Skip to main content

Advertisement

Log in

Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.

Objectives

We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.

Results

Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.

Conclusions

The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Amato L, Davoli M, Minozzi S, Ferroni E, Ali R, Ferri M (2013) Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database Syst Rev 2:CD003409

  • Andreassen TN, Klepstad P, Davies A, Bjordal K, Lundstrom S, Kaasa S, Dale O (2011) Influences on the pharmacokinetics of oxycodone: a multicentre cross-sectional study in 439 adult cancer patients. Eur J Clin Pharmacol 67:493–506

    Article  CAS  PubMed  Google Scholar 

  • Angst MS, Clark JD (2006) Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104:570–587

    Article  CAS  PubMed  Google Scholar 

  • Baars MY, Muller MJ, Gallhofer B, Netter P (2013) Relapse (number of detoxifications) in abstinent male alcohol-depenFnt patients as related to personality traits and types of tolerance to frustration. Neuropsychobiology 67:241–248

    Article  CAS  PubMed  Google Scholar 

  • Back SE, Payne RL, Wahlquist AH, Carter RE, Stroud Z, Haynes L, Hillhouse M, Brady KT, Ling W (2011) Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial. Am J Drug Alcohol Abuse 37:313–323

    Article  PubMed  PubMed Central  Google Scholar 

  • Bagdas D, Alkhlaif Y, Jackson A, Carroll FI, Ditre JW, Damaj MI (2018) New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice. Neuropharmacology 138:72–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caine SB, Koob GF (1993) Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260:1814–1816

    Article  CAS  PubMed  Google Scholar 

  • Carcoba LM, Contreras AE, Cepeda-Benito A, Meagher MW (2011) Negative affect heightens opiate withdrawal-induced hyperalgesia in heroin dependent individuals. J Addict Dis 30:258–270

    Article  PubMed  PubMed Central  Google Scholar 

  • Cardoso JM, Barbosa A, Ismail F, Pombo S (2006) NETER alcoholic typology (NAT). Alcohol Alcohol 41:133–139

    Article  PubMed  Google Scholar 

  • Centers for Disease Control and Prevention (2017) Multiple cause of death files, 1999–2016. wonder.cdc.gov/mcd-icd10.html. Accessed 13 Feb 2020

  • Choo EK, Douriez C, Green T (2014) Gender and prescription opioid misuse in the emergency department. Acad Emerg Med 21:1493–1498

    Article  PubMed  PubMed Central  Google Scholar 

  • Chu LF, Angst MS, Clark D (2008) Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain 24:479–496

    Article  PubMed  Google Scholar 

  • Cohen A, Treweek J, Edwards S, Leao RM, Schulteis G, Koob GF, George O (2015) Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats. Addict Biol 20:56–68

    Article  CAS  PubMed  Google Scholar 

  • Compton P, Athanasos P, Elashoff D (2003) Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain 4:511–519

    Article  PubMed  Google Scholar 

  • Compton WM, Jones CM, Baldwin GT (2016) Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med 374:154–163

    Article  CAS  PubMed  Google Scholar 

  • de Guglielmo G, Cippitelli A, Somaini L, Gerra G, Li H, Stopponi S, Ubaldi M, Kallupi M, Ciccocioppo R (2013) Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. Addict Biol 18:644–653

    Article  PubMed  CAS  Google Scholar 

  • de Guglielmo G, Melis M, de Luca MA, Kallupi M, Li HW, Niswender K, Giordano A, Senzacqua M, Somaini L, Cippitelli A, Gaitanaris G, Demopulos G, Damadzic R, Tapocik J, Heilig M, Ciccocioppo R (2015) PPARgamma activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. Neuropsycho-pharmacology 40:927–937

  • de Guglielmo G, Kallupi M, Cole MD, George O (2017a) Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration. Psychopharmacology 234:2009–2018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de Guglielmo G, Matzeu A, Kononoff J, Mattioni J, Martin-Fardon R, George O (2017b) Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats. J Pharmacol Exp Ther 362:378–384

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de Guglielmo G, Kallupi M, Sedighim S, Newman AH, George O (2020) Dopamine D3 receptor antagonism reverses the escalation of oxycodone self-administration and decreases withdrawal-induced hyperalgesia and irritability-like behavior in oxycodone-dependent heterogeneous stock rats. Front Behav Neurosci 13:292

  • Dixon WJ (1980) Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 20:441–462

    Article  CAS  PubMed  Google Scholar 

  • Edwards S, Vendruscolo LF, Schlosburg JE, Misra KK, Wee S, Park PE, Schulteis G, Koob GF (2012) Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF(1) receptor antagonism. Neuropharmacology 62:1142–1151

    Article  CAS  PubMed  Google Scholar 

  • Elder NM, Atayee RS, Best BM, Ma JD (2014) Observations of urinary oxycodone and metabolite distributions in pain patients. J Anal Toxicol 38:129–134

    Article  CAS  PubMed  Google Scholar 

  • Enga RM, Jackson A, Damaj MI, Beardsley PM (2016) Oxycodone physical dependence and its oral self-administration in C57BL/6J mice. Eur J Pharmacol 789:75–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gowing L, Ali R, White JM (2017) Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev 5:CD002021

    PubMed  Google Scholar 

  • Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, Fabisiak TJ, Anderson ND, Cheng K, Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH, Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441–E3450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamouda AK, Jackson A, Bagdas D, Imad Damaj M (2018) Reversal of nicotine withdrawal signs through positive allosteric modulation of alpha4beta2 nicotinic acetylcholine receptors in male mice. Nicotine Tob Res 20:903–907

    Article  CAS  PubMed  Google Scholar 

  • Jackson A, Papke RL, Damaj MI (2018) Pharmacological modulation of the alpha7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psycho-pharmacology 235:1897–1905

  • Kaiko RF, Benziger DP, Fitzmartin RD, Burke BE, Reder RF, Goldenheim PD (1996) Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther 59:52–61

    Article  CAS  PubMed  Google Scholar 

  • Kallupi M, Xue S, Zhou B, Janda KD, George O (2018) An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse. Sci Adv 4:eaat4751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kallupi M, Carrette LLG, Kononoff J, Solberg Woods LC, Palmer AA, Schweitzer P, George O, De Guglielmo G (2020) Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats. Proc Natl Acad Sci U S A 117:2140–2148

  • Kantak KM, Miczek KA (1986) Aggression during morphine withdrawal: effects of method of withdrawal, fighting experience, and social role. Psychopharmacology 90:451–456

    Article  CAS  PubMed  Google Scholar 

  • Kimbrough A, de Guglielmo G, Kononoff J, Kallupi M, Zorrilla EP, George O (2017) CRF1 receptor-dependent increases in irritability-like behavior during abstinence from chronic intermittent ethanol vapor exposure. Alcohol Clin Exp Res 41:1886–1895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimbrough A, Lurie D, Collazo A, Kreifeldt M, Sidhu H, Macedo GC, D’esposito M, Contet C, George O (2020) Brain-wide functional architecture remodeling by alcohol dependence and abstinence. Proc Natl Acad Sci U S A 117:2149–2159

  • Kolodny A, Courtwright DT, Hwang CS, Kreiner P, Eadie JL, Clark TW, Alexander GC (2015) The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu Rev Public Health 36:559–574

    Article  PubMed  Google Scholar 

  • Kononoff J, Kallupi M, Kimbrough A, Conlisk D, de Guglielmo G, George O (2018a) Systemic and intra-Habenular activation of the orphan G protein-coupled receptor GPR139 decreases compulsive-like alcohol drinking and hyperalgesia in alcohol-dependent rats. eNeuro 5(3). https://doi.org/10.1523/ENEURO.0153-18.2018

  • Kononoff J, Melas PA, Kallupi M, de Guglielmo G, Kimbrough A, Scherma M, Fadda P, Kandel DB, Kandel ER, George O (2018b) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238

    Article  PubMed  Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O'dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Article  CAS  PubMed  Google Scholar 

  • Kumar V, Bonifazi A, Ellenberger MP, Keck TM, Pommier E, Rais R, Slusher BS, Gardner E, You ZB, Xi ZX, Newman AH (2016) Highly selective dopamine D3 receptor (D3R) antagonists and partial agonists based on eticlopride and the D3R crystal structure: new leads for opioid dependence treatment. J Med Chem 59:7634–7650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lagerspetz K, Portin R (1968) Simulation of cues eliciting aggressive responses in mice at two age levels. J Genet Psychol 113:53–63

    Article  CAS  PubMed  Google Scholar 

  • Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79:461–479

    Article  CAS  PubMed  Google Scholar 

  • Lubman A, Emrick C, Mosimann WF, Freedman R (1983) Altered mood and norepinephrine metabolism following withdrawal from alcohol. Drug Alcohol Depend 12:3–13

    Article  CAS  PubMed  Google Scholar 

  • Lucantonio F, Kambhampati S, Haney RZ, Atalayer D, Rowland NE, Shaham Y, Schoenbaum G (2015) Effects of prior cocaine versus morphine or heroin self-administration on extinction learning driven by overexpectation versus omission of reward. Biol Psychiatry 77:912–920

    Article  CAS  PubMed  Google Scholar 

  • Manchikanti L, Singh A (2008) Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician 11:S63–S88

    PubMed  Google Scholar 

  • Manchikanti L, Fellows B, Ailinani H, Pampati V (2010) Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician 13:401–435

    PubMed  Google Scholar 

  • Mavrikaki M, Pravetoni M, Page S, Potter D, Chartoff E (2017) Oxycodone self-administration in male and female rats. Psychopharmacology 234:977–987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mchugh RK, Devito EE, Dodd D, Carroll KM, Potter JS, Greenfield SF, Connery HS, Weiss RD (2013) Gender differences in a clinical trial for prescription opioid dependence. J Subst Abus Treat 45:38–43

    Article  Google Scholar 

  • Mckernan LC, Nash MR, Gottdiener WH, Anderson SE, Lambert WE, Carr ER (2015) Further evidence of self-medication: personality factors influencing drug choice in substance use disorders. Psychodyn Psychiatry 43:243–275

    Article  PubMed  Google Scholar 

  • Miczek KA, Debold JF, Hwa LS, Newman EL, de Almeida RM (2015) Alcohol and violence: neuropeptidergic modulation of monoamine systems. Ann N Y Acad Sci 1349:96–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore BC, Easton CJ, Mcmahon TJ (2011) Drug abuse and intimate partner violence: a comparative study of opioid-dependent fathers. Am J Orthop 81:218–227

    Article  Google Scholar 

  • Narita M, Nakamura A, Ozaki M, Imai S, Miyoshi K, Suzuki M, Suzuki T (2008) Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: evidence for less sensitivity to morphine. Neuropsychopharmacology 33:1097–1112

    Article  CAS  PubMed  Google Scholar 

  • Nguyen JD, Grant Y, Creehan KM, Hwang CS, Vandewater SA, Janda KD, Cole M, Taffe MA (2019) Delta(9)-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions. Neuropharmacology 151:127–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM (2010) Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 70:189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park PE, Schlosburg JE, Vendruscolo LF, Schulteis G, Edwards S, Koob GF (2015) Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia. Addict Biol 20:275–284

    Article  CAS  PubMed  Google Scholar 

  • Rieb LM, Norman WV, Martin RE, Berkowitz J, Wood E, Mcneil R, Milloy MJ (2016) Withdrawal-associated injury site pain (WISP): a descriptive case series of an opioid cessation phenomenon. Pain 157:2865–2874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riittinen ML, Lindroos F, Kimanen A, Pieninkeroinen E, Pieninkeroinen I, Sippola J, Veilahti J, Bergstrom M, Johansson G (1986) Impoverished rearing conditions increase stress-induced irritability in mice. Dev Psychobiol 19:105–111

    Article  CAS  PubMed  Google Scholar 

  • Riley JL 3rd, Robinson ME, Wise EA, Myers CD, Fillingim RB (1998) Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 74:181–187

    Article  PubMed  Google Scholar 

  • Schmeichel BE, Barbier E, Misra KK, Contet C, Schlosburg JE, Grigoriadis D, Williams JP, Karlsson C, Pitcairn C, Heilig M, Koob GF, Vendruscolo LF (2015) Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats. Neuropsychopharmacology 40:1123–1129

    Article  CAS  PubMed  Google Scholar 

  • Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G (2018) Drug and opioid-involved overdose deaths - United States, 2013-2017. MMWR Morb Mortal Wkly Rep 67:1419–1427

    Article  PubMed  PubMed Central  Google Scholar 

  • Sidhu H, Kreifeldt M, Contet C (2018) Affective disturbances during withdrawal from chronic intermittent ethanol inhalation in C57BL/6J and DBA/2J male mice. Alcohol Clin Exp Res 42:1281–1290

  • Somkuwar SS, Vendruscolo LF, Fannon MJ, Schmeichel BE, Nguyen TB, Guevara J, Sidhu H, Contet C, Zorrilla EP, Mandyam CD (2017) Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors. Psychoneuroendocrinology 84:17–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steidl S, Myal S, Wise RA (2015) Supplemental morphine infusion into the posterior ventral tegmentum extends the satiating effects of self-administered intravenous heroin. Pharmacol Biochem Behav 134:1–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Substance Abuse and Mental Health Services Administration (2013) Results from the 2012 National Survey on drug use and health: summary of National Findings. In: ADMINISTRATION, S. A. A. M. H. S (ed) NSDUH Series H-46. HHS, Rockville

    Google Scholar 

  • Substance Abuse and Mental Health Services Administration (2014) The TEDS report: gender differences in primary substance of abuse across age groups. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, Rockville, MD

  • Tidey JW, Miczek KA (1992a) Heightened aggressive behavior during morphine withdrawal: effects of d-amphetamine. Psychopharma-cology 107:297–302

  • Tidey JW, Miczek KA (1992b) Morphine withdrawal aggression: modification with D1 and D2 receptor agonists. Psychopharmacology 108:177–184

    Article  CAS  PubMed  Google Scholar 

  • Wade CL, Vendruscolo LF, Schlosburg JE, Hernandez DO, Koob GF (2015) Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40:421–428

    Article  CAS  PubMed  Google Scholar 

  • Wade CL, Kallupi M, Hernandez DO, Breysse E, de Guglielmo G, Crawford E, Koob GF, Schweitzer P, Baunez C, George O (2017) High-frequency stimulation of the subthalamic nucleus blocks compulsive-like re-escalation of heroin taking in rats. Neuropsychopharmacology 42:1850–1859

    Article  PubMed  PubMed Central  Google Scholar 

  • Wesson DR, Ling W (2003) The clinical opiate withdrawal scale (COWS). J Psychoactive Drugs 35:253–259

    Article  PubMed  Google Scholar 

  • Winward JL, Bekman NM, Hanson KL, Lejuez CW, Brown SA (2014) Changes in emotional reactivity and distress tolerance among heavy drinking adolescents during sustained abstinence. Alcohol Clin Exp Res 38:1761–1769

    Article  PubMed  PubMed Central  Google Scholar 

  • Xue S, Kallupi M, Zhou B, Smith LC, Miranda PO, George O, Janda KD (2018) An enzymatic advance in nicotine cessation therapy. Chem Commun (Camb) 54:1686–1689

    Article  CAS  Google Scholar 

  • You ZB, Gao JT, Bi GH, He Y, Boateng C, Cao J, Gardner EL, Newman AH, Xi ZX (2017) The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats. Neuropharmacology 126:190–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • You ZB, Bi GH, Galaj E, Kumar V, Cao J, Gadiano A, Rais R, Slusher BS, Gardner EL, Xi ZX, Newman AH (2018) Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects. Neuropsychopharmacology 44:1415–1424

  • Yuferov V, Zhang Y, Liang Y, Zhao C, Randesi M, Kreek MJ (2018) Oxycodone self-administration induces alterations in expression of integrin, semaphorin and ephrin genes in the mouse striatum. Front Psychiatry 9:257

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Mayer-Blackwell B, Schlussman SD, Randesi M, Butelman ER, Ho A, Ott J, Kreek MJ (2014) Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice. Psychopharma-cology 231:1277–1287

  • Zhang Y, Liang Y, Levran O, Randesi M, Yuferov V, Zhao C, Kreek MJ (2017) Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study. Psychopharmacology 234:2259–2275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Liang Y, Randesi M, Yuferov V, Zhao C, Kreek MJ (2018) Chronic oxycodone self-administration altered reward-related genes in the ventral and dorsal striatum of C57BL/6J mice: an RNA-seq analysis. Neuroscience 393:333–349

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Michael Arends for proofreading the manuscript.

Funding

This work was supported by National Institutes of Health grants DA044451, DA043799, AA007456, and AA027301, the Sigrid Juselius Foundation, and the Pearson Center for Alcoholism and Addiction Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Olivier George.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kimbrough, A., Kononoff, J., Simpson, S. et al. Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats. Psychopharmacology 237, 1545–1555 (2020). https://doi.org/10.1007/s00213-020-05479-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-020-05479-y

Keywords

Navigation