title: Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort.
abstract: Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.
authors.affiliation: Research Assistant Professor of Neuroscience, Addiction Treatment Research Center, Department of Psychiatry, University of Pennsylvania School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104, USA. franklin_t@mail.trc.upenn.edu
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Franklin
authors.forename: Ze
authors.initials: Z
authors.lastname: Wang
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Suh
authors.forename: Marina
authors.initials: M
authors.lastname: Goldman
authors.forename: Falk W
authors.initials: FW
authors.lastname: Lohoff
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cruz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hazan
authors.forename: Will
authors.initials: W
authors.lastname: Jens
authors.forename: John A
authors.initials: JA
authors.lastname: Detre
authors.forename: Wade
authors.initials: W
authors.lastname: Berrettini
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; D000679:Amygdala / Q000502:physiology; D001479:Basal Ganglia / Q000503:physiopathology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000503:physiopathology; D015331:Cohort Studies; D003463:Cues; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D006580:Genetic Carrier Screening; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009042:Motivation / Q000502:physiology*; D010296:Parietal Lobe / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics; D017397:Prefrontal Cortex / Q000503:physiopathology; D012907:Smoking / Q000235:genetics* / Q000503:physiopathology*; D016540:Smoking Cessation / Q000523:psychology; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human