Training phase

Rats (n = 42) were randomly assigned to either saline (Sal) (n = 8) or oxycodone (n = 33) conditions. Rats were trained to self-administer oxycodone-HCL (NIDA Pharmacy, Baltimore, MD) for one 3 h daily session for the short-access (ShA) condition (n = 10) or one to three 3 h sessions for long-access (LgA) condition (n = 23) (Fig. 1A). For the LgA group, the 3 h sessions were separated by 30 min intervals from day 6 to day 20 (Fig. 1A). Lever presses were reinforced using a fixed ratio-1 with a 20-s timeout accompanied by a 5-s compound tone-light cue. We used a scheduling pattern of 5 days of drug SA and 2 days off to control for weight loss, a common side effect of oxycodone intake in laboratory animals²⁵. Rats self-administered oxycodone at a dose of 0.1 mg/kg per infusion over 3.5-s (0.1 ml per infusion). The house light was turned off, and the active lever retracted at the end of the 3 h session.

Rats exposed to long-access, but not short-access, oxycodone SA escalate their drug intake. (A) Experimental timeline of oxycodone self-administration (SA) training. Rats self-administered oxycodone using either short-access (ShA) (n = 10) (trained for 3 h for 20 days) or long-access (LgA) (n = 21–23) (trained for 3 h for 1–5 days, 6 h for 6–10 days, then 9 h for 11–20 days) paradigms. (B) LgA rats escalate their intake of oxycodone after the first 5 days of SA training. (C) LgA rats show significant increases in active lever presses during SA training. (D) LgA-H rats show two distinct intake phenotypes, high (LgA-H) (n = 10) and low (LgA-L) (n = 13) oxycodone takers, during the escalation phase. (E) LgA-H rats took substantially more oxycodone than LgA-L and ShA rats. Key to statistics: *, **, *** = p < 0.05, 0.01, 0.001, respectively, in comparison to Sal rats; #, ##, ### = p < 0.05, 0.01, 0.001, respectively, in comparison to SHA rats; $$, $$$ = p < 0.01, 0.001 in comparison to LgA-L rats. Stats were performed by either one-way or two-way ANOVA followed by Bonferroni or Fisher’s PLSD post hoc test.