An FSCV Study on the Effects of Targeted Typical and Atypical DAT Inhibition on Dopamine Dynamics in the Nucleus Accumbens Shell of Male and Female Mice

Understanding the neurochemistry underlying sex differencesinpsychostimulant use disorders (PSUD) is essential for developing relatedtherapeutics. Many psychostimulants, like cocaine, inhibit the dopaminetransporter (DAT), which is largely thought to account for actionsrelated to their misuse and dependence. Cocaine-like, typical DATinhibitors preferentially bind DAT in an outward-facing conformation,while atypical DAT inhibitors, like modafinil, prefer a more inward-facingDAT conformation. Modafinil and R-modafinil haveemerged as potential therapeutic options for selected populationsof individuals affected by PSUD. In addition, analogs of modafinil(JJC8-088 and JJC8-091) with different pharmacological profiles havebeen explored as potential PSUD medications in preclinical models.In this work, we employ fast scan cyclic voltammetry (FSCV) to probenucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 maleand female mice. We find that cocaine slowed DA clearance in bothmale and female mice but produced more robust increases in evokedNAS DA in female mice. R-Modafinil produced mildincreases in evoked NAS DA and slowed DA clearance across the sexes.The modafinil analog JJC8-088, a typical DAT inhibitor, produced increasesin evoked NAS DA in female and male mice. Finally, JJC8-091, an atypicalDAT inhibitor, produced limited increases in evoked NAS DA and slowedDA clearance in both sexes. In this work we begin to tease out howsex differences may alter the effects of DAT targeting and highlighthow this may help focus research toward effective treatment optionsfor PSUD.