Role of orbitofrontal cortex in incubation of oxycodone craving in male rats

One of the main challenges in treating opioid‐use disorders is relapse during abstinence, triggered by re‐exposure to drug‐associated cues. Previous studies have demonstrated that drug‐seeking in rats progressively increases over time during withdrawal (incubation of drug craving). Here, we used male rats and examined neural mechanisms underlying incubation of craving to oxycodone, a commonly abused prescription opioid, and we focused on orbitofrontal cortex (OFC), a brain region previously implicated in incubation of heroin craving. We first used neuronal activity marker Fos and measured neuronal activation in OFC (ventral and lateral OFC) associated with day‐1 and day‐15 relapse tests. Next, we determined the effect of pharmacological reversible inactivation of OFC on incubated oxycodone seeking on withdrawal day 15. Finally, we determined the effect of reversible inactivation of OFC on nonincubated oxycodone seeking on withdrawal day 1. We found that lever presses during relapse tests were higher on withdrawal day 15 than on withdrawal day 1 (incubation of oxycodone craving). Incubation of oxycodone craving is accompanied with a time‐dependent increase of Fos protein expression in both ventral and lateral OFC. Lastly, OFC inactivation decreased oxycodone seeking on withdrawal day 15 but had no effect on withdrawal day 1. Together with the previous heroin study, results here show that OFC plays a critical role in incubation of opioid craving. We combined Fos immunohistochemistry and pharmacological inactivation to determine the role of orbitofrontal cortex (OFC) in incubation of oxycodone craving in male rats. We found that OFC exhibited a time‐dependent increase of neuronal activation (assessed by the neuronal activity marker Fos) associated with oxycodone seeking during withdrawal, and OFC inactivation with GABA receptor agonists decreased oxycodone seeking on withdrawal day 15 but not day 1. Overall, our results demonstrated a critical role of OFC in incubation of oxycodone craving.