Fig. 1. Bidirectional effect of remifentanil self-administration on PrLC L5/6 pyramidal neurons in males and females.

a Self-administration, abstinence timeline, and location of whole-cell recordings in the PrLC. b For mice that received 10–16 days of self-administration, no difference was observed for active presses during maintenance between remifentanil males (blue, unfilled) and females (blue, filled) whereas females had greater inactive responses (gray, filled) compared to males (gray, unfilled). c Cumulative remifentanil infusions during the entire 10–16-day self-administration procedure did not differ in males (M) vs. females (F). d Comparison of mean action potential (AP) threshold (rheobase) in PrLC L5/6 pyramidal neurons following 14–21-day abstinence from 10- to 16-day self-administration in males and females showed that rheobase was similar in females compared to males under saline conditions (SAL). Alternatively, remifentanil (REM) increased rheobase in females but reduced it in males compared to respective controls. e For 25–30-day self-administration groups, active lever responding did not differ between remifentanil males (orange, unfilled) and females (orange, filled) or across days during maintenance. Alternatively, males exhibited significantly lower inactive lever responding compared to females on days 9, 13, and 19–25. f Cumulative remifentanil infusions were elevated in females (F) compared to males (M). g Comparison of rheobase following 14–21-day abstinence from 25–30 days of self-administration showed a significantly higher firing threshold in remifentanil males and females compared to respective saline controls. h–i Current-spike analysis in 10–16-day self-administering mice showed a trend toward increased firing frequency in remifentanil vs. saline males (h) whereas i remifentanil females exhibited similar firing at lower currents and increased firing at higher potentials (380 pA) compared to controls. j Following 25–30 days of self-administration, current-spike analysis showed firing frequency was reduced at lower currents (140–220 pA) but increased at more depolarized potentials (340–380 pA) in remifentanil vs. saline males. k Remifentanil females showed reduced firing frequency at lower currents (100–180 pA) but similar firing frequency at more depolarized potentials vs. saline females. Representative scale bars: 20 pA/200 ms. Representative spike firing following 200 pA current injection. All data are presented as the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001; ^^^p < 0.001 main effect of treatment.