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


METHODS
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.


METHODS
Academic brain imaging center.


METHODS
Forty-five tobacco-dependent smokers.


METHODS
Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning.


METHODS
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.
Brody
Arthur L
AL
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA. abrody@ucla.edu
Mandelkern
Mark A
MA
Olmstead
Richard E
RE
Scheibal
David
D
Hahn
Emily
E
Shiraga
Sharon
S
Zamora-Paja
Eleanor
E
Farahi
Judah
J
Saxena
Sanjaya
S
London
Edythe D
ED
McCracken
James T
JT
D000328:Adult; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000000981:diagnostic imaging* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography / Q000706:statistics & numerical data; D020891:Raclopride; D011954:Receptors, Dopamine / Q000235:genetics* / Q000378:metabolism; D012054:Reinforcement, Psychology; D012907:Smoking / Q000235:genetics* / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000378:metabolism
D002250:Carbon Radioisotopes; D011954:Receptors, Dopamine; D020891:Raclopride; D009538:Nicotine; D004298:Dopamine