Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors

Abstract

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

Keywords: DAT; cocaine; dopamine; modafinil.

Figure 1

Normal DA neurotransmission and typical DAT inhibition. (Left panel) During normal DA neurotransmission, a signal travels down the transmitting neuron’s axon causing the release of DA stored in vesicles. DA diffuses across the synaptic cleft and binds to receptors on the post-synaptic receiving neuron. Once the signal has been transduced, the DA diffuses back across the synaptic cleft, then is transported back into the transmitting neuron via the membrane transporter DAT and is recycled back into synaptic vesicles. (Right panel) With a typical DAT inhibitor, DAT is blocked, and when DA is electrically evoked, DA increases in the synapse due to increased DA vesicular packaging and release, as well as decreased DA clearance.

Figure 2

Female estrus cycles compared in humans and rodents. Female mammals undergo regular cycling in levels of estrogen and progesterone hormones during the reproductive cycle. In rodents, this cycle is known as the estrous cycle and lasts approximately 4–5 days; in humans, this cycle is known as the menstrual cycle, which lasts about 28 days (Adapted from [39,40]).

Figure 3

Atypical DAT inhibition effects on neurotransmission. Based on our recent studies, distinct DAT conformations may play a role in its interactions with other membrane proteins. Cocaine binding to DAT stabilizes an inward-facing DAT conformation that facilitates such interactions and produces downstream effects, for example, increasing the availability of the releasable pool of DA-containing vesicles and an enhancement of stimulus-evoked DA release. At variance with cocaine-like DAT inhibitors, atypical DAT blockers preferentially bind DAT in an inward-facing conformation, resulting in less, potentiation of stimulus-evoked DA release compared to typical DAT inhibition.