Intermittent Access to Oxycodone Decreases Dopamine Uptake in the Nucleus Accumbens Core During Abstinence

Overview

Journal Addict Biol

Specialty Psychiatry

Date 2022 Oct 27

PMID 36301217

Authors

Kyle R Samson

Wei Xu

Sandhya Kortagere

Rodrigo A Espana

Affiliations

Soon will be listed here.

Abstract

A major obstacle in treating opioid use disorder is the persistence of drug seeking or craving during periods of abstinence, which is believed to contribute to relapse. Dopamine transmission in the mesolimbic pathway is posited to contribute to opioid reinforcement, but the processes by which dopamine influences drug seeking have not been completely elucidated. To examine whether opioid seeking during abstinence is associated with alterations in dopamine transmission, female and male rats self-administered oxycodone under an intermittent access schedule of reinforcement. Following self-administration, rats underwent a forced abstinence period, and cue-induced seeking tests were conducted to assess oxycodone seeking. One day following the final seeking test, rats were sacrificed to perform ex vivo fast scan cyclic voltammetry and western blotting in the nucleus accumbens. Rats displayed reduced dopamine uptake rate on abstinence day 2 and abstinence day 15, compared to oxycodone-naïve rats. Further, on abstinence day 15, rats had reduced phosphorylation of the dopamine transporter. Additionally, local application of oxycodone to the nucleus accumbens reduced dopamine uptake in oxycodone-naïve rats and in rats during oxycodone abstinence, on abstinence day 2 and abstinence day 15. These observations suggest that abstinence from oxycodone results in dysfunctional dopamine transmission, which may contribute to sustained oxycodone seeking during abstinence.

Citing Articles

Dissociation of intake and incentive sensitization during intermittent- and continuous-access heroin self-administration in rats.

Rakowski E, King C, Thompson B, Santos G, Holmes E, Solberg Woods L Psychopharmacology (Berl). 2025; 242(4):867-883.

PMID: 39979648 PMC: 11890364. DOI: 10.1007/s00213-025-06762-6.

EAAT2 Activation Regulates Glutamate Excitotoxicity and Reduces Impulsivity in a Rodent Model of Parkinson's Disease.

Das S, McCloskey K, Nepal B, Kortagere S Mol Neurobiol. 2024; .

PMID: 39630405 DOI: 10.1007/s12035-024-04644-0.

Opioid craving does not incubate over time in inpatient or outpatient treatment studies: Is the preclinical incubation of craving model lost in translation?.

Bergeria C, Gipson C, Smith K, Stoops W, Strickland J Neurosci Biobehav Rev. 2024; 160:105618.

PMID: 38492446 PMC: 11046527. DOI: 10.1016/j.neubiorev.2024.105618.

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

Black E, Samels S, Xu W, Barson J, Bass C, Kortagere S Addict Neurosci. 2023; 7.

PMID: 37854172 PMC: 10583964. DOI: 10.1016/j.addicn.2023.100104.

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Barrett J, Shekarabi A, Inan S Pharmacol Rev. 2023; 75(6):1062-1118.

PMID: 37321860 PMC: 10595024. DOI: 10.1124/pharmrev.121.000506.

References

Shah N, Galai N, Celentano D, Vlahov D, Strathdee S . Longitudinal predictors of injection cessation and subsequent relapse among a cohort of injection drug users in Baltimore, MD, 1988-2000. Drug Alcohol Depend. 2005; 83(2):147-56. DOI: 10.1016/j.drugalcdep.2005.11.007. View

Hipolito L, Sanchez-Catalan M, Zanolini I, Polache A, Granero L . Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens. Neuropharmacology. 2008; 55(2):183-9. DOI: 10.1016/j.neuropharm.2008.05.012. View

Fattore L, Vigano D, Fadda P, Rubino T, Fratta W, Parolaro D . Bidirectional regulation of mu-opioid and CB1-cannabinoid receptor in rats self-administering heroin or WIN 55,212-2. Eur J Neurosci. 2007; 25(7):2191-200. DOI: 10.1111/j.1460-9568.2007.05470.x. View

Kakko J, Alho H, Baldacchino A, Molina R, Nava F, Shaya G . Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice. Front Psychiatry. 2019; 10:592. PMC: 6728888. DOI: 10.3389/fpsyt.2019.00592. View

Foster J, Yang J, Moritz A, ChallaSivaKanaka S, Smith M, Holy M . Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux. J Biol Chem. 2012; 287(35):29702-12. PMC: 3436161. DOI: 10.1074/jbc.M112.367706. View

Koob G, Moal M . Addiction and the brain antireward system. Annu Rev Psychol. 2007; 59:29-53. DOI: 10.1146/annurev.psych.59.103006.093548. View

Airavaara M, Pickens C, Stern A, Wihbey K, Harvey B, Bossert J . Endogenous GDNF in ventral tegmental area and nucleus accumbens does not play a role in the incubation of heroin craving. Addict Biol. 2010; 16(2):261-72. PMC: 3059093. DOI: 10.1111/j.1369-1600.2010.00281.x. View

Alonso I, OConnor B, Bryant K, Mandalaywala R, Espana R . Incubation of cocaine craving coincides with changes in dopamine terminal neurotransmission. Addict Neurosci. 2022; 3. PMC: 9451023. DOI: 10.1016/j.addicn.2022.100029. View

Yoshida Y, Koide S, Hirose N, Takada K, Tomiyama K, Koshikawa N . Fentanyl increases dopamine release in rat nucleus accumbens: involvement of mesolimbic mu- and delta-2-opioid receptors. Neuroscience. 1999; 92(4):1357-65. DOI: 10.1016/s0306-4522(99)00046-9. View

10.

Diester C, Banks M, Neigh G, Negus S . Experimental design and analysis for consideration of sex as a biological variable. Neuropsychopharmacology. 2019; 44(13):2159-2162. PMC: 6897955. DOI: 10.1038/s41386-019-0458-9. View

11.

Badiani A, Belin D, Epstein D, Calu D, Shaham Y . Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci. 2011; 12(11):685-700. PMC: 3721140. DOI: 10.1038/nrn3104. View

12.

Fanous S, Goldart E, Theberge F, Bossert J, Shaham Y, Hope B . Role of orbitofrontal cortex neuronal ensembles in the expression of incubation of heroin craving. J Neurosci. 2012; 32(34):11600-9. PMC: 3435881. DOI: 10.1523/JNEUROSCI.1914-12.2012. View

13.

Brown M, Bellone C, Mameli M, Labouebe G, Bocklisch C, Balland B . Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLoS One. 2011; 5(12):e15870. PMC: 3013137. DOI: 10.1371/journal.pone.0015870. View

14.

Hser Y, Hoffman V, Grella C, Anglin M . A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry. 2001; 58(5):503-8. DOI: 10.1001/archpsyc.58.5.503. View

15.

Edwards S, Koob G . Escalation of drug self-administration as a hallmark of persistent addiction liability. Behav Pharmacol. 2013; 24(5-6):356-62. PMC: 3866817. DOI: 10.1097/FBP.0b013e3283644d15. View

16.

Trovero F, Herve D, Desban M, Glowinski J, Tassin J . Striatal opiate mu-receptors are not located on dopamine nerve endings in the rat. Neuroscience. 1990; 39(2):313-21. DOI: 10.1016/0306-4522(90)90270-e. View

17.

George B, Barth S, Kuiper L, Holleran K, Lacy R, Raab-Graham K . Enhanced heroin self-administration and distinct dopamine adaptations in female rats. Neuropsychopharmacology. 2021; 46(10):1724-1733. PMC: 8358024. DOI: 10.1038/s41386-021-01035-0. View

18.

Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen L, Shen D . Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther. 2006; 79(5):461-79. DOI: 10.1016/j.clpt.2006.01.009. View

19.

Yoburn B, Shah S, Chan K, Duttaroy A, Davis T . Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity. Pharmacol Biochem Behav. 1995; 51(2-3):535-9. DOI: 10.1016/0091-3057(94)00375-s. View

20.

Vaughan R, Foster J . Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci. 2013; 34(9):489-96. PMC: 3831354. DOI: 10.1016/j.tips.2013.07.005. View