Chronic cocaine exposure modulates decision-making in mice in a sex-dependent manner

Women progress from initial cocaine use to cocaine use disorder more rapidly than men, possibly reflecting cocaine-induced impairments in decision-making. Human gambling task (GT) studies investigating the effects of cocaine use have shown inconsistent findings, with many excluding female participants. We hypothesised that cocaine exposure may affect decision-making in males and females differently. To this end, male and female C57BL/6JRj mice were injected with cocaine or saline for 21 days. Beginning on the first day of cocaine withdrawal, they were tested on the acquisition of a mouse GT, loosely based on the human Iowa GT. In order to investigate the mechanistic underpinnings of potential sex differences, the effects of chronic cocaine exposure on total dopamine levels in the striatum (estimated using high-performance liquid chromatography), on cell death in the prefrontal cortex (assessed using 4',6-diamidino-2-phenylindole/propidium iodide staining), and on glutamate dynamics in the prefrontal cortex (measured using in vivo fibre photometry) were investigated in separate mouse cohorts. Chronic cocaine exposure impaired the acquisition of optimal decision-making strategy in female mice, but facilitated it in male mice. The cocaine exposure regimen did not drive sex-dependent changes in striatal dopamine levels but was associated with higher amplitudes of glutamate events and greater cell death in the prefrontal cortex in females compared with males. Thus, cocaine use disorder may affect decision-making in a sex-dependent manner. Investigating such differences may offer valuable insights into the telescoping effect of cocaine use disorder in women.