Sex differences in psychostimulant effects at the dopamine transporter

Abstract

Substance Use Disorder (SUD) is characterized by drug seeking, increased drug taking, and relapse. Females are particularly vulnerable to the debilitating effects of SUD and show increases in drug taking, a faster transition from first drug use to the development of SUD, and enhanced relapse. The mesolimbic dopamine pathway, which connects the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is an essential component of the neural circuit that promotes reward-seeking behavior. This is because nearly all drugs of abuse increase levels of the neurotransmitter dopamine in the NAc. The ability of stimulant substances of abuse, like cocaine, to drive drug taking/seeking has been linked to their ability to inhibit the function of the dopamine transporter (DAT) - thus increasing dopamine levels in the synaptic cleft in the NAc. A major factor that could be contributing to sex differences in psychostimulant effects on dopamine neurotransmission and DAT kinetics, is estrous cycle dependent ovarian hormone fluctuations. Taking this into consideration, we took a multifaceted approach to understand how sex differences in psychostimulant effects at the DAT could be driven by estrous cycle-dependent neurochemical mechanisms. First, using positive reinforcement operant conditioning to measure sex differences in reward-seeking behavior, we found that female mice consumed more sucrose than males, suggesting that female mice are more motivated to work for non-drug rewards. Next, using fast-scan cyclic voltammetry (FSCV) paired with pharmacology, we measured the effect of cocaine on sub-second dopamine release and DAT kinetics in male and female mice in either diestrus (low circulating hormones) or estrus (high circulating hormones). We found that cocaine potency was increased specifically during estrus (high circulating hormones), compared to males and females in diestrus (low circulating hormones). Together, these data suggest that psychostimulant effects on DAT in females during estrus increases dopamine levels in the NAc and likely drives enhanced reward seeking behavior in females. Moving forward it will be critical to determine whether this effect in females is unique to cocaine or generalizes across all stimulant drugs and further determine how these mechanisms play a key role in increasing reward seeking behavior in female subjects compared to males.