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Title: Studies of genetic influences on nicotine dependence utilising functional neuroimaging
Author: David, Sean P.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2005
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A major contributor to relapse following smoking cessation is nicotine craving triggered by environmental cues, such as the sight of a lighted cigarette. Therefore, three integrated functional neuroimaging studies were conducted to examine the biological mechanisms underling cue-elicited craving for cigarettes. (1) First, I examined the effect of smoking-related pictorial cues on neural activation hi brain regions of interest (ROI) associated with reward signalling using functional magnetic resonance imaging (fMRI). Voxel-wise analysis demonstrated that smokers, but not nonsmokers, demonstrated significant activation associated with smoking-related pictorial cues in the anterior cingulate cortex, orbitofrontal cortex, and ventral striatum. Upon ROI analysis of the ventral striatum including the nucleus accumbens (VS/NAc), smokers exhibited significantly greater VS/NAc activation than non-smokers. (2) Next, I examined whether pre-specifled serotonergic polymorphisms would affect binding potential (BP) to a serotonin (5-HT) receptor implicated in the behavioural sensitisation process to nicotine (5-HTiA receptor). Healthy volunteers who had undergone positron emission tomography (PET) with a 5-HTiA-specific ligand [ U C]WAY-100635 were genotyped for the 5-HT1 A -1018 G>C and 5-HT transporter (5-HTT) 5-HTT gene-linked polymorphic region (5-HTTLPR) polymorphisms. Participants carrying the 5-HTTLPR S allele (SS or SL genotypes) demonstrated significantly lower global presynaptic and postsynaptic BP compared to subjects with LL genotypes. (3) Finally, I triangulated the two initial studies to examine whether pre-specified trait (5- HTTLPR genotype) and/or state (smoking vs. abstinence) variables would influence cueelicited activation of the VS/NAc. There was greater activation to smoking-related cues in the VS/NAc of smokers during the smoking condition than the abstinent condition and a significant correlation between tobacco craving and VS/NAc activation in the smoking condition. The 5-HTTLPR polymorphism was not associated with VS/NAc activation. Power calculations are presented as the basis for future examination of genetic hypotheses. These data have implications for the ultimate goal of enhancing the efficacy of smoking cessation pharmacotherapy.
Supervisor: Sim, Edith Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Nicotine addiction ; Tobacco use ; Brain ; Imaging ; Substance abuse ; Genetic aspects