Brief antibiotics exposure during adolescence produces persistent effects on the microbiome and fentanyl-seeking during adulthood in rats.

Introduction: Adolescence is a developmentally sensitive period during which individuals begin experimenting with drugs of abuse. This window coincides with maturation of brain structures critical to reward and decision-making, including the prefrontal cortex, as well as peripheral physiological systems such as the gut microbiome - making it a period of heightened vulnerability to the long-lasting effects of drug exposure. Work from our lab has shown that manipulations to the gut microbiome influence drug reward, reinforcement, and drug seeking after abstinence. Critically, some of these effects are age-dependent with adolescents demonstrating greater sensitivity to the effects of microbiome disturbance on drug reward. Behavioral changes induced by microbiome disruption occur in parallel with molecular changes in reward-related brain regions like the medial prefrontal cortex. However, whether adolescent microbiome disruption produces alterations in opioid seeking and molecular changes in brain reward regions that persist into early adulthood has not been investigated. Methods: In the current study, we examined the effects of oral antibiotics during adolescent fentanyl self-administration on drug seeking, microbiome composition, and proteomic changes in the prefrontal cortex in adulthood. Results: Adolescent antibiotics reduced contextual but not cue-induced drug seeking and changes in the medial prefrontal cortex proteome suggest global alterations in pathways regulating cellular metabolism and neurotransmitter release. Discussion: Together this work indicates that brief oral antibiotics during adolescence produces long-lasting impacts on both brain and behavior.