Interactions between Biological Sex and Hormonal Cycles in Stimulant Effects on Motor Behavior

Abstract

Substance use disorder (SUD) is a chronic neuropsychiatric disease characterized by long-lasting changes in behavior in response to drugs of abuse. These behavioral changes have previously been linked to drug-induced alternations in dopamine signaling. Although women are more susceptible to developing SUD and are more likely to relapse following periods of abstinence, a majority of work on the behavior basis of SUD has focused on male subjects. Emerging data has identified that estrous cycle-dependent hormone fluctuations play a key role in dopamine release regulation and may also play a role in sex differences in motor behavior in response to stimulant administration. Previous studies have shown that females display enhanced locomotor activity after cocaine exposure, but it is unclear if this increase is cycle-stage dependent and if this effect is similar across structurally dissimilar psychostimulants. Here we investigated a range of doses of each stimulantcocaine (3, 10, or 30 mg/kg), amphetamine (1, 3, or 10 mg/kg), and methylphenidate (3, 10, or 30 mg/kg)in males and freely cycling females to analyze the psychostimulant's effect on locomotor activity. For cocaine, we observed a dose-dependent effect of cycle stage, where females in estrus (high circulating hormones) showed elevated motor responses as compared to females in diestrus (low circulating hormones) and males at the high doses. In contrast, for amphetamine, females were more responsive than males at the lower doses, but these effects were less sensitive to changes in estrous cycle. Finally, for methylphenidate, there was an upward shift in the dose-response curve in males but not females. Interestingly, there was also an estrous-cycle effect in females with diestrus females showing more motor activity than males. Together, these data suggest each psychostimulant displays unique sex-and cycle stage-dependent differences depending on its dose. In the future, it will be critical to directly link these differences to reward processing for the development of sex-specific pharmacotherapies for SUD.