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 (C-11) 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, D-2 receptor Taq A(1)/A(2), D-4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [C-11] 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 D-4 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.