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

Br J Pharmacol. 2021 Sep;178(18):3797-3812. doi: 10.1111/bph.15520. Epub 2021 Jun 8.


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.

Keywords: escalation; intracranial self-stimulation reward; oxycodone; self-administration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain
  • Male
  • Oxycodone*
  • Rats
  • Rats, Wistar
  • Reinforcement, Psychology
  • Reward*
  • Self Administration


  • Oxycodone