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

Abstract

Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and R-modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. R-Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats

“…Previous studies have shown that JJC8‐091 produced neurochemical effects that diverge from the effects produced by other psychostimulants. For example, JJC8‐091 has been shown to slow DA clearance and produce only a limited increase in evoked DA release in the NAS of rodents (Hersey, Chen, et al, 2023; Keighron et al, 2023; Keighron, Giancola, et al, 2019; Keighron, Quarterman, et al, 2019).…”

“…All animal procedures were approved and performed in accordance with guidelines from the Animal Care and Use Committee of the NIDA‐IRP, Baltimore, MD, which is fully accredited by the AAALAC International. Female rats will be included in future studies (Hersey, Chen, et al, 2023) (reviewed in: Hersey, Bartole, et al, 2023).…”