Towards the Treatment of Neuropsychiatric Disorders: The Impact of Amphetamine on the Dopamine System in Relation to Ovarian Hormone Cycles

Overview

Amphetamine is a psychostimulant that is widely prescribed for neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), due to its ability in enhancing striatal dopamine processing. Biological sex critically affects this process as sex differences in both basal and stimulant-induced processes influence the expression and treatment of ADHD symptoms. This project aimed to elucidate the mechanism underlying this process and test the hypothesis that circulating ovarian hormones in females enhance basal dopamine activity, leading to increased stimulant efficacy. Using ex -vivo fast scan cyclic voltammetry, I investigated sex differences in dopamine release and clearance in rodent striatal brain slices at baseline and with increasing d oses of amphetamine. To monitor ovarian sex hormone effects on dopamine processing, female rodents were categorized by their estrous cycle stage. Dopamine measurements were taken in males, females in proestrus/estrus when estradiol levels are highest, and females in metestrus/diestrus when estradiol levels are low and comparable to males. When the data were separated by biological sex, baseline dopamine release and clearance were sensitive to ovarian hormone cycle and enhanced in proestrus/estrus females. Additionally, amphetamine’s effects at the dopamine transporter (DAT), which mediates dopamine clearance, was highly sensitive to ovarian hormone cycle and further enhanced in proestrus/estrus females. The results of these studies provide valuable mechanist ic insights into the sex differences observed in response to stimulant medications, suggesting there may be larger implications in how these medications are prescribed to women for treatment of many neuropsychiatric disorders, such as ADHD. Texas