Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.

CONTEXT Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. OBJECTIVE To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. DESIGN Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. SETTING Academic brain imaging center. PARTICIPANTS Forty-five tobacco-dependent smokers. INTERVENTIONS Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. MAIN OUTCOME MEASURES Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. RESULTS For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. CONCLUSIONS Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.