Female and male rats readily consume and prefer oxycodone to water in a chronic, continuous access, two-bottle oral voluntary paradigm

Zanni, Giulia; DeSalle, Matthew J.; Deutsch, Hannah M.; Barr, Gordon A.; Eisch, Amelia J.

doi:10.1016/j.neuropharm.2020.107978

Cited by 34 publications

(41 citation statements)

References 107 publications

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Section: Discussionmentioning

confidence: 96%

“…Because the investigation was only conducted in males, the findings reported in this paper cannot be assumed to generalize to female rats. Sex differences in oral (Fulenwider et al, 2020; Zanni et al, 2020) and intravenous (Kimbrough et al, 2020; Nguyen et al, 2020) oxycodone intake have been reported in rats, although another study found no sex difference in sustained IVSA of oxycodone under varying training conditions (Mavrikaki et al, 2017). Interestingly, even when sex differences in IVSA under fixed‐ratio conditions were reported, there were no sex differences under a progressive ratio dose substitution (Nguyen et al, 2020) or in withdrawal‐induced behaviours (Kimbrough et al, 2020), suggesting similar motivation and similar induction of negative affect across sexes.…”

Section: Discussionmentioning

confidence: 99%

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

Nguyen

Grant

Taffe

2021

British J Pharmacology

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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.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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

Nguyen

Grant

Taffe

2021

British J Pharmacology

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“…Since the investigation was only conducted in males, the findings reported in this paper cannot be assumed to generalize to female rats. Sex differences in oral (Fulenwider et al, 2020; Zanni, DeSalle, Deutsch, Barr & Eisch, 2020) and intravenous (Kimbrough et al, 2020; Nguyen, Creehan, Kerr & Taffe, 2020) oxycodone intake have been reported in rats, although another study found no sex difference in sustained IVSA of oxycodone under varying training conditions (Mavrikaki, Pravetoni, Page, Potter & Chartoff, 2017). Interestingly, even when sex differences in IVSA under fixed-ratio conditions were reported, there were no sex differences under a progressive ratio dose substitution (Nguyen, Creehan, Kerr & Taffe, 2020) or in withdrawal-induced behaviors (Kimbrough et al, 2020), suggesting similar motivation and similar induction of negative affect across sexes.…”

Section: Discussionmentioning

confidence: 97%

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

Nguyen

Grant

Taffe

2018

Preprint

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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.

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“…Moreover, pups experience withdrawal at birth if the maternal opioid is discontinued or pups are cross-fostered to non-exposed surrogates [12][13][14][15] . Here, using a continuous (24/7) oral self-administration paradigm, dams had access to oxycodone prior to conception and through lactation and could titrate their intake, reducing the likelihood of spontaneous withdrawal 27 , thus dissociating the consequences or drug exposure from withdrawal for the offspring. These parameters more closely mimic human fetal exposure both when the mother is using opioids illicitly and in clinical practice where mothers are maintained on opioid assisted programs to avoid the adverse effects of withdrawal on the newborn [1][2][3][4] .…”

Section: Maternal Continuous Oral Self-administration Oxycodone Presementioning

confidence: 99%

“…Interestingly, females did not increase USVs although there are sexdependent effects in oxycodone pharmacokinetics 49 . Our previous study in adult oxycodone oral self-administration showed how blood levels greatly differed between sexes 27…”

Section: Withdrawal Behavior Is Differentially-expressed In Oxycodonementioning

confidence: 99%

Maternal Continuous Oral Oxycodone Self-Administration Alters Pup Affective/Social Communication but not Spatial Learning or Sensory-Motor Function

Zanni

Robinson-Drummer

Dougher

et al. 2020

Preprint

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The broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infants diagnosed with Neonatal Opioid Withdrawal Syndrome (NOWS). Shortterm irritability and neurological complications are hallmarks of NOWS, but the longterm consequences are unknown. Our newly-developed preclinical model of oxycodone self-administration enables adult female rats to readily drink oxycodone (0.06-0.12 mg/ml, ~10/mg/kg/day) continuously before and during pregnancy and after delivery, to achieve similar liquid intake in oxycodone moms relative to water-only controls.Oxycodone levels were detected in the serum of mothers and pups. Growth parameters in dams and pups, and litter mass and size were similar to controls. Maternal behavior at postnatal day 1 (PN1) was unchanged by perinatal oxycodone consumption.Regarding the plantar thermal response, there were no differences in paw retraction latency between oxycodone and control pups at PN2 or PN14. Oxycodone and control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in oxycodone pups relative to controls. Finally, during naltrexone precipitated withdrawal at PN9, oxycodone males vocalized more than control pups, consistent with a previously-published withdrawal phenotype. Thus, our rat model of continuous oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and locomotion. Our preclinical, high face validity NOWS model reproduces key aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring. HIGHLIGHTS•Female rats self-administered oxycodone at clinically relevant doses before and during pregnancy and for the first two weeks after parturition. 2 •Both dams and pups, for the14 day postnatal experimental period, had detectable levels of oxycodone in their blood •Dams drinking oxycodone only or water only did not differ in weight gain, water intake, or the number of pups born and their pups did not differ in weight throughout.•Sensory and motor function in the pups was not altered, nor was hippocampal dependent spatial learning. •Oxycodone exposed pups were physically dependent and displayed increased withdrawal behaviors with or without the opioid antagonist naltrexone.•Pups expressed more negative affect, expressed by increased ultrasonic vocalizations, following naltrexone precipitated withdrawal or when separated from their mother.

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Female and male rats readily consume and prefer oxycodone to water in a chronic, continuous access, two-bottle oral voluntary paradigm

Cited by 34 publications

References 107 publications

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

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

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

Maternal Continuous Oral Oxycodone Self-Administration Alters Pup Affective/Social Communication but not Spatial Learning or Sensory-Motor Function

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