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Title: Effects of catechol-O-methyltransferase on reinforcement learning and mesolimbic dopamine transmission
Author: Huber, Anna
ISNI:       0000 0004 6346 6967
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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The enzyme catechol-O-methyltransferase (COMT) plays an important role in the breakdown of dopamine in prefrontal cortex (PFC), but relatively little is known about its effects on nucleus accumbens (NAc) dopamine function. In this study, a transgenic mouse model of the Val158Met polymorphism found in the human COMT gene was used (a) to investigate the effects of COMT on associative learning, a process dependent on NAc dopamine, and (b) to relate this to potential changes in phasic dopamine release in the NAc core in awake behaving mice. In the first set of experiments (Chapter 3), animals were trained on a Pavlovian auditory discrimination task with white noise (WN) and a constant tone (Tone) as the rewarded (CS+) or unrewarded (CS-) conditioned stimulus (assignment of stimulus type counterbalanced between subjects). Whilst both COMT-Met mice and wild-type (WT) littermates acquired the cue-reward associations, learning rates of COMT-Met mice were significantly higher than those of WTs when WN was the CS+ and significantly lower when Tone was the CS+. Further experiments revealed that this effect was mediated by an interaction between COMT genotype and the unconditioned salience of the CS+, an effect that persisted even in the absence of a CS- (Chapter4). Cue-dependency of learning could not be explained by NAc dopamine release in response to auditory stimuli, as both genotypes showed similar response patterns as measured by fast-scan cyclic voltammetry at the start of training (Chapter 6). In a separate experiment, COMT-Met mice showed greater phasic dopamine levels in NAc core evoked by unsignalled reward than WT mice, especially when rewards were smaller than expected. Taken together, behavioural studies of associative learning in COMT-Met and WT mice revealed that COMT genotype affected the impact unconditioned cue salience had on associative learning. Direct measurements of phasic release of dopamine in the NAc core further showed a task-dependent effect of COMT genotype on dopamine release.
Supervisor: Tunbridge, Elizabeth M. ; Walton, Mark E. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available