Escalated Oxycodone Self-Administration and Punishment: Differential Expression of Opioid Receptors and Immediate Early Genes in the Rat Dorsal Striatum and Prefrontal Cortex

Overview

Journal Front Neurosci

Date 2020 Jan 31

PMID 31998063

Citations 15

Authors

Christopher A Blackwood

Michael T McCoy

Bruce Ladenheim

Jean Lud Cadet

Affiliations

Soon will be listed here.

Abstract

Opioid use disorder (OUD) is characterized by compulsive drug taking despite adverse life consequences. Here, we sought to identify neurobiological consequences associated with the behavioral effects of contingent footshocks administered after escalation of oxycodone self-administration. To reach these goals, Sprague-Dawley rats were trained to self-administer oxycodone for 4 weeks and were then exposed to contingent electric footshocks. This paradigm helped to dichotomize rats into two distinct behavioral phenotypes: (1) those that reduce lever pressing (shock-sensitive) and (2) others that continue lever pressing (shock-resistant) for oxycodone during contingent punishment. The rats were euthanized at 2-h after the last oxycodone plus footshock session. The dorsal striata and prefrontal cortices were dissected for use in western blot and RT-qPCR analyses. All oxycodone self-administration rats showed significant decreased expression of Mu and Kappa opioid receptor proteins only in the dorsal striatum. However, expression of Delta opioid receptor protein was decreased in both brain regions. RT-qPCR analyses documented significant decreases in the expression of , , , , , and mRNAs in the dorsal striatum (but not in PFC) of the shock-sensitive rats. In the PFC, expression was reduced in both phenotypes. However, mRNA expression was increased in the PFC of only shock-resistant rats. These results reveal that, similar to psychostimulants and alcohol, footshocks can dichotomize rats that escalated their intake of oxycodone into two distinct behavioral phenotypes. These animals also show significant differences in the mRNA expression of immediate early genes, mainly, in the dorsal striatum. The increases in PFC expression in the shock-resistant rats suggest that Egr3 might be involved in the persistence of oxycodone-associated memory under aversive conditions. This punishment-driven model may help to identify neurobiological substrates of persistent oxycodone taking and abstinence in the presence of adverse consequences.

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References

Burns J, Kroll D, Feldman D, Kure Liu C, Manza P, Wiers C . Molecular Imaging of Opioid and Dopamine Systems: Insights Into the Pharmacogenetics of Opioid Use Disorders. Front Psychiatry. 2019; 10:626. PMC: 6759955. DOI: 10.3389/fpsyt.2019.00626. View

Bisagno V, Cadet J . Expression of immediate early genes in brain reward circuitries: Differential regulation by psychostimulant and opioid drugs. Neurochem Int. 2018; 124:10-18. DOI: 10.1016/j.neuint.2018.12.004. View

Zhang Y, Liang Y, Randesi M, Yuferov V, Zhao C, Kreek M . Chronic Oxycodone Self-administration Altered Reward-related Genes in the Ventral and Dorsal Striatum of C57BL/6J Mice: An RNA-seq Analysis. Neuroscience. 2018; 393:333-349. DOI: 10.1016/j.neuroscience.2018.07.032. View

Keller B, La Harpe R, Garcia-Sevilla J . Upregulation of IRAS/nischarin (I-imidazoline receptor), a regulatory protein of μ-opioid receptor trafficking, in postmortem prefrontal cortex of long-term opiate and mixed opiate/cocaine abusers. Neurochem Int. 2017; 108:282-286. DOI: 10.1016/j.neuint.2017.04.017. View

Hodebourg R, Murray J, Fouyssac M, Puaud M, Everitt B, Belin D . Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. Eur J Neurosci. 2018; 50(3):2036-2044. PMC: 6767855. DOI: 10.1111/ejn.13894. View

Krasnova I, Chiflikyan M, Justinova Z, McCoy M, Ladenheim B, Jayanthi S . CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis. 2013; 58:132-43. PMC: 3748236. DOI: 10.1016/j.nbd.2013.05.009. View

Mague S, Isiegas C, Huang P, Liu-Chen L, Lerman C, Blendy J . Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc Natl Acad Sci U S A. 2009; 106(26):10847-52. PMC: 2705603. DOI: 10.1073/pnas.0901800106. View

Zhang Y, Picetti R, Butelman E, Ho A, Blendy J, Kreek M . Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Neuropsychopharmacology. 2014; 40(5):1091-100. PMC: 4367451. DOI: 10.1038/npp.2014.286. View

Frost J, Wagner Jr H, Dannals R, Ravert H, Links J, Wilson A . Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr. 1985; 9(2):231-6. DOI: 10.1097/00004728-198503000-00001. View

10.

McCoy M, Jayanthi S, Wulu J, Beauvais G, Ladenheim B, Martin T . Chronic methamphetamine exposure suppresses the striatal expression of members of multiple families of immediate early genes (IEGs) in the rat: normalization by an acute methamphetamine injection. Psychopharmacology (Berl). 2011; 215(2):353-65. PMC: 3803141. DOI: 10.1007/s00213-010-2146-7. View

11.

Everitt B, Robbins T . Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On. Annu Rev Psychol. 2015; 67:23-50. DOI: 10.1146/annurev-psych-122414-033457. View

12.

Rudd R, Aleshire N, Zibbell J, Gladden R . Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2016; 64(50-51):1378-82. DOI: 10.15585/mmwr.mm6450a3. View

13.

Fornili K . The Opioid Crisis, Suicides, and Related Conditions: Multiple Clustered Syndemics, not Singular Epidemics. J Addict Nurs. 2018; 29(3):214-220. DOI: 10.1097/JAN.0000000000000240. View

14.

Bossert J, Hoots J, Fredriksson I, Adhikary S, Zhang M, Venniro M . Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking. Eur J Neurosci. 2018; 50(3):2075-2085. DOI: 10.1111/ejn.13955. View

15.

Miller N, Flaherty J . Effectiveness of coerced addiction treatment (alternative consequences): a review of the clinical research. J Subst Abuse Treat. 2000; 18(1):9-16. DOI: 10.1016/s0740-5472(99)00073-2. View

16.

Gaskell H, Derry S, Stannard C, Moore R . Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev. 2016; 7:CD010692. PMC: 6457997. DOI: 10.1002/14651858.CD010692.pub3. View

17.

Blanco C, Volkow N . Management of opioid use disorder in the USA: present status and future directions. Lancet. 2019; 393(10182):1760-1772. DOI: 10.1016/S0140-6736(18)33078-2. View

18.

Williams J, Ingram S, Henderson G, Chavkin C, Von Zastrow M, Schulz S . Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev. 2013; 65(1):223-54. PMC: 3565916. DOI: 10.1124/pr.112.005942. View

19.

Cicero T, Inciardi J, Munoz A . Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004. J Pain. 2005; 6(10):662-72. DOI: 10.1016/j.jpain.2005.05.004. View

20.

Saint-Preux F, Bores L, Tulloch I, Ladenheim B, Kim R, Thanos P . Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats. Neuroscience. 2013; 243:89-96. PMC: 3665347. DOI: 10.1016/j.neuroscience.2013.03.052. View