Development and validation of a novel oral oxycodone self-administration protocol for female and male rats

ABSTRACT The increased abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Here we present a novel oral oxycodone self-administration paradigm in rats that recapitulates key aspects of prescription opioid abuse: voluntary drug intake, long-term opioid exposure, measurable levels of dependence, and increased motivation to take drug. Adult female and male Long-Evans rats were given unlimited, home cage access to two bottles containing water (Control rats) or one bottle of water and one bottle of Oxycodone dissolved in water (Experimental rats). Virtually all Experimental rats voluntarily drank oxycodone (~10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater levels of oxycodone in blood, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes in the total withdrawal score and in individual withdrawal behaviors. Reflecting motivation to drink oxycodone, citric acid at ascendant concentrations suppressed the intake of oxycodone (Experimental rats) and the intake of water (Control rats); however Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Finally, long-term exposure to oxycodone reduced the alpha diversity of the gut microbiome compared to water Controls but had varying effects on the relative abundance of select bacterial Phyla. Thus, our model reproduces in female and male rats many of the features of human oxycodone abuse, and provides a paradigm for both understanding mechanisms that mediate long-term voluntary drug use and for exploring potential treatment options.