EARLY-LIFE METHYLPHENIDATE DECREASES SOCIAL ANXIETY IN ADULT FEMALE RATS WITHOUT CENTRAL DOPAMINE DEFICIENCY

Methylphenidate (MPH) is the most commonly-prescribed medication for treating ADHD. Despite high prescription rates among kindergarten-aged children, MPH was not approved for use in children younger than nine, and research into its long-term consequences is lacking. Here, we examined the effects of early-life MPH exposure on anxiety-like behaviors in adulthood in normal rats and rats with dysfunctional central dopamine. On postnatal day (PD) 3, male and female rat pups were injected intracisternally with 6-OHDA or vehicle to generate normal and dopamine-deficient groups. In an initial pair of experiments, 6-OHDA (50, 100 and 150 µg/10µL infusion) was assessed for its ability to induce an ADHD-like phenotype. Subsequently, rats were lesioned with 6-OHDA (100 µg/infusion) or vehicle on PD3 and given MPH (0, 0.5, 2 or 5 mg/kg, i.p.) once daily for 10 days, starting on PD11. On PD60, anxiety-like behavior was assessed with light/dark box or social interaction tests. On PD65, all rats were tested on the elevated plus maze (EPM). Rats with neonatal 6-OHDA lesions exhibited anxiety-like behavior in the light/dark box test and on the EPM. However, there was a complex interaction between sex, lesion, and drug dose in the social interaction test. Pretreatment with 2 mg/kg MPH increased investigatory behaviors in non-lesioned females and decreased investigatory behaviors in lesioned females, suggesting that the long-term effects of early-life MPH in females depend on normal dopamine levels. Together, these experiments support the efficacy of preclinical ADHD models and diverse measures of anxiety-like behaviors when studying the effects of early-life MPH exposure