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The UK government are currently engaged in a campaign to reduce adult smoking rates from 26 per cent in 2002 to 21 per cent or less in 2010 (Milne, 2005). The cornerstone of this strategy is the promotion of Nicotine Replacement Therapy (NRT) to aid the withdrawal process. The importance of a market based product (NRT) within government strategy poses a topical area for investigation. This research aims to understand and clarify the role of emotion within a decision making framework resulting in a detailed understanding of the consumer decision making process involved when using NRT to aid smoking cessation. In order to achieve this; the Extended Model of Goal directed Behaviour (EMGB: Perugini & Conner, 2000) will operationalised. The EMGB is the latest model posed to gain a better understanding of the cognitive and affective decision making process.

Smoking is now recognized as the single largest avoidable cause of premature death and disability in Britain and probably the greatest avoidable threat to public health worldwide. There are several therapies available to combat nicotine addiction ranging from psychological therapy to pharmacological interventions such as Nicotine Replacement Therapy. However, success rates for these therapies individually and mixture of therapies together, are still low and can be improved. A new strategy in helping quit rates is immunotherapy. This research project has focused on targeting cotinine, the major metabolite of nicotine, to produce a vaccine as a cessation method. The effect of cotinine on nicotine-evoked dopamine release was first examined using 96-well plate assay in chapter 2. Cotinine was shown to decrease nicotine - evoked dopamine release, probably by desensitising the nAChRs. a6p2*, a4p2 receptor subtypes were implicated, using competitive antagonists. Trans-4-thiol cotinine was produced as a viable derivative and conjugated to ovalbumin in the appendix and chapter 3. Vaccination of rats generated anti-cotinine antibodies, although mid-point titres were low. Improvements were made in chapter 4 which increased the mid-point antibody titres. The improvements included change of carrier molecule to Tenatus Toxoid, allowing for 15 derivative attachments per carrier molecule, and change of adjuvant. The best concentration of conjugate to be used in vaccination was determined to be 5 pg which produced specific antibodies towards cotinine. Blood nicotine and cotinine concentrations after chronic nicotine treatment showed vaccination resulted in the retention of cotinine in the blood, presumably reducing the concentration reaching the brain, in chapters 4 and 5. Similar results were also obtained after acute nicotine treatment in chapter 5. The effect of vaccination on nicotine - evoked dopamine release was studied in chapters 4 and 5; an increase in nicotine-evoked dopamine release was observed in vaccinated animals. This suggests the retention of cotinine in the blood and the consequent reduction of antagonism of the actions of nicotine by cotinine, allowed nicotine to have a larger effect. Nicotineinduced locomotor activity was not affected by vaccination, however future work is needed to give conclusive results. These results have provided preliminary proof of concept for this immunotherapy approach. Future in vivo experiments will elucidate the actions of this vaccine on addiction mechanisms and facilitate the development of this approach as a therapy to help people overcome nicotine addiction.

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.