SEX difference in cocaine-induced impulsivity: contribution of the mesocorticolimbic dopamine system and estradiol

Oberlin College received a $400,836 Project Grant from the National Institute on Drug Abuse (NIDA) under the Drug Use and Addiction Research Programs (CFDA 93.279), awarded July 15, 2025, with a completion date of June 30, 2028. The research project investigates sex differences in cocaine-induced impulsivity, focusing on the role of the mesocorticolimbic dopamine system and ovarian hormones, particularly estradiol. The primary deliverables include behavioral assessments measuring impulsive action using the 5-Choice Serial Reaction Time task and the Differential Reinforcement of Low Rates of Responding task, as well as molecular analysis of dopamine-related proteins in brain regions regulating impulse control through Western blot techniques.

The research aims to elucidate mechanisms underlying observed sex differences in drug-taking behavior by determining whether dopamine D1 receptors contribute to enhanced cocaine-induced impulsivity in female rats, whether such impulsivity fluctuates across the estrous cycle, and whether exogenous hormone administration affects impulsivity outcomes. This work will contribute foundational knowledge toward developing more targeted treatment approaches for substance use disorders, addressing the clinical observation that female drug users escalate to problematic drug use patterns more rapidly than males.

Abstract

Female drug users escalate to more problematic patterns of drug use more rapidly than male drug users. Further they exhibit greater dysregulation in their drug-taking behavior. IT is hypothesized that fluctuations in circulating ovarian hormones (estradiol and progesterone) contribute to the variability in drug-taking behavior. For example, when estradiol levels are high, females exhibit enhanced cocaine-self- administration, cocaine reward and increased cocaine-induced locomotor activity. Furthermore, estradiol enhances psychostimulant-mediated dopamine release. We have recently found that female rats exhibit enhanced cocaine-induced impulsive action and exhibit increases in D1 receptors in brain regions regulating impulsivity. The goals of this proposal are to determine 1) if dopamine D1 receptors contribute to the enhancement of cocaine-induced impulsivity in female rats, 2) if cocaine-induced impulsivity fluctuates across the estrous cycle and, 3) if exogenous administration of either estradiol or progesterone affects cocaine-induced impulsivity in ovariectomized rats. In all cases impulsive action will be measured using the 5-choice serial reaction time (5CSRT) task and the differential reinforcement of low rates of responding (DRL) task. Additionally, we will determine if ovarian hormones affect the expression dopamine-related proteins (e.g., D1 receptors, D2 receptors, tyrosine hydroxylase, dopamine transporter, and the vesicular monoamine transporter) in brain areas that regulate impulsive action (e.g., prefrontal cortex, ventral striatum, dorsal striatum) using western blots. This work will determine if changes drug-induced impulsivity could contribute to observed SEX differences in drug-taking behavior; ultimately this may lead to more targeted approaches to treatment. Furthermore, this work will help inspire and train undergraduate researchers at oberlin college to conduct experiments that involve a unique combination of behavioral and molecular techniques. Not only will students learn a variety of techniques, but they will be involved in the experimental design, data collection and analysis, presentation of data at conferences and the preparation of resulting manuscripts. Thus, this proposal will enhance the students' education and will enhance the research environment at oberlin college.