Effects of Early-Life Acetaminophen and Interleukin-1B Exposures on Anxiety, Motor, and Play Behaviors in Long-Evans Rats

Acetaminophen (APAP) is the leading antipyretic and analgesic drug administered to infants and pregnant women. Nevertheless, epidemiological evidence has implicated both early-life APAP (ELA) and early-life inflammation (ELI) as risk-factors for neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). Moreover, both APAP-induced toxicity and high levels of inflammation may be more prevalent among males, which may make them more susceptible to neurodevelopmental effects of these exposures. Rodent studies of ELA and ELI to date support epidemiological findings in humans, with each respective exposure altering social, anxiety, and motor behaviors. Additionally, previous studies have shown sex-specific effects of both exposures, with males being more prone to social alterations than females. Given that both ELA and ELI have effects on dopaminergic signaling, this dissertation aimed to examine whether these exposures alter social play and anxiety (i.e., DA-dependent behaviors) in rats. Long-Evans rats were injected subcutaneously with IL1B+Veh, Veh+APAP, IL1B+APAP, or Veh+Veh during postnatal days 9 (P9), P11, and P13. Anxiety and motor behaviors were quantified during adolescence and adulthood using open field assays. Social play was quantified during adolescence in a social interaction test with an unfamiliar partner. IL1B treatment led to lower fecal boli count in adulthood, indicating decreased anxiety. APAP-treated rats showed a decrease in activity levels in adolescence, but an increase in adulthood. These results suggest that IL1B and APAP have varying impacts on anxiety behaviors and activity levels, depending on the stage of development during which these behaviors were assayed. Moreover, IL1B x APAP interactions showed that APAP and IL1B increased total duration of social approach. However, IL1B+APAP-treated rats showed total duration of approach comparable to control rats. These findings suggest that the behavioral effects of IL1B and APAP are not synergistic. Moreover, sex-specific effects of IL1B were found as IL1B-treated females showed more dramatic differences in exploratory behaviors (i.e., frequency in the center) and average bout duration of play compared to IL1B-treated males. Furthermore, APAP decreased clockwise rotations in females, not males. As such, these findings also suggest that females may be more vulnerable to IL1B- and APAP-induced behavioral changes compared to males when exposed during infancy.