Advertisement

Psychopharmacology

, Volume 236, Issue 1, pp 531–543 | Cite as

Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens

  • Mary M. TorregrossaEmail author
  • Matthew MacDonald
  • Kathryn L. Stone
  • TuKiet T. Lam
  • Angus C. Nairn
  • Jane R. Taylor
Original Investigation
  • 120 Downloads

Abstract

Rationale

Environmental stimuli, or cues, associated with the use of drugs such as cocaine are one of the primary drivers of relapse. Thus, identifying mechanisms to reduce the motivational properties of drug cues is an important research goal.

Objectives

The purpose of this study was to identify cellular signaling events in the nucleus accumbens (NAc) that are induced when a cocaine cue memory is either extinguished through repeated cue presentation in the absence of drug, or when the memory is reactivated and reconsolidated by a brief cue re-exposure. Signaling events specific to extinction or reconsolidation represent potential targets for pharmacotherapeutics that may enhance extinction or disrupt reconsolidation to reduce the likelihood of relapse.

Methods

Male Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. Following a period of self-administration, the memory for the cocaine-associated cue was either extinguished, reactivated, or not manipulated (control) 15 min before sacrifice. Tissue from the NAc was subsequently analyzed using mass spectrometry based phosphoproteomics to identify cellular signaling events induced by each condition.

Results

Extinction and reconsolidation of the cocaine cue memory produced both common and distinct changes in protein phosphorylation. Notably, there were no significant changes in protein phosphorylation that were modulated in the opposite direction by the two behavioral conditions. Comparison of NAc phosphoproteomic changes to previously identified changes in the basolateral amygdala (BLA) revealed that cue extinction increases phosphorylation at serine (S) 883 of the GABAB receptor subunit 2 and on S14 of syntaxin 1a in both regions, while no common regional signaling events were identified in the reconsolidation group.

Conclusions

Phosphoproteomics is a useful tool for identifying signaling cascades involved in different memory processes and revealed novel potential targets for selectively targeting extinction versus reconsolidation of a cocaine cue memory. Furthermore, cross region analysis suggests that cue extinction may produce unique signaling events associated with increased inhibitory signaling.

Keywords

Cocaine Proteomics Memory Extinction Reconsolidation Self-administration Phosphorylation 

Notes

Funding information

This work received financial support from USPHS grants DA042029 (M.M.T.), K01DA031745 (M.M.T.), DA018343 (A.C.N., T.T.L.), and DA015222 (J.R.T.).

Compliance with ethical standards

Conflicts of interest

The authors declare that there is no conflict of interest.

Supplementary material

213_2018_5071_MOESM1_ESM.docx (277 kb)
ESM 1 (DOCX 277 kb)
213_2018_5071_MOESM2_ESM.xlsx (107 kb)
ESM 2 (XLSX 106 kb)

References

  1. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300Google Scholar
  2. Bouton ME, Winterbauer NE, Todd TP (2012) Relapse processes after the extinction of instrumental learning: renewal, resurgence, and reacquisition. Behav Process 90:130–141.  https://doi.org/10.1016/j.beproc.2012.03.004 CrossRefGoogle Scholar
  3. Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18CrossRefGoogle Scholar
  4. Conklin CA, Tiffany ST (2002) Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97:155–167CrossRefGoogle Scholar
  5. Couve A, Thomas P, Calver AR, Hirst WD, Pangalos MN, Walsh FS, Smart TG, Moss SJ (2002) Cyclic AMP-dependent protein kinase phosphorylation facilitates GABA(B) receptor-effector coupling. Nat Neurosci 5:415–424.  https://doi.org/10.1038/nn833 CrossRefPubMedGoogle Scholar
  6. Eisenberg M, Dudai Y (2004) Reconsolidation of fresh, remote, and extinguished fear memory in medaka: old fears don’t die. Eur J Neurosci 20:3397–3403.  https://doi.org/10.1111/j.1460-9568.2004.03818.x CrossRefPubMedGoogle Scholar
  7. Fox HC, Bergquist KL, Hong K-I, Sinha R (2007) Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Alcohol Clin Exp Res 31:395–403.  https://doi.org/10.1111/j.1530-0277.2006.00320.x CrossRefPubMedGoogle Scholar
  8. Fuchs RA, Evans KA, Parker MC, See RE (2004) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 176:459–465.  https://doi.org/10.1007/s00213-004-1895-6 CrossRefGoogle Scholar
  9. Fuchs RA, Feltenstein MW, See RE (2006) The role of the basolateral amygdala in stimulus-reward memory and extinction memory consolidation and in subsequent conditioned cued reinstatement of cocaine seeking. Eur J Neurosci 23:2809–2813.  https://doi.org/10.1111/j.1460-9568.2006.04806.x CrossRefPubMedGoogle Scholar
  10. Fuchs RA, Bell GH, Ramirez DR, Eaddy JL, Su ZI (2009) Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking. Eur J Neurosci 30:889–900.  https://doi.org/10.1111/j.1460-9568.2009.06888.x CrossRefPubMedPubMedCentralGoogle Scholar
  11. Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ, Salmeron BJ, Risinger R, Kelley D, Stein EA (2000) Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 157:1789–1798CrossRefGoogle Scholar
  12. Gil C, Falqués A, Sarró E, Cubí R, Blasi J, Aguilera J, Itarte E (2011) Protein kinase CK2 associates to lipid rafts and its pharmacological inhibition enhances neurotransmitter release. FEBS Lett 585:414–420.  https://doi.org/10.1016/j.febslet.2010.12.029 CrossRefPubMedGoogle Scholar
  13. Hellemans KGC, Everitt BJ, Lee JLC (2006) Disrupting reconsolidation of conditioned withdrawal memories in the basolateral amygdala reduces suppression of heroin seeking in rats. J Neurosci 26:12694–12699.  https://doi.org/10.1523/JNEUROSCI.3101-06.2006 CrossRefPubMedGoogle Scholar
  14. Hirosawa M, Hoshida M, Ishikawa M, Toya T (1993) MASCOT: multiple alignment system for protein sequences based on three-way dynamic programming. Comput Appl Biosci 9:161–167PubMedGoogle Scholar
  15. Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villén J, Haas W, Sowa ME, Gygi SP (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143:1174–1189.  https://doi.org/10.1016/j.cell.2010.12.001 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Lee JLC, Di Ciano P, Thomas KL, Everitt BJ (2005) Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47:795–801.  https://doi.org/10.1016/j.neuron.2005.08.007 CrossRefPubMedGoogle Scholar
  17. Lee JLC, Milton AL, Everitt BJ (2006) Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26:10051–10056.  https://doi.org/10.1523/JNEUROSCI.2466-06.2006 CrossRefPubMedGoogle Scholar
  18. Maren S (2014) Out with the old and in with the new: synaptic mechanisms of extinction in the amygdala. Brain Res 1621:231–238.  https://doi.org/10.1016/j.brainres.2014.10.010 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Merlo E, Milton AL, Goozee ZY, Theobald DE, Everitt BJ (2014a) Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence. J Neurosci 34:2422–2431.  https://doi.org/10.1523/JNEUROSCI.4001-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Merlo E, Milton AL, Goozée ZY et al (2014b) Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence. J Neurosci 34:2422–2431.  https://doi.org/10.1523/JNEUROSCI.4001-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873–884.  https://doi.org/10.1016/j.neuron.2005.08.006 CrossRefPubMedGoogle Scholar
  22. Nørskov-Lauritsen L, Bräuner-Osborne H (2015) Role of post-translational modifications on structure, function and pharmacology of class C G protein-coupled receptors. Eur J Pharmacol 763:233–240.  https://doi.org/10.1016/j.ejphar.2015.05.015 CrossRefPubMedGoogle Scholar
  23. O’Brien CP, Childress AR, McLellan T, Ehrman R (1990) Integrating systemic cue exposure with standard treatment in recovering drug dependent patients. Addict Behav 15:355–365CrossRefGoogle Scholar
  24. O’Brien CP, Childress AR, McLellan AT, Ehrman R (1993) Developing treatments that address classical conditioning. NIDA Res Monogr 135:71–91PubMedGoogle Scholar
  25. Orsini CA, Maren S (2012) Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev 36:1773–1802.  https://doi.org/10.1016/j.neubiorev.2011.12.014 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Price KL, Baker NL, McRae-Clark AL et al (2013) A randomized, placebo-controlled laboratory study of the effects of d-cycloserine on craving in cocaine-dependent individuals. Psychopharmacology 226:739–746.  https://doi.org/10.1007/s00213-011-2592-x CrossRefPubMedGoogle Scholar
  27. Rich MT, Abbott TB, Chung L, Gulcicek EE, Stone KL, Colangelo CM, Lam TT, Nairn AC, Taylor JR, Torregrossa MM (2016) Phosphoproteomic analysis reveals a novel mechanism of CaMKIIα regulation inversely induced by cocaine memory extinction versus reconsolidation. J Neurosci 36:7613–7627.  https://doi.org/10.1523/JNEUROSCI.1108-16.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Rich MT, Huang YH, Torregrossa MM (2018) Plasticity at thalamo-amygdala synapses regulates cocaine-cue memory formation and extinction. SSRN Electron J.  https://doi.org/10.2139/ssrn.3205405
  29. Rizo J (2018) Mechanism of neurotransmitter release coming into focus. Protein Sci 27:1364–1391.  https://doi.org/10.1002/pro.3445 CrossRefPubMedGoogle Scholar
  30. Sanchez H, Quinn JJ, Torregrossa MM, Taylor JR (2010) Reconsolidation of a cocaine-associated stimulus requires amygdalar protein kinase A. J Neurosci 30:4401–4407.  https://doi.org/10.1523/JNEUROSCI.3149-09.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Sinha R, Li CSR (2007) Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev 26:25–31CrossRefGoogle Scholar
  32. Taylor JR, Olausson P, Quinn JJ, Torregrossa MM (2009) Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction. Neuropharmacology 56(Suppl 1):186–195.  https://doi.org/10.1016/j.neuropharm.2008.07.027 CrossRefPubMedGoogle Scholar
  33. Théberge FRM, Milton AL, Belin D et al (2010) The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation. Learn Mem 17:444–453.  https://doi.org/10.1101/lm.1757410 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Torregrossa MM, Kalivas PW (2008) Neurotensin in the ventral pallidum increases extracellular gamma-aminobutyric acid and differentially affects cue- and cocaine-primed reinstatement. J Pharmacol Exp Ther 325:556–566.  https://doi.org/10.1124/jpet.107.130310 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Torregrossa MMM, Taylor JRJR (2012) Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology 226:659–672.  https://doi.org/10.1007/s00213-012-2750-9 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Torregrossa MMM, Sanchez H, Taylor JRR (2010) D-cycloserine reduces the context specificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens. J Neurosci 30:10526–10533.  https://doi.org/10.1523/JNEUROSCI.2523-10.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Torregrossa MMM, Gordon J, Taylor JRR (2013) Double dissociation between the anterior cingulate cortex and nucleus accumbens core in encoding the context versus the content of pavlovian cocaine cue extinction. J Neurosci 33:8370–8377.  https://doi.org/10.1523/JNEUROSCI.0489-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Tronson NC, Taylor JR (2007) Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 8:262–275.  https://doi.org/10.1038/nrn2090 CrossRefPubMedGoogle Scholar
  39. Wan X, Torregrossa MMM, Sanchez H et al (2014) Activation of exchange protein activated by cAMP in the rat basolateral amygdala impairs reconsolidation of a memory associated with self-administered cocaine. PLoS One 9:e107359.  https://doi.org/10.1371/journal.pone.0107359 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Wells AM, Arguello AA, Xie X, Blanton MA, Lasseter HC, Reittinger AM, Fuchs RA (2013) Extracellular signal-regulated kinase in the basolateral amygdala, but not the nucleus accumbens core, is critical for context-response-cocaine memory reconsolidation in rats. Neuropsychopharmacology 38:753–762.  https://doi.org/10.1038/npp.2012.238 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Translational Neuroscience Program, Department of PsychiatryUniversity of PittsburghPittsburghUSA
  2. 2.Department of Molecular Biophysics and Biochemistry, Yale/Keck MS & Proteomics ResourceYale UniversityNew HavenUSA
  3. 3.Department of PsychiatryYale UniversityNew HavenUSA
  4. 4.Department of PharmacologyYale UniversityNew HavenUSA
  5. 5.Department of PsychologyYale UniversityNew HavenUSA

Personalised recommendations