Prenatal, but not neonatal, paracetamol exposure disrupts neuroendocrine regulation of stress and emotional behavior in adult male rats

Paracetamol is a widely used analgesic and antipyretic, commonly administered during pregnancy and early postnatal life. Its mechanism of action involves inhibiting cyclooxygenase-2/3 (COX-2/3) enzymes, which play a critical role in normal brain development during the perinatal period. In this study, we investigated anxiety-like behavior, depression-like behavior, and corticosterone levels in adult male rats following either prenatal or neonatal paracetamol exposure. Pregnant dams received subcutaneous injections of paracetamol (60 mg/kg) or saline every 12 h from gestational day (GD) 16 to 20, while neonatal pups received the same treatment from postnatal day (PD) 1 to 5. At PD70, a subset of males was allowed to gain sexual experience, while others remained sexually naïve. Behavioral assessments were conducted on PD94 and PD95 using the elevated plus maze and the forced swim test, respectively. On PD107, males were exposed to bedding from estrous females as a social stimulus, and serum corticosterone levels were measured. Prenatal paracetamol exposure resulted in significantly reduced anxiety-like behavior and serum corticosterone, along with increased depression-like behavior in adulthood. In contrast, neonatal exposure produced no significant behavioral or hormonal alterations. These findings reveal differential sensitivity to paracetamol during distinct developmental windows, with prenatal exposure leading to long-lasting disruptions in emotional regulation and neuroendocrine stress responses. These effects may be mediated by COX inhibition or interference with neural circuits involved in stress regulation and motivational processing.