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

Abstract

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 mgÁkg À1 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.

Impact of Δ9-Tetrahydrocannabinol and oxycodone co-administration on measures of antinociception, dependence, circadian activity, and reward in mice

“…When nonpreference producing doses of Δ 9 -THC (3 mg/kg) and oxycodone (1 mg/kg) were administered, it resulted in the development of CPP in both sexes. These findings parallel recent literature reporting that vaporized or injected Δ 9 -THC reduces oxycodone (Nguyen et al, 2019;Nguyen et al, 2021;Nguyen et al, 2023) and heroin (Gutierrez et al, 2022) self-administration in rats. The authors in (Nguyen et al, 2021;Nguyen et al, 2023) suggest that Δ 9 -THC may be increasing the rewarding efficacy of a "unit dose" of oxycodone when self-administered.…”

“…These findings parallel recent literature reporting that vaporized or injected Δ 9 -THC reduces oxycodone (Nguyen et al, 2019;Nguyen et al, 2021;Nguyen et al, 2023) and heroin (Gutierrez et al, 2022) self-administration in rats. The authors in (Nguyen et al, 2021;Nguyen et al, 2023) suggest that Δ 9 -THC may be increasing the rewarding efficacy of a "unit dose" of oxycodone when self-administered. Our findings in the CPP paradigm are consistent with this hypothesis.…”

Oxycodone Self-Administration in Female Rats is Enhanced by Δ9-tetrahydrocannabinol, but not by Cannabidiol, in a Progressive Ratio Procedure

“…It was somewhat unexpected that rats reached similar breakpoints for 0.06 and 0.15 mg/kg/infusion in the PR under control condi ons (PG here, also true in the notreatment acclima on sessions) given an apparent difference across this dose range that was observed in prior work with male rats trained in sessions of 1 h or 12 h dura on (Nguyen et al, 2021;Nguyen et al, 2018;Wade et al, 2015). In par cular, Wade and colleagues showed that the largest difference was between the 0.06 and 0.15 mg/kg/infusion doses in the animals trained in 12 h sessions and between the 0.15 and 0.30 mg/kg/infusion doses in the animals trained in 1 h sessions.…”

Systemic kappa opioid receptor antagonism accelerates reinforcement learning via augmentation of novelty processing in male mice

“…The theory states that KOR activity is involved in negative valence domains (e.g., acute threat, potential threat, sustained threat, loss, and frustrative nonreward) and is critical for the development of subsequent behavioral responses to aversive stimuli, such as negative reinforcement [ 12 , 22 , 25 , 42 , 43 ]. The role of KORs in these constructs are typically tested in behavioral assays such as learned helplessness [ 44 ], forced swim stress [ 18 ], stress-induced reinstatement [ 45 , 46 ], and intracranial self-stimulation [ 47 ].…”