title: DAT genotype modulates brain and behavioral responses elicited by cigarette cues.
abstract: We previously demonstrated differential activation of the mesocorticolimbic reward circuitry in response to cigarette cues independent of withdrawal. Despite robust effects, we noted considerable individual variability in brain and subjective responses. As dopamine (DA) is critical for reward and its predictive signals, genetically driven variation in DA transmission may account for the observed differences. Evidence suggests that a variable number of tandem repeats (VNTRs) polymorphism in the DA transporter (DAT) SLC6A3 gene may influence DA transport. Brain and behavioral responses may be enhanced in probands carrying the 9-repeat allele. To test this hypothesis, perfusion fMR images were acquired during cue exposure in 19 smokers genotyped for the 40 bp VNTR polymorphism in the SLC6A3 gene. Contrasts between groups revealed that 9-repeat (9-repeats) had a greater response to smoking (vs nonsmoking) cues than smokers homozygous for the 10-repeat allele (10/10-repeats) bilaterally in the interconnected ventral striatal/pallidal/orbitofrontal cortex regions (VS/VP/OFC). Activity was increased in 9-repeats and decreased in 10/10-repeats in the VS/VP/OFC (p<0.001 for all analyses). Brain activity and craving was strongly correlated in 10/10-repeats in these regions and others (anterior cingulate, parahippocampal gyrus, and insula; r(2)=0.79-0.86, p<0.001 in all regions). Alternatively, there were no significant correlations between brain and behavior in 9-repeats. There were no differences in cigarette dependence, demographics, or resting baseline neural activity between groups. These results provide evidence that genetic variation in the DAT gene contributes to the neural and behavioral responses elicited by smoking cues.
authors.affiliation: Department of Psychiatry, Addiction Treatment Research Center, University of Pennsylvania and Philadelphia VA Medical Center, Philadelphia, PA 19104, USA. franklin_t@mail.trc.upenn.edu
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Franklin
authors.forename: Falk W
authors.initials: FW
authors.lastname: Lohoff
authors.forename: Ze
authors.initials: Z
authors.lastname: Wang
authors.forename: Nathan
authors.initials: N
authors.lastname: Sciortino
authors.forename: Derek
authors.initials: D
authors.lastname: Harper
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.forename: Will
authors.initials: W
authors.lastname: Jens
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cruz
authors.forename: Kyle
authors.initials: K
authors.lastname: Kampman
authors.forename: Ron
authors.initials: R
authors.lastname: Ehrman
authors.forename: Wade
authors.initials: W
authors.lastname: Berrettini
authors.forename: John A
authors.initials: JA
authors.lastname: Detre
authors.forename: Charles P
authors.initials: CP
authors.lastname: O'Brien
authors.forename: Anna Rose
authors.initials: AR
authors.lastname: Childress
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002540:Cerebral Cortex / Q000502:physiology*; D003463:Cues; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000502:physiology; D012906:Smoke; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D012906:Smoke