Oxycodone self-administration in male and female rats

Abstract

Rationale: Oxycodone is one of the most widely prescribed painkillers in the USA. However, its use is complicated by high abuse potential. As sex differences have been described in drug addiction, the present study tested for sex differences in intravenous oxycodone self-administration in rats.

Methods: Male and female Sprague-Dawley rats were implanted with jugular vein catheters and trained to self-administer oxycodone (0.03 mg/kg/infusion) under fixed ratio 1 (FR1), FR2, and FR5 schedules of reinforcement followed by a dose-response study to assess sensitivity to the reinforcing effects of oxycodone. In separate rats, sucrose pellet self-administration was assessed under an FR1 schedule to determine whether sex differences in oxycodone self-administration could be generalized across reinforcers. In separate rats, oxycodone distribution to plasma and brain was measured after intravenous drug delivery.

Results: In the first 3 trials under an FR1 schedule of reinforcement, male rats self-administered more oxycodone than females. In contrast, females self-administered more sucrose pellets. Under FR2 and FR5 schedules, no significant sex differences in oxycodone intake were observed, although female rats had significantly more inactive lever presses. Male and female rats showed similar inverted U-shaped dose-effect functions, with females tending to self-administer more oxycodone than males at higher doses. No significant sex differences were observed in plasma or brain oxycodone levels, suggesting that sex differences in oxycodone self-administration behavior were not due to pharmacokinetics.

Conclusion: Our results suggest subtle sex differences in oxycodone self-administration, which may influence the abuse liability of oxycodone and have ramifications for prescription opioid addiction treatment.

Keywords: Motivation; Oxycodone; Self-administration; Sex differences; Sucrose reward.

Fig. 1. a

Active and inactive lever presses and b total number of oxycodone infusions (0.03 mg/kg/infusion) under an FR1 schedule of reinforcement in male (n = 12) and female (n = 11) rats with overnight fasting. Data are expressed as mean ± SEM; Black circles and white circles indicate active lever presses () or infusions (b) in males and females respectively; Black squares and white squares indicate inactive lever presses in males and females respectively (); *p < 0.05 main effect of sex. c Active and inactive lever presses for sucrose and d total sucrose consumed (mg of sucrose adjusted to body weight). There are eight rats/sex (n = 8/sex). Data are expressed as mean ± SEM. Black circles and white circles indicate active lever presses (c) or infusions (d) in males and females respectively; Black squares and white squares indicate inactive lever presses in males and females respectively (c); ++p < 0.01 and +++p < 0.001 compared to the males on the same trial

Fig. 2. a

Active and inactive lever presses and b total number of oxycodone infusions under FR1 schedule of reinforcement and ad libitum feeding conditions in male (n = 12) and female (n = 11) rats. Data are expressed as mean ± SEM; Black circles and white circles indicate active lever presses (a) or infusions (b) in males and females respectively; Black squares and white squares indicate inactive lever presses in males and females respectively (). c Active and inactive lever presses and d total number of oxycodone infusions under FR2 and FR5 schedule of reinforcement and ad libitum feeding conditions in the same male (n = 12) and female (n = 11) rats. Data are expressed as mean ± SEM; Black circles and white circles indicate active lever presses (c) or infusions (d) in males and females respectively; Black squares and white squares indicate inactive lever presses in males and females respectively (c). The gray background represents results collected under an FR2 schedule of reinforcement. Data are presented as mean ± SEM; ***p < 0.0001 main effect of sex for inactive lever presses

Fig. 3. a

The total number of oxycodone infusions during trials 1–10 under the FR5 schedule were plotted for each male and female rat. b Representative drug infusion patterns are plotted for male and female rats that showed either high or low intake compared to the mean of total intake (represented by horizontal lines in a). c Estrous cycles are plotted for each female rat over the 25 trials comprising FR1, FR2, and FR5 schedules of reinforcement. Dark gray squares represent days on which cell types corresponded to estrus. Light gray squares represent days on which estrus would be predicted to occur based on the preceding and following days’ cytology or days in which epithelial cytology was an intermediate of estrus and either proestrus or metestrus

Fig. 4

Oxycodone was replaced by saline for 3 consecutive trials and a active and inactive lever presses and b total number of infusions were assessed. There are six males (n = 6) and seven females (n = 7). Data are expressed as mean ± SEM; Black circles and white circles indicate active lever presses (a) or infusions (b) in males and females respectively; Black squares and white squares indicate inactive lever presses in males and females respectively (a). The gray background represents results collected on the last day of oxycodone self-administration. c Total number of oxycodone infusions during the dose-response in which rats self-administered ascending doses of oxycodone (0.0003–0.3 mg/kg/infusion; one dose per trial/day) in 1-h trials under an FR5 schedule of reinforcement. There are six males (n = 6) and seven females (n = 7). Data are expressed as mean ± SEM; Black circles and white circles indicate total number of oxycodone infusions in males and females respectively. Data are presented as mean ± SEM; *p < 0.05 main effect of sex

Fig. 5. a

Oxycodone distribution in plasma; before (Time = 0) and after (Time = 5, 15, 30, and 60 min) a single injection of oxycodone (0.15 mg/kg, i.v.). There are three males (n = 3) and five females (n = 5). Data are expressed as mean ± SEM; Black circles and white circles indicate oxycodone levels in plasma in males and females respectively. Oxycodone was measured in b plasma and c brain 5-min post-infusion (0.15 mg/kg, i.v.). There are four males (n = 4) and five females (n = 5). Data are presented as mean ± SEM; The black bars represent oxycodone levels in males and the white bars represent oxycodone levels in females