PT  - JOURNAL ARTICLE
AU  - Jacques D. Nguyen
AU  - Yanabel Grant
AU  - Michael A. Taffe
TI  - Paradoxical changes in brain reward status during opioid self-administration in a novel test of the negative reinforcement hypothesis
AID  - 10.1101/460048
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 460048
4099  - http://biorxiv.org/content/early/2019/11/17/460048.short
4100  - http://biorxiv.org/content/early/2019/11/17/460048.full
AB  - Background and Purpose The extra-medical use and addiction of 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/infusion, i.v.) in Short Access (ShA; 1 h) or Long Access (LgA; 12 h) sessions for 5 sessions/week followed by intermittent 60 h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. A separate group was 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 significant increases following 60 h discontinuations. Pre-session 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 administered the long-acting kappa opioid antagonist norBNI prior to IVSA training.Conclusions and Implications Changes in brain reward function during escalation of oxycodone selfadministration is driven by an interplay between kappa opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.