Effects of Nicotine on Brain Activity as Measured by fMRI

Objective: The overall goal of this protocol is to employ fMRI to define nicotine's neural pharmacokinetic and pharmacodynamic properties and neurochemical sites and mechanisms of action in experienced smokers and to correlate these with monoamine and nicotinic receptor genotypes as well as to determine behavioral correlates of nicotine during various conditions of delivery and regress behavioral correlates of nicotine administration against neuroanatomical sites of activation across subjects. Study Population: The study population will consist of adult (18-50 y.o.) non-treatment seeking smokers. Subjects must smoke at least 20 cigarettes per day for at least 1 year. They cannot be dependent on any drug or alcohol except nicotine and caffeine. In addition, they must be appropriate candidates for fMRI scanning. Design: The study is divided into 5 separate arms with a maximum of two arms being conducted at one time. The experimental arms explore the effect of intravenous nicotine delivery with respect to the following parameters: dosage, interval of delivery, rate of delivery and emotional processing. Specifically the arms are as follows: Experiment 1: 3 fMRI scan sessions each administering either 0.25, 0.75 and 1.5 mg IV nicotine; Experiment 2: 4 fMRI scan sessions administering two doses of 1.25 mg nicotine separated by 0.25, 0.75, 3 and 24 hours; Experiment 3: two injection series separated by 45 minutes, each injection series containing 5 rapid injections of 0.25 mg each, much like 5 puffs on a cigarette; Experiment 4: 3 fMRI sessions administering a single injection of 1.5 mg nicotine at 3 different rates- over 15, 60 or 120 seconds; and Experiment 5: 3 fMRI session administering 1.5 mg nicotine followed by exposure to either neutral, negative, or positive affect pictures. Since experimental arms are conducted in series, rather than in parallel, there are very few subjects common to more than one experimental arm. Outcome Measures: The relevant outcome measures in this study are the behavioral and physiological effects and the patterns of brain regions activated (or suppressed) following the intravenous administration of nicotine across varying doses, intervals, rates and the effect on these parameters of emotional processing in the context of nicotine of stimuli with different affective valence.