Antibiotic-induced Microbiome Depletion Selectively Reduces Baseline Hypothalamic Oxytocin Signaling without Affecting MDMA-induced Oxytocin Response in Rats

Objective: To determine whether antibiotic-induced microbiome depletion influences baseline or 3,4-methylenedioxymethamphetamine (MDMA)-induced oxytocin signaling in rats. Methods: Male Wistar rats received broad-spectrum antibiotics (ABX) or water for 7 days, followed by a single oral administration of MDMA (30 mg/kg). Plasma oxytocin levels were measured by ELISA, and oxytocin-immunoreactivity in the paraventricular (PVN) and supraoptic (SON) nuclei were quantified by immunofluorescence. Results: ABX treatment induced marked cecal enlargement without affecting body weight, confirming microbiome disruption while maintaining systemic stability. Peripheral oxytocin concentrations were unchanged; however, baseline central oxytocin expression in both the PVN and SON was significantly reduced after ABX treatment. MDMA increased central oxytocin expression, and this response was not significantly altered by microbiome depletion. Similarly, MDMA-induced peripheral oxytocin levels did not differ between control and ABX-treated rats. Conclusion: Antibiotic-induced microbiome depletion selectively attenuates baseline central oxytocin signaling while leaving peripheral oxytocin regulation intact. In contrast, MDMA-induced oxytocin responses in both the brain and circulation are preserved despite microbiome disruption. These findings suggest that gut microbiota contribute to central oxytocin homeostasis under basal conditions but are not essential for acute MDMA-induced oxytocin activation.