Brief exposure to oral antibiotics has age-dependent effects on morphine reward and gene expression in the medial prefrontal cortex of adolescent and adult mice_1

Adolescence is a critical period for the initiation of problematic drug use, which significantly increases the risk of developing substance use disorders later in life. This heightened vulnerability is partly attributed to the immaturity of the prefrontal cortex, a brain region both essential for decision-making and implicated in drug reward. During adolescence, peripheral systems, such as the gut microbiome, also undergo substantial changes. Emerging evidence suggests that disruptions to the gut microbiome can influence gene expression and drug reward behaviors in rodent models. In this study, we investigated the effects of oral antibiotics on morphine reward and prefrontal cortical gene expression in adolescent and adult mice. Using oral antibiotics to transiently disrupt the microbiome, we found that short-term antibiotic exposure reduced morphine place preference specifically in adolescent mice. In a separate cohort, we observed that antibiotic treatment altered the transcriptomic response to morphine in the medial prefrontal cortex across all age groups. Notably, the transcriptomic changes induced by antibiotics and morphine were age-specific, with distinct gene expression patterns observed in adolescents compared to adults. These findings establish a foundation for future research into the role of the gut microbiome in opioid reward and highlight potential gene pathways underlying age-dependent differences in opioid sensitivity. Male C57BL/6J wild type mice adolescent (start PND 25) or adult (start PND 55) given oral antibiotics (Abx) or remained on water and were given injections (s.c.) of saline or morphine (15 mg/kg) for 5 days.