PPAR-α activation by fenofibrate modulates anxiety-like behaviors in a ketamine-induced schizophrenia-like rat model

Introduction: The pathophysiology of schizophrenia involves complex interactions among multiple neural systems, including glutamatergic and dopaminergic neurotransmission, as well as synaptic dysfunction, neuroinflammation, and oxidative disturbances. The current study investigated the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, on anxiety-like behaviors and locomotor activity in a ketamine-induced schizophrenia-like rat model.
Materials and Methods: Twenty-eight male Wistar rats were randomly divided into four groups: control, ketamine-induced schizophrenia, and two schizophrenia groups treated with fenofibrate at doses of 100 and 200 mg/kg/day. Ketamine (30 mg/kg/day) was administered for 10 consecutive days to induce schizophrenia-like model. Subsequently, anxiety-like behaviors and locomotor activity were evaluated using the elevated plus-maze (EPM) test. The percentage of time spent in, and the percentage of entries into, the open and closed arms were recorded as behavioral indices.
Results: Ketamine administration significantly reduced locomotor activity and the percentage of time spent in the open arms, while increasing the percentage of time spent in the closed arms. Treatment with fenofibrate at 100 mg/kg significantly altered EPM time-related indices, with the percentages of time spent in the open and closed arms approaching those observed in the control group. In contrast, fenofibrate at 200 mg/kg exhibited a different pattern, which was similar to that observed in the schizophrenia group.
Conclusion: Fenofibrate treatment partially ameliorated anxiety-like behaviors, suggesting that PPAR-α activation may have a modulatory role in anxiety-related behavioral defects associated with the ketamine-induced schizophrenia-like model.