Milton AL, Schramm MJW, Wawrzynski JR, Gore F, Oikonomou-Mpegeti F, Wang NQ 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 (Berl) 219: 751-761

Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
Psychopharmacology (Impact Factor: 3.88). 07/2011; 219(3):751-61. DOI: 10.1007/s00213-011-2399-9
Source: PubMed


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.
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.
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.
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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Available from: Amy L Milton, Jun 30, 2015
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    • "No effect EtOH (PIT) Milton et al (2012) Abbreviations: CR, conditioned reinforcement; PCA, Pavlovian conditioned approach; PIT, Pavlovian-to-instrumental transfer. "
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    ABSTRACT: Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction.
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    • "The demonstration of memory reconsolidation has not been limited to aversive memory settings, and reconsolidation impairments have also been observed in a number of non-aversive experimental paradigms including spatial memory (Morris et al., 2006), object recognition (Akirav and Maroun, 2006; Rossato et al., 2007), odor discrimination (Portero-Tresserra et al., 2013) and appetitive Pavlovian memories with both natural and addictive drug rewards (Lee and Everitt, 2008a; Milton et al., 2008b). The latter of these is of particular interest, given the therapeutic potential of disrupting the reconsolidation of Pavlovian cue-drug memories as a pro-abstinence/anti-relapse treatment for drug addiction (Tronson and Taylor, 2007; Milton et al., 2012). The intensive research on reconsolidation in both aversive and appetitive memory settings, especially with their relevant translational foci, raises the important question of to what extent do the findings from each field generalize across experimental paradigms. "
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    ABSTRACT: Memory reconsolidation has been observed across species and in a number of behavioral paradigms. The majority of memory reconsolidation studies have been carried out in Pavlovian fear conditioning and other aversive memory settings, with potential implications for the treatment of post-traumatic stress disorder. However, there is a growing literature on memory reconsolidation in appetitive reward-related memory paradigms, including translational models of drug addiction. While there appears to be substantial similarity in the basic phenomenon and underlying mechanisms of memory reconsolidation across unconditioned stimulus valence, there are also notable discrepancies. These arise both when comparing aversive to appetitive paradigms and also across different paradigms within the same valence of memory. We review the demonstration of memory reconsolidation across different aversive and appetitive memory paradigms, the commonalities and differences in underlying mechanisms and the conditions under which each memory undergoes reconsolidation. We focus particularly on whether principles derived from the aversive literature are applicable to appetitive settings, and also whether the expanding literature in appetitive paradigms is informative for fear memory reconsolidation.
    Full-text · Article · Jan 2013 · Frontiers in Behavioral Neuroscience
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    • "However, post-reactivation anisomycin did not disrupt memory reconsolidation under any of the training conditions used. In contrast, there is some weak evidence that within a Pavlovian sign-tracking setting, in which a cue light indicated the availability of an appetitive reward, goal-tracking behavior was impaired when reconsolidation was disrupted (Lee and Everitt 2008a; Milton et al. 2012). These observations resulted from the amnestic effects of the systemic administration of the NMDA receptor antagonist MK-801. "
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    ABSTRACT: Despite extensive evidence that appetitive memories undergo reconsolidation, two notable failures to observe reconsolidation have been reported: instrumental responding and goal-tracking. However, these studies do not provide conclusive evidence for a lack of memory reconsolidation due to the numerous boundary conditions that dictate whether a memory will undergo reconsolidation. In this study we sought to reexamine reconsolidation in an appetitive, Pavlovian conditioned approach procedure and the behavioral boundary conditions within which memories are destabilized and reconsolidated. This study demonstrated that a Pavlovian goal-tracking memory, previously thought to be resistant to destabilization, will undergo memory reconsolidation under discrete conditions that favor reconsolidation as opposed to extinction, and that this is dependent on the amount of training rats received. With restricted training, systemic administration of MK-801 impaired memory extinction. In contrast, with more extended training, MK-801 administration impaired memory reconsolidation. We also demonstrate that behavioral boundary conditions that exist for appetitive memory reconsolidation are much more complex than simple parametric calculations. Moreover, extinction per se is not a boundary on reconsolidation, in that MK-801 also has no behavioral effect under some conditions.
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