1. ¹Department of Psychiatry, Addiction Treatment Research Center, University of Pennsylvania, Philadelphia, PA, USA
2. ²VA VISN 4 MIRECC, Philadelphia, Department of Veteran's Affairs Medical Center, Philadelphia, PA, USA
3. ³Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
4. ⁴Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: Dr TR Franklin, Department of Psychiatry, Addiction Treatment Research Center, University of Pennsylvania and Philadelphia VA Medical Center, 3900 Chestnut Street, Philadelphia, PA 19104, USA. Tel: +1 215 222 3200, ext. 119; Fax: +1 215 386 6770; E-mail: franklin_t@mail.trc.upenn.edu

Received 16 April 2008; Revised 11 July 2008; Accepted 15 July 2008; Published online 13 August 2008.

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; r²=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.