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Psychopharmacology

, Volume 224, Issue 4, pp 559–571 | Cite as

Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving

  • Florence R. M. Theberge
  • Charles L. Pickens
  • Evan Goldart
  • Sanya Fanous
  • Bruce T. Hope
  • Qing-Rong Liu
  • Yavin Shaham
Original Investigation

Abstract

Rationale and objectives

Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.

Methods

We trained rats to self-administer heroin or saline for 9–10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone’s (0–1.0 mg/kg) effect on extinction responding after 1 and 15 days.

Results

Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day.

Conclusions

Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving.

Keywords

BDNF Extinction MeCP2 μ opioid receptor Heroin self-administration Relapse Withdrawal Incubation of drug craving Naloxone 

Notes

Acknowledgments

Research was supported by the National Institute on Drug Abuse’s Intramural Research Program. We thank Xingyu Hou for helping with the molecular assays and Brittany Navarre and Anna Stern for helping with the intravenous surgeries. We also thank Dr. Anne E. West (Duke University) for helpful comments on the molecular aspects of our work. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript.

Supplementary material

213_2012_2784_MOESM1_ESM.pdf (131 kb)
Suppl. Fig. 1 (A) Approximate dissection areas for nucleus accumbens and dorsal striatum and (Bregma +1.4 to +2.4) or mPFC (Bregma +2.7 to +3.7) (Paxinos and Watson 2005). (B) Representatives pictures of the Western Blots of MeCP2, BDNF, TrkB, and (phospho)-tyrosine 817 TrkB (pY817TrkB) in nucleus accumbens, dorsal striatum, and medial prefrontal cortex. (PDF 131 kb)

References

  1. Airavaara M, Pickens CL, Stern AL, Wihbey KA, Harvey BK, Bossert JM, Liu QR, Hoffer BJ, Shaham Y (2011) Endogenous GDNF in ventral tegmental area and nucleus accumbens does not play a role in the incubation of heroin craving. Addict Biol 16:261–272PubMedCrossRefGoogle Scholar
  2. Badiani A, Belin D, Epstein D, Calu D, Shaham Y (2011) Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci 12:685–700PubMedCrossRefGoogle Scholar
  3. Bahi A, Boyer F, Chandrasekar V, Dreyer JL (2008) Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats. Psychopharmacology 199:169–182Google Scholar
  4. Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ (2009) Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res 199:89–102PubMedCrossRefGoogle Scholar
  5. Berglind WJ, See RE, Fuchs RA, Ghee SM, Whitfield TW Jr, Miller SW, McGinty JF (2007) A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur J Neurosci 26:757–766PubMedCrossRefGoogle Scholar
  6. Bossert JM, Wihbey KA, Pickens CL, Nair SG, Shaham Y (2009) Role of dopamine D(1)-family receptors in dorsolateral striatum in context-induced reinstatement of heroin seeking in rats. Psychopharmacology 206:51–60PubMedCrossRefGoogle Scholar
  7. Bossert JM, Stern AL, Theberge FR, Cifani C, Koya E, Hope BT, Shaham Y (2011) Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nat Neurosci 14:420–422PubMedCrossRefGoogle Scholar
  8. Bossert JM, Stern AL, Theberge FR, Marchant NJ, Wang HL, Morales M, Shaham Y (2012) Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci 32:4982–4991PubMedCrossRefGoogle Scholar
  9. Brodsky M, Elliott K, Hynansky A, Inturrisi CE (1995) CNS levels of mu opioid receptor (MOR-1) mRNA during chronic treatment with morphine or naltrexone. Brain Res Bull 38:135–141PubMedCrossRefGoogle Scholar
  10. Burattini C, Gill TM, Aicardi G, Janak PH (2006) The ethanol self-administration context as a reinstatement cue: acute effects of naltrexone. Neuroscience 139:877–887PubMedCrossRefGoogle Scholar
  11. Burattini C, Burbassi S, Aicardi G, Cervo L (2008) Effects of naltrexone on cocaine- and sucrose-seeking behaviour in response to associated stimuli in rats. Int J Neuropsychopharmacol 11:103–109PubMedCrossRefGoogle Scholar
  12. Buzas B, Rosenberger J, Cox BM (1996) Mu and delta opioid receptor gene expression after chronic treatment with opioid agonist. Neuroreport 7:1505–1508PubMedCrossRefGoogle Scholar
  13. Castelli MP, Melis M, Mameli M, Fadda P, Diaz G, Gessa GL (1997) Chronic morphine and naltrexone fail to modify mu-opioid receptor mRNA levels in the rat brain. Brain Res Mol Brain Res 45:149–153PubMedCrossRefGoogle Scholar
  14. Chao MV, Hempstead BL (1995) p75 and Trk: a two-receptor system. Trends Neurosci 18:321–326PubMedCrossRefGoogle Scholar
  15. Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, Marinelli M, Wolf ME (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118–121PubMedCrossRefGoogle Scholar
  16. Crombag H, Bossert JM, Koya E, Shaham Y (2008) Context-induced relapse to drug seeking: a review. Trans R Soc Lond B: Biol Sci 363:3233–3243CrossRefGoogle Scholar
  17. Deng JV, Rodriguiz RM, Hutchinson AN, Kim IH, Wetsel WC, West AE (2010) MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nat Neurosci 13:1128–1136PubMedCrossRefGoogle Scholar
  18. Doherty JM, Frantz KJ (2012) Heroin self-administration and reinstatement of heroin-seeking in adolescent vs. adult male rats. Psychopharmacology (Berl) 219:763–773Google Scholar
  19. Duttaroy A, Yoburn BC (2000) In vivo regulation of mu-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice. Synapse 37:118–124PubMedCrossRefGoogle Scholar
  20. Ghitza UE, Zhai H, Wu P, Airavaara M, Shaham Y, Lu L (2010) Role of BDNF and GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev 35:157–171PubMedCrossRefGoogle Scholar
  21. Goldstein A, Naidu A (1989) Multiple opioid receptors: ligand selectivity profiles and binding sties signatures. Mol Pharmacol 36:265–272PubMedGoogle Scholar
  22. Graham DL, Edwards S, Bachtell RK, DiLeone RJ, Rios M, Self DW (2007) Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10:1029–1037PubMedCrossRefGoogle Scholar
  23. Graham DL, Krishnan V, Larson EB, Graham A, Edwards S, Bachtell RK, Simmons D, Gent LM, Berton O, Bolanos CA, DiLeone RJ, Parada LF, Nestler EJ, Self DW (2009) Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward. Biol Psychiatry 65:696–701PubMedCrossRefGoogle Scholar
  24. Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142PubMedCrossRefGoogle Scholar
  25. Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747PubMedGoogle Scholar
  26. Grimm JW, Manaois M, Osincup D, Wells B, Buse C (2007) Naloxone attenuates incubated sucrose craving in rats. Psychopharmacology (Berl) 194:537–544CrossRefGoogle Scholar
  27. Hearing MC, Miller SW, See RE, McGinty JF (2008) Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology (Berl) 198:77–91CrossRefGoogle Scholar
  28. Hollander JA, Carelli RM (2007) Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence. J Neurosci 27:3535–3539PubMedCrossRefGoogle Scholar
  29. Im HI, Hollander JA, Bali P, Kenny PJ (2010) MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci 13:1120–1127PubMedCrossRefGoogle Scholar
  30. Jacobs E, Smit A, de Vries T, Schoffelmeer A (2005) Long-Term gene expression in the nucleus accumbens following heroin administration is subregion-specific and depends on the nature of drug administration. Addict Biol 10:91–100PubMedCrossRefGoogle Scholar
  31. Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci 10:1513–1514PubMedCrossRefGoogle Scholar
  32. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184PubMedCrossRefGoogle Scholar
  33. Kourrich S, Thomas MJ (2009) Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J Neurosci 29:12275–12283PubMedCrossRefGoogle Scholar
  34. Koya E, Uejima JL, Wihbey KA, Bossert JM, Hope BT, Shaham Y (2009) Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology 56(Suppl 1):177–185PubMedCrossRefGoogle Scholar
  35. Kuntz-Melcavage KL, Brucklacher RM, Grigson PS, Freeman WM, Vrana KE (2009) Gene expression changes following extinction testing in a heroin behavioral incubation model. BMC Neurosci 10:95PubMedCrossRefGoogle Scholar
  36. Kuntz KL, Patel KM, Grigson PS, Freeman WM, Vrana KE (2008) Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior. Pharmacol Biochem Behav 90:349–356PubMedCrossRefGoogle Scholar
  37. Lau AG, Irier HA, Gu J, Tian D, Ku L, Liu G, Xia M, Fritsch B, Zheng JQ, Dingledine R, Xu B, Lu B, Feng Y (2010) Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc Natl Acad Sci 107:15945–15950PubMedCrossRefGoogle Scholar
  38. Lecca D, Valentini V, Cacciapaglia F, Acquas E, Di Chiara G (2007) Reciprocal effects of response contingent and noncontingent intravenous heroin on in vivo nucleus accumbens shell versus core dopamine in the rat: a repeated sampling microdialysis study. Psychopharmacology 194:103–116PubMedCrossRefGoogle Scholar
  39. Li YQ, Xue YX, He YY, Li FQ, Xue LF, Xu CM, Sacktor TC, Shaham Y, Lu L (2011) Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory. J Neurosci 31:5436–5446CrossRefGoogle Scholar
  40. Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861PubMedGoogle Scholar
  41. Liu X, Palmatier MI, Caggiula AR, Sved AF, Donny EC, Gharib M, Booth S (2009) Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats. Psychopharmacology 202:589–598PubMedCrossRefGoogle Scholar
  42. Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y (2004) A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 24:1604–1611PubMedCrossRefGoogle Scholar
  43. Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y (2007) Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving. Biol Psychiatry 61:591–598PubMedCrossRefGoogle Scholar
  44. Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212–219PubMedCrossRefGoogle Scholar
  45. Lu L, Wang X, Wu P, Xu C, Zhao M, Morales M, Harvey BK, Hoffer BJ, Shaham Y (2009) Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry 66:137–145PubMedCrossRefGoogle Scholar
  46. Marin MT, Berkow A, Golden SA, Koya E, Planeta CS, Hope BT (2009) Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens. Eur J Neurosci 30:1931–1940PubMedCrossRefGoogle Scholar
  47. McGinty JF, Whitfield TW, Jr., Berglind WJ (2010) Brain-derived neurotrophic factor and cocaine addiction. Brain Res (in press)Google Scholar
  48. Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805PubMedGoogle Scholar
  49. O’Brien CP, Ehrman RN, Ternes JW (1986) Classical conditioning in human opioid dependence. In: Goldberg S, Stolerman I (eds) Behavioral analysis of drug dependence. Academic, Orlando, pp 329–356Google Scholar
  50. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier, AmsterdamGoogle Scholar
  51. Pelton JT, Kazmierski W, Gulya K, Yamamura HI, Hruby VJ (1986) Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors. J Med Chem 29:2370–2375PubMedCrossRefGoogle Scholar
  52. Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011) Neurobiology of the incubation of drug craving. Trends Neurosci 34:411–420PubMedCrossRefGoogle Scholar
  53. Portoghese PS, Sultana M, Takemori AE (1990) Naltrindole 5′-isothiocyanate: a nonequilibrium, highly selective delta opioid receptor antagonist. J Med Chem 33:1547–1548PubMedCrossRefGoogle Scholar
  54. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564PubMedCrossRefGoogle Scholar
  55. Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151:579–588PubMedCrossRefGoogle Scholar
  56. Ronnekleiv OK, Bosch MA, Cunningham MJ, Wagner EJ, Grandy DK, Kelly MJ (1996) Downregulation of mu-opioid receptor mRNA in the mediobasal hypothalamus of the female guinea pig following morphine treatment. Neurosci Lett 216:129–132PubMedGoogle Scholar
  57. Sadri-Vakili G, Kumaresan V, Schmidt HD, Famous KR, Chawla P, Vassoler FM, Overland RP, Xia E, Bass CE, Terwilliger EF, Pierce RC, Cha JH (2010) Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine. J Neurosci 30:11735–11744PubMedCrossRefGoogle Scholar
  58. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108PubMedCrossRefGoogle Scholar
  59. Sehba F, Duttaroy A, Shah S, Chen B, Carroll J, Yoburn BC (1997) In vivo homologous regulation of mu-opioid receptor gene expression in the mouse. Eur J Pharmacol 339:33–41PubMedCrossRefGoogle Scholar
  60. Self DW (2004) Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47(Suppl 1):242–255PubMedCrossRefGoogle Scholar
  61. Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology 156:98–107PubMedCrossRefGoogle Scholar
  62. Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D, Karanian DA, Monteggia LM, Neve RL, Self DW (2003) Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421:70–75PubMedCrossRefGoogle Scholar
  63. Takemori AE, Larson DL, Portoghese PS (1981) The irreversible narcotic antagonistic and reversible agonistic properties of the fumaramate methyl ester derivative of naltrexone. Eur J Pharmacol 70:445–451PubMedCrossRefGoogle Scholar
  64. Vaccarino FJ, Bloom FE, Koob GF (1985) Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat. Psychopharmacology 86:37–42PubMedCrossRefGoogle Scholar
  65. Wikler A (1973) Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch Gen Psychiatry 28:611–616PubMedCrossRefGoogle Scholar
  66. Wolf ME (2003) Effects of psychomotor stimulants on glutamate receptor expression. Methods Mol Med 79:13–31PubMedGoogle Scholar
  67. Wolf ME, Ferrario CR (2010) AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci Biobehav Rev 35:185–211PubMedCrossRefGoogle Scholar
  68. Zhou W, Zhang F, Liu H, Tang S, Lai M, Zhu H, Kalivas PW (2009) Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse. Psychopharmacology (Berl) 203:677–684CrossRefGoogle Scholar
  69. Zhou Y, Bendor J, Hofmann L, Randesi M, Ho A, Kreek MJ (2006) Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal. J Endocrinol 191:137–145PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2012

Authors and Affiliations

  • Florence R. M. Theberge
    • 1
  • Charles L. Pickens
    • 1
  • Evan Goldart
    • 1
  • Sanya Fanous
    • 1
  • Bruce T. Hope
    • 1
  • Qing-Rong Liu
    • 1
  • Yavin Shaham
    • 1
  1. 1.Behavioral Neuroscience BranchIRP/NIDA/NIH/DHHSBaltimoreUSA

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