Paradoxical changes in brain reward status during oxycodone self‐administration in a novel test of the negative reinforcement hypothesis

Background and Purpose The extra medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self‐stimulation (ICSS) reward and oxycodone intravenous self‐administration (IVSA) models. Experimental Approach Male Wistar rats were given access to oxycodone IVSA (0.15 mg·kg −1 per infusion, i.v.) in short‐access (ShA; 1 h) or long‐access (LgA; 12 h) sessions for five sessions per week followed by intermittent 60‐h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11‐h LgA sessions. Key Results Rats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60‐h discontinuation. Presession brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1‐h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60‐h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long‐acting κ‐opioid antagonist norbinaltorphimine prior to IVSA training. Conclusion and Implications Changes in brain reward function during escalation of oxycodone self‐administration are driven by an interplay between κ‐opioid receptor‐mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.