Intermittent abstinence potentiates oxycodone self-administration under extended access conditions and alters brain reward sensitivity

Prescription opioid addiction is a significant health problem characterized by compulsive drug seeking, withdrawal and chronic relapse. This study investigated the neurobiological consequences of escalation of prescription opioid use using an oxycodone intravenous self-administration (IVSA) model in rats. Male Wistar rats were trained oxycodone self-administration (0.15 mg/kg/infusion, i.v.) in 1h or 11-12h access sessions. Rats given 12 h Long Access (LgA) to oxycodone for 5 sessions/week escalated their responding more than rats given 1h oxycodone Short Access (ShA). Interestingly, a significant increase in oxycodone intake was observed after 60 h weekend discontinuations from drug access. A separate group of rats was trained in the intracranial self-stimulation (ICSS) reward procedure and then intravenous oxycodone self-administration in LgA sessions. Pre-IVSA brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily abstinence cycles. A 1 h IVSA interval was sufficient to normalize these elevated reward thresholds. Interestingly, the brain reward thresholds normalized to baseline across 60 h weekend abstinences. This latter finding is consistent with a normalization of brain reward status suggesting the associated increased IVSA of drug was not driven entirely by a persisting negative affective state. Escalated oxycodone taking when abstinence periods vary may be driven by a complex mix of negative and positive reinforcing effects of the drug.