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OBJECTIVE: The purpose of the study was to determine the effects of cigarette smoking on brain regional function in a group of chronic smokers by using cerebral blood flow (CBF) measures and positron emission tomography (PET). METHOD: Nineteen tobacco smokers were studied after about 12 hours of smoking abstinence. Regional CBF (rCBF) measures were obtained with PET and [15O]H2O in six consecutive scans. Two average-nicotine-yield (1.0 mg) and one denicotinized (0.08 mg) research cigarettes with similar tar yields (9.5 mg and 9.1 mg, respectively) were smoked in a double-blind design, preceded and followed by baseline scans. The rCBF effects of smoking were compared to baseline measures and between cigarettes, as well as to subjective ratings of craving for cigarettes. RESULTS: Smoking the first cigarette of the day resulted in increases in rCBF in the visual cortex and the cerebellum and reductions in the anterior cingulate, the right hippocampus, and the ventral striatum, including the nucleus accumbens. Cigarette craving scores correlated with rCBF changes in the dorsal anterior cingulate and right hippocampus. Less pronounced effects were observed with the second cigarette and the denicotinized cigarette. CONCLUSIONS: Smoking affects rCBF not only in areas of the brain rich in nicotinic cholinergic receptors but also in areas implicated in the rewarding effects of drugs of abuse. Furthermore, craving for a cigarette in chronic smokers was correlated with rCBF in the right hippocampus, an area involved in associating environmental cues with drugs, and in the left dorsal anterior cingulate, an area implicated in drug craving and relapse to drug-seeking behavior.