Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats

Abstract

Clinical evidence suggest that men are more sensitive than women to the abuse-related effects of mu-opioid agonists. In contrast, preclinical studies suggest the opposite sex difference. The aim of the present study was to clarify this discrepancy using a fentanyl vs. diluted Ensure^® choice procedure to assess sex differences in opioid reinforcement. Sex differences in intravenous (IV) fentanyl self-administration were examined under a fixed-ratio (FR5) schedule, a multi-day progressive-ratio (PR) schedule for behavioral economic analysis, and a concurrent (choice) schedule of fentanyl and diluted Ensure^® reinforcement in Sprague-Dawley male and female rats. The fentanyl dose-effect function under the FR5 schedule was significantly shifted upward in females compared to males. Similarly, the reinforcing effectiveness of both fentanyl (3.2 and 10 µg/kg per injection, IV) and diluted Ensure^® (18 and 56%) were greater in females than in males as assessed using behavioral economic analysis, irrespective of dose or concentration. However, under a fentanyl vs. foodchoice procedure, males chose 3.2 µg/kg per injection fentanyl injections over 18%, but not 56%, diluted Ensure^® at a higher percentage compared to females. Overall, these results suggest that the expression of sex differences in opioid reinforcement depends upon the schedule of reinforcement and that preclinical opioid vs. food choice procedures provide a translationally relevant measure (i.e., behavioral allocation) consistent with the direction of sex differences reported in the clinical literature.

Fig. 1

Fentanyl self-administration in male (circles; n = 12) and female (squares; n = 11) rats under a fixed-ratio 5 (FR5) schedule of reinforcement. Ordinate: number of fentanyl injections earned per 120-min behavioral session. Abscissa: unit dose of fentanyl in µg/kg per injection. All points depict mean ± SEM. Filled symbols denote significantly (p < 0.05) different from saline. * denotes a significant difference between sexes at a particular unit dose of fentanyl

Fig. 2

Diluted Ensure^®-maintained responding under a multi-day progressive-ratio schedule for 18% (top panel) or 56% (bottom panel) diluted Ensure^® in male (circles; n = 6) and female (squares; n = 6) rats. a, d depict aggregate demand functions and nonlinear regression using the exponential model of demand for 18 and 56% diluted Ensure^®, respectively. Ordinate: number of reinforcers earned per 120-min behavioral session. Abscissa: response requirement. Individually determined essential values for 18 and 56% diluted Ensure^® are depicted in b and e, respectively. Individually determined Q₀ values for 18 and 56% diluted Ensure^® are depicted in c and f, respectively. *denotes significant (p < 0.05) difference between male and female rats

Fig. 3

Fentanyl-maintained responding under a multi-day progressive-ratio schedule for 3.2 (top panel) or 10 (bottom panel) µg/kg per injection fentanyl in male (circles; n = 6) and female (squares; n = 6) rats. a, d depict aggregate demand functions and nonlinear regression using the exponential model of demand for 3.2 or 10 µg/kg per injection fentanyl, respectively. Ordinate: number of reinforcers earned per 120-min behavioral session. Abscissa: response requirement. Individually determined essential values for 3.2 or 10 µg/kg per injection fentanyl are depicted in b and e, respectively. Individually determined Q₀ values for 3.2 or 10 µg/kg per injection fentanyl are depicted in c and f, respectively. *denotes significant (p < 0.05) difference between male and female rats

Fig. 4

Fentanyl self-administration under a fentanyl vs. food choice procedure in male (circles; n = 14) and female (squares; n = 14) rats. Left panels show results for intravenous fentanyl and 18% diluted Ensure^®. Right panels show results for intravenous fentanyl and 56% diluted Ensure^®. Abscissa: unit dose of fentanyl in µg/kg per injection. Top ordinate: percentage of completed ratio requirements on the fentanyl-associated lever. Bottom ordinate: number of choices completed per component. All points represent mean ± SEM obtained during three consecutive sessions. * denotes significant (p < 0.05) difference in the percent fentanyl choice at a given unit dose between sexes