Skip to main content
SpringerLink
Log in

Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

A Correction to this article was published on 20 July 2020

This article has been updated

Abstract

Background

Several studies strongly support the role of the dopamine D2-like and glutamate mGlu5 receptors in psychostimulant reward and relapse.

Methods

The present study employed cocaine or MDMA self-administration with yoked-triad procedure in rats to explore whether extinction training affects the drug-seeking behavior and the D2-like and mGlu5 receptor Bmax and Kd values in several regions of the animal brain.

Results

Both cocaine and MDMA rats developed maintenance of self-administration, but MDMA evoked lower response rates and speed of self-administration acquisition. During reinstatement tests, cocaine or MDMA seeking behavior was produced by either exposure to the drug-associated cues or drug-priming injections. The extinction training after cocaine self-administration did not alter significantly D2-like receptor expression the in the limbic and subcortical brain areas, while MDMA yoked rats showed a decrease of the D2-like binding density in the nucleus accumbens and increase in the hippocampus and a rise of affinity in the striatum and hippocampus. Interestingly, in the prefrontal cortex a reduction in the mGlu5 receptor density in cocaine- or MDMA-abstinent rats was demonstrated, with significant effects being observed after previous MDMA exposure. Moreover, rats self-administered cocaine showed a rise in the density of mGlu5 receptor for the nucleus accumbens.

Conclusion

This study first time shows that abstinence followed extinction training after cocaine or MDMA self- or passive-injections changes the D2-like and mGlu5 density and affinity. The observed changes in the expression of both receptors are brain-region specific and related to either pharmacological and/or motivational features of cocaine or MDMA.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Change history

  • 20 July 2020

    In this published article, Fig.��5 contained a mistake���graphs on the right

References

  1. Alterman AI, McDermott PA, Cook TG, Cacciola JS, McKay JR, McLellan AT, etal. Generalizability of the clinical dimensions of the addiction severity index to nonopioid-dependent patients. Psychol Addict Behav 2000;14:287–94.

    Article  CAS  PubMed  Google Scholar 

  2. Pasareanu AR, Vederhus J-K, Opsal A, Kristensen Ø, Clausen T. Improved drug-use patterns at 6 months post-discharge from inpatient substance use disorder treatment: results from compulsorily and voluntarily admitted patients. BMC Health Serv Res 2016;16:291, doi:https://doi.org/10.1186/s12913-016-1548-6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Koob GF. The neurobiologyof addiction: a neuroadaptational view relevant for diagnosis. Addiction 2006;101(Suppl 1):23–30, doi:https://doi.org/10.1111/j.1360-0443.2006.01586.x.

    Article  PubMed  Google Scholar 

  4. Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 2001;24:97–129, doi:https://doi.org/10.1016/S0893-133X(00)00195-0.

    Article  CAS  PubMed  Google Scholar 

  5. Nutt DJ. The neurochemistry of addiction. Hum Psychopharm Clin 1997;12:53–8.

    Article  Google Scholar 

  6. Di Chiara G. The role of dopamine in drugabuse viewed from the perspective of its role in motivation. Drug Alcohol Depend 1995;38:95–137.

    Article  PubMed  Google Scholar 

  7. D’Souza MS. Glutamatergic transmission in drug reward: implications for drug addiction. Front Neurosci 2015;9:404, doi:https://doi.org/10.3389/fnins.2015.00404.

    PubMed  PubMed Central  Google Scholar 

  8. Spencer S, Kalivas PW. Glutamate transport: a New bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol 2017;20:797–812, doi:https://doi.org/10.1093/ijnp/pyx050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wydra K, Golembiowska K, Suder A, Kaminska K, Fuxe K, Filip M. On the role of adenosine (a) 2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Psychopharmacology (Berl) 2015;232:421–35, doi:https://doi.org/10.1007/s00213-014-3675-2.

    Article  CAS  Google Scholar 

  10. Bennett BA, Wichems CH, Hollingsworth CK, Davies HM, Thornley C, Sexton T, et al. Novel 2-substituted cocaine analogs: uptake and ligand binding studies at dopamine, serotonin and norepinephrine transport sites in the rat brain. J Pharmacol Exp Ther 1995;272:1176–86.

    CAS  PubMed  Google Scholar 

  11. Nestler EJ. The neurobiology of cocaine addiction. Sci Pract Perspect 2005;3:4–10.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bowyer JF, Young JF, Slikker W, Itzak Y, Mayorga AJ, Newport GD, et al. Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 2003;24:379–90, doi:https://doi.org/10.1016/S0161-813X(03)00030-5.

    Article  CAS  PubMed  Google Scholar 

  13. Green AR, Mechan AO, Elliott JM, O’shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”). Pharmacol Rev 2003;55:463–508, doi:https://doi.org/10.1124/pr.55.3.3.

    Article  CAS  PubMed  Google Scholar 

  14. McCann U, Szabo Z, Scheffel U, Dannals R, Ricaurte G. Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. Lancet 1998;352:1433–7, doi:https://doi.org/10.1016/S0140-6736(98)04329-3.

    Article  CAS  PubMed  Google Scholar 

  15. Battaglia G, Yeh SY, De Souza EB. MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem Behav 1988;29:269–74, doi:https://doi.org/10.1016/0091-3057(88)90155-4.

    Article  CAS  PubMed  Google Scholar 

  16. Steele TD, Nichols DE, Yim GKW. Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain. Biochem Pharmacol 1987;36:2297–303, doi:https://doi.org/10.1016/0006-2952(87)90594-6.

    Article  CAS  PubMed  Google Scholar 

  17. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 2001;39:32–41, doi:https://doi.org/10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  18. Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 2009;56(Suppl 1):3–8, doi: https://doi.org/10.1016/j.neuropharm.2008.05.022.

    Article  CAS  PubMed  Google Scholar 

  19. Gould RW, Porrino LJ, Nader MA. Nonhuman primate models of addiction and PET imaging: dopamine system dysregulation. Curr Top Behav Neurosci 2012;11:25–44, doi:https://doi.org/10.1007/7854_2011_168.

    Article  PubMed  Google Scholar 

  20. Brown RM, Mustafa S, Akli Ayoub M, Dodd PR, GPfleger KD, Lawrence AJ, et al. mGlu5 receptor functional interactions and addiction. Front Pharmacol 2012;3:84, doi:https://doi.org/10.3389/fphar.2012.00084.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 2001;4:873–4, doi:https://doi.org/10.1038/nn0901-873.

    Article  CAS  PubMed  Google Scholar 

  22. Cabello N, Gandia J, Bertarelli DCG, Watanabe M, Lluis C, Franco R, et al. Metabotropic glutamate type 5, dopamine d 2 and adenosine a 2a receptors form higher-order oligomers in living cells NIH public access. J Neurochem 2009;109:1497–507, doi:https://doi.org/10.1111/j.1471-4159.2009.06078.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Frankowska M, Miszkiel J, Pomierny-Chamiolo L, Pomierny B, Giannotti G, Suder A, et al. Alternation in dopamine D 2 -like and metabotropic glutamate type 5 receptor density caused by differing housing conditions during abstinence from cocaine self-administration in rats. J Psychopharmacol 2019;33:372–82, doi:https://doi.org/10.1177/0269881118821113.

    Article  CAS  PubMed  Google Scholar 

  24. Schenk S, Gittings D, Johnstone M, Daniela E. Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats. Psychopharmacology (Berl) 2003;169:21–7, doi:https://doi.org/10.1007/s00213-003-1407-0.

    Article  CAS  Google Scholar 

  25. Daniela E, Brennan K, Gittings D, Hely L, Schenk S. Effect of SCH 23390 on (F)-3,4-methylenedioxymethamphetamine hyperactivity and self-administration in rats. Pharmacol Biochem Behav 2004;77:745–50, doi:https://doi.org/10.1016/j.pbb.2004.01.008.

    Article  CAS  PubMed  Google Scholar 

  26. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. Cambridge MA: Academic Press; 1998.

    Google Scholar 

  27. Pomierny-Chamiolo L, Miszkiel J, Frankowska M, Bystrowska B, Filip M. Cocaine self-administration, extinction training and drug-induced relapse change metabotropic glutamate mGlu5 receptors expression: evidence from radioligand binding and immunohistochemistry assays. Brain Res 2017;1655:66–76, doi:https://doi.org/10.1016/j.brainres.2016.11.014.

    Article  CAS  PubMed  Google Scholar 

  28. Filip M, Faron-Gorecka A, Kusmider M, Golda A, Frankowska M, Dziedzicka-Wasylewska M. Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal. Brain Res 2006;1071:218–25, doi:https://doi.org/10.1016/j.brainres.2005.11.099.

    Article  CAS  PubMed  Google Scholar 

  29. Filip M, Frankowska M, Przegalmski E. Effects of GABA B receptor antagonist, agonists and allosteric positive modulator on the cocaine-induced self-administration and drug discrimination. Eur J Pharmacol 2007;574:148–57, doi:https://doi.org/10.1016/j.ejphar.2007.07.048.

    Article  CAS  PubMed  Google Scholar 

  30. Filip M, Frankowska M. Effects of GABA B receptor agents on cocaine priming, discrete contextual cue and food induced relapses. Eur J Pharmacol 2007;571:166–73, doi:https://doi.org/10.1016/j.ejphar.2007.05.069.

    Article  CAS  PubMed  Google Scholar 

  31. Schenk S, Hely L, Gittings D, Lake B, Daniela E. Effects of priming injections of MDMA and cocaine on reinstatement of MDMA-and cocaine-seeking in rats. Drug Alcohol Depend 2008;96:249–55, doi:https://doi.org/10.1016/j.drugalcdep.2008.03.014.

    Article  CAS  PubMed  Google Scholar 

  32. Nawata Y, Kitaichi K, Yamamoto T. Prevention of drug priming-and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptorantagonist AM251. Drug Alcohol Depend 2016;160:76–81, doi:https://doi.org/10.1016/j.drugalcdep.2015.12.016.

    Article  CAS  PubMed  Google Scholar 

  33. Wei C, Han X, Weng D, Feng Q, Qi X, Li J, et al. Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA. Cell Discov 2018;4:60, doi:https://doi.org/10.1038/s41421-018-0060-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Kelamangalath L, Swant J, Stramiello M, Wagner JJ. The effects of extinction training in reducing the reinstatement of drug-seeking behavior: involvement of NMDA receptors. Behav Brain Res 2007;185:119–28, doi:https://doi.org/10.1016/j.bbr.2007.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology (Berl) 2013;229:453–76, doi: https://doi.org/10.1007/s00213-013-3120-y.

    Article  CAS  Google Scholar 

  36. Grimm JW, Hope BT, Wise RA, Shaham Y. Incubation of cocaine craving after withdrawal NIH public access. Nature 2001;412:141–2, doi:https://doi.org/10.1038/35084134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Frankowska M, Marcellino D, Adamczyk P, Filip M, Fuxe K. Effects of cocaine self-administration and extinction on D2 -like and A2A receptor recognition and D2 -like/Gi protein coupling in rat striatum. Addict Biol 2013;18:455–66, doi:https://doi.org/10.1111/j.1369-1600.2012.00452.x.

    Article  CAS  PubMed  Google Scholar 

  38. Briand LA, Flagel SB, Garcia-Fuster MJ, Watson SJ, Akil H, Sarter M, et al. Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology 2008;33:2969–80, doi:https://doi.org/10.1038/npp.2008.18.

    Article  CAS  PubMed  Google Scholar 

  39. Briand LA, Flagel SB, Seeman P, Robinson TE. Cocaine self-administration produces a persistent increase in dopamine D2 high receptors. Eur Neuropsychopharmacol 2008;18:551–6, doi:https://doi.org/10.1016/j.euroneuro.2008.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wallace DR, Mactutus CF, Booze RM. Repeated intravenous cocaine administration: locomotor activity and dopamine D2/D3 receptors. Synapse 1996;23:152–63, doi:https://doi.org/10.1002/(SICI)1098-2396(199607)23:3<152::AID-SYN4>3.0.CO;2-.

    Article  CAS  PubMed  Google Scholar 

  41. Wydra K, Golembiowska K, Zaniewska M, Kaminska K, Ferraro L, Fuxe K, et al. Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self-administration and its extinctionin rats. Addict Biol 2013;18:307-24, doi:https://doi.org/10.1111/adb.12031.

    Article  CAS  PubMed  Google Scholar 

  42. Mutschler NH, Miczek KA. Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats. Psychopharmacology (Berl) 1998;136:402–8.

    Article  CAS  Google Scholar 

  43. Pomierny-Chamiolo L, Miszkiel J, Frankowska M, Pomierny B, Niedzielska E, Smaga I, et al. Withdrawal from cocaine self-administration and yoked cocaine delivery dysregulates glutamatergic mGlu 5 and NMDA receptors in the rat brain fixed ratio DA dopamine NA norepinephrine 5-HT serotonin. Neurotox Res 2015;27:246–58, doi:https://doi.org/10.1007/s12640-014-9502-z.

    Article  CAS  PubMed  Google Scholar 

  44. Knackstedt LA, Schwendt M. mGlu5 receptors and relapse to cocaine-seeking: the role of receptor trafficking in postrelapse extinction learning deficits. Neural Plast 2016;9312508, doi:https://doi.org/10.1155/2016/9312508.

    Google Scholar 

  45. Kim JH, Perry C, Luikinga S, Zbukvic I, Brown RM, Lawrence AJ. Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor. Addict Biol 2015;20:482–9, doi:https://doi.org/10.1111/adb.12142.

    Article  CAS  PubMed  Google Scholar 

  46. Cleva RM, Olive MF. mGlu receptors and drug addiction. Wiley Interdiscip Rev Membr Transp Signal 2012;1:281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Andre MA, Gunturkun O, Manahan-Vaughan D. The metabotropic glutamate receptor, mGlu5, Is required for extinction learning that occurs in the absence of a context change. Hippocampus 2015;25:149–58, doi:https://doi.org/10.1002/hipo.22359.

    Article  CAS  PubMed  Google Scholar 

  48. Peters J, Kalivas PW, Quirk GJ. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 2009;16:279–88, doi:https://doi.org/10.1101/lm.1041309.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Behnam Ghasemzadeh M, Vasudevan P, Giles C, Purgianto A, Seubert C, Mantsch JR. Glutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration. Brain Res 2011;1413:60–71, doi:https://doi.org/10.1016/j.brainres.2011.06.041.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Ben-Shahar O, Obara I, Ary AW, Ma N, Mangiardi MA, Medina RL, et al. Extended daily access to cocaine results in distinct alterations in homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex. Psychopharmacology 2009;63:598–609, doi:https://doi.org/10.1002/syn.20640.

    CAS  Google Scholar 

  51. Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 2011;12:652–69, doi:https://doi.org/10.1038/nrn3119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gass JT, Chandler LJ. The plasticityofextinction: contributionof the prefrontal cortex in treating addiction through inhibitory learning. Front Psychiatry 2013;4:46, doi:https://doi.org/10.3389/fpsyt.2013.00046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Kraków, Poland

    Małgorzata Frankowska, Joanna Miszkiel, Agata Suder & Małgorzata Filip

  2. Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, Kraków, Poland

    Lucyna Pomierny-Chamioło & Bartosz Pomierny

  3. Department of of Medical Sciences, University of Ferrara, Ferrara, Italy

    Andrea Celeste Borelli

Authors
  1. Małgorzata Frankowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna Miszkiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucyna Pomierny-Chamioło
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bartosz Pomierny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrea Celeste Borelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Agata Suder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Małgorzata Filip
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Małgorzata Frankowska.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frankowska, M., Miszkiel, J., Pomierny-Chamioło, L. et al. Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain. Pharmacol. Rep 71, 870–878 (2019). https://doi.org/10.1016/j.pharep.2019.05.001

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2019.05.001

Keywords

Search

Navigation