INDIVIDUAL VARIATION IN NICOTINE SENSITIVITY IN HUMANS

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Individual variation in sensitivity to drugs (i.e., acute responsiveness to drug effects) may help explain vulnerability to onset and persistence of drug abuse, including nicotine dependence. In the previous funding period of this research program, the results identified and characterized tolerance to nicotine in tobacco smokers, defined as reduction in functional sensitivity to nicotine due to smoking history. In this competing renewal, this line of investigation will be extended in two directions: 1) examination of genetic and personality (primarily novelty-seeking) factors that are associated with variation in nicotine responses and reinforcement; and 2) focus on an earlier point in the dependence process-initial nicotine exposure. Variation of this "initial" sensitivity to nicotine likely accounts for some of the differences in the reinforcing effects of nicotine upon initial exposure and, thus, smoking onset. Because nicotine's reinforcing effects likely are related to its dopaminergic actions, genes involved in moderating these actions may be critically important in understanding vulnerability to nicotine dependence. The primary genotypes to be examined involve variants on the SLC6A3 ("dopamine transporter" gene)--specifically presence ("-9") or absence ("-*") of the -9 repeat allele. Nicotine administration will be carefully controlled to allow determination of dose-response relationships for each genotype on acute subjective, behavioral, and physiological effects of nicotine (i.e. "sensitivity"), as well as on nicotine reinforcement (i.e. self-administration). Two hundred never-smokers will be examined, approximately half with each variant, instead of smokers in order to rule out confounds due to nicotine tolerance and withdrawal. It is hypothesized that nicotine sensitivity and reinforcement will be greater in never-smokers with the -* versus -9 alleles of SLC6A3. Because the personality characteristic of novelty-seeking may help clarify the influence of dopamine genotype, comparisons will be made between nicotine sensitivity and reinforcement as a function of novelty-seeking. Secondary analyses will examine responses as a function of DRD2 ("dopamine receptor density") genotypes and explore the possibility of gene-gene interactions. This research will be the first to comprehensively examine factors associated with individual variability in initial nicotine sensitivity and reinforcement (i.e., in nicotine-naive individuals). Results will provide directions for future research on vulnerability to tobacco dependence and for targeted efforts to prevent smoking onset.