Das, RK; (2015) Manipulating Maladaptive Motivational Memories via Reconsolidation. Doctoral thesis , UCL (University College London).

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Abstract

Substance Use Disorders (SUDs), are generally viewed as disorders of maladaptive reward memory and motivation. In SUDs, memories formed during drug use associate environmental stimuli with the rewarding effects of drugs. These stimuli can subsequently trigger craving, highly motivated drug-seeking and relapse, even after years of abstinence. An exciting new approach to combatting these maladaptive memories is via reconsolidation, the process by which memories become briefly unstable upon recall in order to strengthen or update before restabilising. In Chapter 1, I review reward memory mechanisms in SUDs along with pharmacological and behavioural determinants of memory reconsolidation to identify potential drug targets for interfering with reconsolidation. In Chapter 2, I use meta-analysis to assess the effects of two classes of drugs; N-methyl D-aspartate (NMDAR) antagonists and β-Blockers on blocking reconsolidation of reward memory in rats and show that NMDAR antagonism is far more effective. Building on this knowledge, in Chapter 3, I show that 10mg of the NMDAR antagonist memantine in combination with the retrieval of smoking cue-drug memory does not affect relapse or craving in a group of quitting smokers. As this null finding may have represented either a failure to destabilise memories or inefficacy of memantine, in Chapter 4 I use a reward conditioning paradigm in hazardous drinkers to show that NMDAR antagonist Nitrous Oxide can interfere with reconsolidation of cue-alcohol memory, when administered after a reminder of learning that induces a negative prediction error. Chapter 5 builds on emerging evidence of the necessity of prediction error to destabilise memory, using guided expectancy violation to destabilise naturalistic cue-alcohol memories in hazardous drinkers. Subsequent disgust counterconditioning updated these memories, reducing motivational salience and liking of alcohol stimuli, with associated reduction in drinking. In Chapter 6 I discuss the research reported and suggest directions for further study.

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