The goal of this research is to determine human brain regions activated by nicotine and cocaine. This will be accomplished by using functional magnetic resonance imaging (FMRI) which has been shown to demonstrate activation in various brain regions in response to sensory, motor, and cognitive stimuli. In contrast to other functional imaging methods such as PET or SPECT, FMRI is noninvasive, offers better spatial resolution and the ability to make within-patient comparisons (e.g. before and after a stimulus). Animal studies indicate that addicting substances such as nicotine and cocaine involve the mesolimbic dopamine system including the nucleus accumbens. This hypothesis has been difficult to test in humans and, to date, has not been tested using FMRI. Because nicotine is a safer drug and because nicotine addicted subjects are more readily studied, investigations will commence using nicotine. The initial period of this research will concentrate on developing FMRI methods which can characterize the effects of nicotine administration and tolerance. The first hypothesis to be tested is that nicotine infusion activates the mesolimbic system in controls and in nicotine addicted subjects. Gradient echo or echoplanar FMRI activation maps coregistered with high resolution T1 weighted images will define brain regions affected by nicotine administration. Subjective and physiologic monitoring of subjects during nicotine injection will be performed. The results derived from nicotine studies may provide unique information concerning nicotine addiction and will establish paradigms for investigating the second drug, cocaine. Mechanisms of cocaine addiction will be studied using three strategies: 1. To determine the pattern of brain activation following cocaine infusion in cocaine addicted subjects; 2. To determine whether the mode of cocaine administration (intravenous, nasal infusion, or smoked alkaloidal cocaine) will affect the pattern of brain activation, 3. To test whether cocaine 'craving' activates the same brain regions as cocaine infusion. The last hypothesis will be tested by establishing classical conditioned responses to cocaine. In summary, animal studies have demonstrated that addicting substance including nicotine and cocaine activate many brain regions, including the mesolimbic dopamine system, notably the nucleus accumbens. Little is known about regions of human brain which may be activated by abused substances or by 'drug craving'. This research proposes to use FMRI to investigate these questions and the results of this study will provide further understanding of addiction mechanisms and directions to guide future therapy.
