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Title: An assessment of reconsolidation blockade to disrupt memories relevant to psychiatric disorders
Author: Vousden, George Henry
ISNI:       0000 0004 6425 5440
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2017
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Consolidated memories can become reactivated in order to permit the integration of new information into the memory trace. Blockade of the resultant process, reconsolidation, with NMDA receptor antagonists or protein synthesis inhibition can lead to a decrease in subsequent memory expression. This may offer a potential tool for the treatment of psychiatric disorders characterised by maladaptive memories, including drug addiction and post-traumatic disorder. Given the importance of instrumental associations in supporting drug addiction experiments in Chapters 3 & 4 aimed to disrupt reconsolidation of these memories. Treatment with an NMDA receptor antagonist prior to retrieval sessions of various durations was not able to consistently prevent reconsolidation of these associations. Drug addiction is characterised by memories that have been formed not over days or weeks, but months or years. Experiments in Chapters 5 & 6 therefore investigated how the extent of training affects the propensity of an appetitive pavlovian memory to reconsolidate. Experiments in Chapter 5 were not able disrupt reconsolidation of these memories after a relatively short period of training. In Chapter 6 attempts to disrupt reconsolidation of a cocaine-seeking memory having undergone extensive training (>1 month, designed to promote the formation of drug-seeking habits) were also unsuccessful. However, when animals were trained in a similar fashion to respond for a food reinforcer treatment with a NMDA receptor antagonist prior to a reactivation session resulted in a decrease in food-seeking behaviour the following day. However, this deficit was only found in the first test session; drug treatment had no effect on responding following reminder of the memory. If data from preclinical studies are to inform future psychiatric treatments the findings from these works must be robust and replicable. Experiments in previous chapters encountered several issues in this regard, namely the repeated inability to prevent reconsolidation with NMDA receptor antagonism. Given that reconsolidation of auditory fear memories is well characterised a final series of experiments in Chapter 7 used this procedure to explore the possible reasons for the fleeting or absent effects of disrupted memory reconsolidation in previous chapters. Despite the use of similar methods as published reports showing decreases in memory expression as a result of blockade of reconsolidation it was not possible to disrupt this process with NMDA receptor antagonism or protein synthesis inhibition. Results suggested that the failure to observe reactivation-dependent amnesia was due to the amnestic agent used not being able to prevent reconsolidation, should it be taking place, and a failure of the given retrieval trial to result in memory reactivation. On numerous occasions throughout this thesis it was not possible to disrupt memory reconsolidation. One difficulty in interpreting null data of this nature is that it is often unclear whether the results are due to insufficient retrieval conditions to result in memory reconsolidation, or an inability of the pharmacological agent to disrupt this process. The final experiments of this thesis raised the possibility both of these issues may have contributed in tandem towards this inability to prevent memory reconsolidation.
Supervisor: Milton, Amy L. ; Everitt, Barry J. Sponsor: Behavioural and Clinical Neuroscience Institute ; Cambridge ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: reconsolidation ; memory ; addiction ; consolidation ; nmda ; ptsd ; post-traumatic stress disorder ; instrumental