Pilot--Nicotine replacement therapy effect on smoking reinforcement by genotype

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Nicotine replacement therapy (NRT) is the common pharmacological treatment for smoking cessation. There appear to be individual differences in the degree to which some formulations of NRT are clinically efficacious. Because of the vastly different speed of nicotine delivery between transdermal (TN) and nasal spray nicotine (NS), some of this individual differences in efficacy may relate to different effects of these products on neurochemical responses. Differences in dopamine transporter genotype, SLAGA3-9 ("protected") versus SLC6A3- *("predisposed"), are related to smoking status, perhaps because of differential effects of nicotine on the dopaminergic reward system. A smoking cessation study (project #2) is planned as part of the main center application to examine whether dopamine transporter genotype may predict differential outcome with TN versus NS treatment. This project includes assessment of the reinforcing value of smoking prior to starting NRT. The present pilot study extends and complements the clinical study by examining under controlled conditions whether the reinforcing value of smoking in response to acute exposure to TN versus may be differentially reduced between smokers of one genotype or the other. In this pilot project, we propose to: 1) Compare the reinforcing value of smoking following acute pre- treatment with TN, NS, and placebo between smokers with the SLC6A3- 9 versus SLC6A3-* dopamine genotypes. We predict that the reinforcing value of smoking will be decreased more by NS versus TN (main effect of NRT type) and that this decrease will differ as a function of genotype (genotype x NRT type interaction). The reinforcing value of smoking will be decreased by NS, but not TN, in SLC6A3-* smokers, while the reinforcing value of smoking will be decreased by either NS or TN in SLC6A3-9 smokers. 2) Compare acute objective mood response to TN, NS, and placebo between dopamine genotypes. Although of secondary, we predict that positive subjective responses (e.g. "alert", "relaxed") will be increased by NS more in smokers with SLC6A3-* versus SLC6A3-9 genotypes, while differences are expected between groups in mood responses to TN (genotype x NRT interaction). Result of this pilot may help explain possible different clinical efficacy of TN and NS between genotypes and aid in the identification of smokers more likely to benefit from one of the other formulation of NRT (i.e. tailor pharmacotherapy).