metabolic, and immune alterations accompanying its behavioral symptoms. While selective serotonin reuptake inhibitors such as fluoxetine are widely used to treat PTSD, their systemic effects during critical developmental periods remain poorly understood. Using a peripubertal rat model of PTSD-like stress, we evaluated the effects of fluoxetine administered during puberty on behavior (passive avoidance), serum biochemistry, hematology, and IL-6 levels. Assessments were conducted in two phases: shortly following the end of fluoxetine treatment and in a delayed post-treatment period. PTSD-like stress enhanced aversive memory retention, an effect attenuated by fluoxetine in the short post-treatment phase but not in the delayed period. Uric acid content in serum was increased in both PTSD and PTSD+fluoxetine groups shortly post-treatment, while LDL elevation was observed only in the delayed phase. The long-term effect of fluoxetine on serum creatinine was observed. Additional hematological alterations were observed in the delayed period. Serum IL-6 levels remained persistently elevated in PTSD group across both phases, indicating sustained inflammation with no clear effect of fluoxetine. Thus, peripubertal PTSD-like stress induces behavioral and metabolic alterations that persist beyond the acute stress period. Fluoxetine partially normalized behavior but failed to prevent long-term biochemical and hematological alterations. These highlight the systemic and time-dependent consequences of peripubertal PTSD and its pharmacological treatment, underscoring the need for longitudinal monitoring of physiological outcomes alongside recovery of behavioral phenotype.