Psychopharmacology

, Volume 219, Issue 3, pp 751–761 | Cite as

Antagonism at NMDA receptors, but not β-adrenergic receptors, disrupts the reconsolidation of pavlovian conditioned approach and instrumental transfer for ethanol-associated conditioned stimuli

  • Amy L. Milton
  • Moritz J. W. Schramm
  • James R. Wawrzynski
  • Felicity Gore
  • Faye Oikonomou-Mpegeti
  • Nancy Q. Wang
  • Daniel Samuel
  • Daina Economidou
  • Barry J. Everitt
Original Investigation

Abstract

Rationale

Reconsolidation is the process by which memories require restabilisation following destabilisation at retrieval. Since even old, well-established memories become susceptible to disruption following reactivation, treatments based upon disrupting reconsolidation could provide a novel form of therapy for neuropsychiatric disorders based upon maladaptive memories, such as drug addiction. Pavlovian cues are potent precipitators of relapse to drug-seeking behaviour and influence instrumental drug seeking through at least three psychologically and neurobiologically distinct processes: conditioned reinforcement, conditioned approach (autoshaping) and conditioned motivation (pavlovian–instrumental transfer or PIT). We have previously demonstrated that the reconsolidation of memories underlying the conditioned reinforcing properties of drug cues depends upon NMDA receptor (NMDAR)- and β-adrenergic receptor (βAR)-mediated signalling. However, it is unknown whether the drug cue memory representations underlying conditioned approach and PIT depend upon the same mechanisms.

Objectives

Using orally self-administered ethanol as a reinforcer in two separate experiments, we investigated whether the reconsolidation of the memories underlying conditioned approach and PIT requires βAR- and NMDAR-dependent neurotransmission.

Results

For ethanol self-administering but non-dependent rats, the memories underlying conditioned approach and PIT for a pavlovian drug cue were disrupted by the administration of the NMDAR antagonist MK-801, but not the administration of the βAR antagonist propranolol, when given in conjunction with memory reactivation.

Conclusions

As for natural reinforcers, NMDARs are required for the reconsolidation of all aspects of pavlovian drug memories, but βARs are only required for the memory representation underlying conditioned reinforcement. These results indicate the potential utility of treatments based upon disrupting cue–drug memory reconsolidation in preventing relapse.

Keywords

Memory reconsolidation NMDA receptor β-adrenergic receptor Pavlovian conditioned approach Pavlovian–instrumental transfer Alcohol 

References

  1. Bernardi RE, Lattal KM, Berger SP (2006) Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport 17:1443–1447PubMedCrossRefGoogle Scholar
  2. Bernardi RE, Ryabinin AE, Berger SP, Lattal KM (2009) Post-retrieval disruption of a cocaine conditioned place preference by systemic and intrabasolateral amygdala β2 and α1-adrenergic antagonists. Learn Mem 16:777–789PubMedCrossRefGoogle Scholar
  3. Burns LH, Robbins TW, Everitt BJ (1993) Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of D-amphetamine. Behav Brain Res 55:167–183PubMedCrossRefGoogle Scholar
  4. Cardinal RN, Aitken MRF (2006) ANOVA for the behavioural sciences researcher. Lawrence Erlbaum Associates, Inc., New JerseyGoogle Scholar
  5. Cardinal RN, Aitken MRF (2010) Whisker: a client-server high-performance multimedia research control system. Behav Res Methods 42:1059–1071PubMedCrossRefGoogle Scholar
  6. Corbit LH, Balleine BW (2005) Double dissociation of basolateral and central amygdala lesions on the general and outcome-specific forms of pavlovian-instrumental transfer. J Neurosci 25:962–970PubMedCrossRefGoogle Scholar
  7. Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169–173PubMedCrossRefGoogle Scholar
  8. de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143PubMedCrossRefGoogle Scholar
  9. Debiec J, LeDoux JE (2004) Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience 129:267–272PubMedCrossRefGoogle Scholar
  10. Debiec J, LeDoux JE, Nader K (2002) Cellular and systems reconsolidation in the hippocampus. Neuron 36:527–538PubMedCrossRefGoogle Scholar
  11. Dickinson A, Smith J, Mirenowicz J (2000) Dissociation of pavlovian and instrumental incentive learning under dopamine antagonists. Behav Neurosci 114:468–483PubMedCrossRefGoogle Scholar
  12. Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003) Stability of retrieved memory: inverse correlation with trace dominance. Science 301:1102–1104PubMedCrossRefGoogle Scholar
  13. Everitt BJ, Cador M, Robbins TW (1989) Interactions between the amygdala and ventral striatum in stimulus-reward associations: studies using a second-order schedule of sexual reinforcement. Neuroscience 30:63–75PubMedCrossRefGoogle Scholar
  14. Everitt BJ, Cardinal RN, Hall J, Parkinson JA, Robbins TW (2000) Differential involvement of amygdala subsystems in appetitive conditioning and drug addiction. In: Aggleton JP (ed) The Amygdala: a functional analysis (2nd ed). Oxford University Press, Oxford, pp 353–390Google Scholar
  15. Everitt BJ, Dickinson A, Robbins TW (2001) The neuropsychological basis of addictive behaviour. Brain Res Rev 36:129–138PubMedCrossRefGoogle Scholar
  16. Falls WA, Miserendino MJD, Davis M (1992) Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci 12:854–863PubMedGoogle Scholar
  17. Feltenstein MW, See RE (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiol Learn Mem 88:435–444PubMedCrossRefGoogle Scholar
  18. Flagel SB, Robinson TE, Clark JJ, Clinton SM, Watson SJ, Seeman P, Phillips PEM, Akil H (2010) An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction. Neuropsychopharmacology 35:388–400PubMedCrossRefGoogle Scholar
  19. Fricks-Gleason AN, Marshall JF (2008) Post-retrieval β-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories. Learn Mem 15:643–648PubMedCrossRefGoogle Scholar
  20. Gawin FH, Kleber HD (1992) Evolving conceptualizations of cocaine dependence. In: Kosten TR and Kleber HD (eds) Clinician’s guide to cocaine addiction: theory, research and treatment. The Guildford Press, New York, pp 33–52Google Scholar
  21. Hall J, Parkinson JA, Connor TM, Dickinson A, Everitt BJ (2001) Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour. Eur J Neurosci 13:1984–1992PubMedCrossRefGoogle Scholar
  22. Hatfield T, Han JS, Conley M, Gallagher M, Holland PC (1996) Neurotoxic lesions of basolateral, but not central, amygdala interfere with Pavlovian second-order conditioning and reinforcer devaluation effects. J Neurosci 16:5256–5265PubMedGoogle Scholar
  23. Holland PC, Gallagher M (2003) Double dissociation of the effects of lesions of basolateral and central amygdala on conditioned stimulus-potentiated feeding and pavlovian-instrumental transfer. Eur J Neurosci 17:1680–1694PubMedCrossRefGoogle Scholar
  24. Kearns DN, Weiss SJ (2004) Sign-tracking (autoshaping) in rats: a comparison of cocaine and food as unconditioned stimuli. Learning Behav 32:463–476CrossRefGoogle Scholar
  25. Krank MD, O'Neill S, Squarey K, Jacob J (2008) Goal- and signal-directed incentive: conditioned approach, seeking, and consumption established with unsweetened alcohol in rats. Psychopharmacology 196:397–405PubMedCrossRefGoogle Scholar
  26. Lee JLC, Everitt BJ (2008a) Appetitive memory reconsolidation depends upon NMDA receptor-mediated neurotransmission. Neurobiol Learn Mem 90:147–154CrossRefGoogle Scholar
  27. Lee JLC, Everitt BJ (2008b) Reactivation-dependent amnesia in pavlovian approach and instrumental transfer. Learn Mem 15:597–602CrossRefGoogle Scholar
  28. Lee JLC, Everitt BJ, Thomas KL (2004) Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 304:839–843PubMedCrossRefGoogle Scholar
  29. Lee JLC, Di Ciano P, Thomas KL, Everitt BJ (2005) Disrupting reconsolidation of drug memories reduces cocaine seeking behavior. Neuron 47:795–801PubMedCrossRefGoogle Scholar
  30. Lee JLC, Milton AL, Everitt BJ (2006a) Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. J Neurosci 26:5881–5887CrossRefGoogle Scholar
  31. Lee JLC, Milton AL, Everitt BJ (2006b) Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26:10051–10056CrossRefGoogle Scholar
  32. Lewis DJ (1979) Psychobiology of active and inactive memory. Psychol Bull 86:1054–1083PubMedCrossRefGoogle Scholar
  33. Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873–884PubMedCrossRefGoogle Scholar
  34. Milton AL, Everitt BJ (2010) The psychological and neurochemical mechanisms of drug memory reconsolidation: implications for the treatment of addiction. Eur J Neurosci 31:2308–2319PubMedCrossRefGoogle Scholar
  35. Milton AL, Lee JLC, Butler VJ, Gardner RJ, Everitt BJ (2008a) Intra-amygdala and systemic antagonism of NMDA receptors prevents the reconsolidation of drug-associated memory and impairs subsequently both novel and previously acquired drug-seeking behaviors. J Neurosci 28:8230–8237CrossRefGoogle Scholar
  36. Milton AL, Lee JLC, Everitt BJ (2008b) Reconsolidation of appetitive memories for both natural and drug reinforcement is dependent on β-adrenergic receptors. Learn Mem 15:88–92CrossRefGoogle Scholar
  37. Muravieva EV, Alberini CM (2010) Limited efficacy of propranolol on the reconsolidation of fear memories. Learn Mem 17:306–313PubMedCrossRefGoogle Scholar
  38. Nader K (2003) Memory traces unbound. Trends Neurosci 26:65–72PubMedCrossRefGoogle Scholar
  39. Nader K, Schafe GE, LeDoux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726PubMedCrossRefGoogle Scholar
  40. Parkinson JA, Olmstead MC, Burns LH, Robbins TW, Everitt BJ (1999) Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J Neurosci 19:2401–2411PubMedGoogle Scholar
  41. Parkinson JA, Cardinal RN, Everitt BJ (2000a) Limbic cortical-ventral striatal systems underlying appetitive conditioning. Prog Brain Res 126:263–285CrossRefGoogle Scholar
  42. Parkinson JA, Robbins TW, Everitt BJ (2000b) Dissociable roles of the central and basolateral amygdala in appetitive emotional learning. Eur J Neurosci 12:405–413CrossRefGoogle Scholar
  43. Parkinson JA, Crofts HS, McGuigan M, Tomic DL, Everitt BJ, Roberts AC (2001) The role of the primate amygdala in conditioned reinforcment. J Neurosci 21:7770–7780PubMedGoogle Scholar
  44. Pedreira ME, Pérez-Cuesta LM, Maldonado H (2004) Mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction. Learn Mem 11:579–585PubMedCrossRefGoogle Scholar
  45. Robinson MJF, Franklin KBJ (2007) Central but not peripheral beta-adrenergic antagonism blocks reconsolidation for a morphine place preference. Behav Brain Res 182:129–134PubMedCrossRefGoogle Scholar
  46. Tomie A, Kuo T, Apor KR, Salomon KE, Pohorecky LA (2004) Autoshaping induces ethanol drinking in nondeprived rats: evidence of long-term retention but no induction of ethanol preference. Pharmacol Biochem Behav 77:797–804PubMedCrossRefGoogle Scholar
  47. von der Goltz C, Vengeliene V, Bilbao A, Perreau-Lenz S, Pawlak CR, Kiefer F, Spanagel R (2009) Cue-induced alcohol seeking behaviour is reduced by disrupting the reconsolidation of alcohol-related memories. Psychopharmacology 205:389–397PubMedCrossRefGoogle Scholar
  48. Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22:2343–2351PubMedGoogle Scholar
  49. Wouda JA, Diergaarde L, Riga D, Van Mourik Y, Schoffelmeer ANM, De Vries TJ (2010) Disruption of long-term alcohol-related memory reconsolidation: role of β-adrenoceptors and NMDA receptors. Front Behav Neurosci 4:179. doi:10.3389/fnbeh.2010.00179 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Amy L. Milton
    • 1
  • Moritz J. W. Schramm
    • 1
  • James R. Wawrzynski
    • 1
  • Felicity Gore
    • 1
  • Faye Oikonomou-Mpegeti
    • 1
  • Nancy Q. Wang
    • 1
  • Daniel Samuel
    • 1
  • Daina Economidou
    • 1
  • Barry J. Everitt
    • 1
  1. 1.Behavioural and Clinical Neuroscience Institute, Department of Experimental PsychologyUniversity of CambridgeCambridgeUK

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