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

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.

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Acknowledgements

This research was supported by a UK Medical Research Council grant (no. 9536855) to BJE and was conducted in the MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute. JRW was supported by Grindley funding from the Department of Experimental Psychology, and MJWS was supported by an MRC Doctoral Training Grant. The authors have no conflicts of interest to declare.

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Correspondence to Amy L. Milton.

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Milton, A.L., Schramm, M.J.W., Wawrzynski, J.R. et al. Antagonism at NMDA receptors, but not β-adrenergic receptors, disrupts the reconsolidation of pavlovian conditioned approach and instrumental transfer for ethanol-associated conditioned stimuli. Psychopharmacology 219, 751–761 (2012). https://doi.org/10.1007/s00213-011-2399-9

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Keywords

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