Fentanyl self-administration is accelerated by methamphetamine co-use and results in worsened hypodopaminergia in male, but not female rats

Combined use of fentanyl and methamphetamine (FENT + METH) has increased in recent years and has been documented in a growing number overdose deaths each year. The impact of FENT + METH on behavior and neurobiology is not well understood. In this study, male and female Long Evans rats were tested on a limited access, fixed ratio 1 self-administration schedule for increasing doses (1.25–5 μg/kg/infusion; iv) of fentanyl, with and without a single dose (0.1 mg/kg/infusion; iv) of methamphetamine, for 15 days. FENT + METH abolished dose responsiveness to fentanyl in all rats and accelerated intake in males, resulting in patterns of responding that may be more likely to result in adverse effects. Ex vivo slice voltammetry in the nucleus accumbens core showed decreases in dopamine release and reuptake (V_max) following FENT + METH exposure, compared with saline, fentanyl, and methamphetamine alone groups at baseline parameters. Further, significant decreases in dopamine release were observed across a range of stimulation intensities following FENT + METH exposure. Overall, male and female rats displayed sex-specific behavioral and neurobiological responses to FENT + METH exposure, with males displaying increased vulnerability.