Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort.

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.

The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study.

The surge in dopamine in ventral striatal regions in response to drugs of abuse and drug-associated stimuli is a final common pathway of addiction processes. GABA B agonists exert their effects indirectly, by quieting dopaminergic afferents. The ability of the GABA B agonist, baclofen to ameliorate nicotine and drug motivated behavior is established within the animal literature, however its potential to do so in humans is understudied, particularly with respect to its possible utility as a smoking cessation agent. We conducted a nine-week double-blind placebo-controlled pilot trial of baclofen for smoking reduction (N=30/group) in smokers contemplating, but not quite ready to quit. Baclofen was titrated upwards to 20mg q.i.d. over a period of twelve days. The primary outcome measure was the number of cigarettes smoked per day (CPD). A significant group by time effect of medication was observed. Baclofen was superior to placebo in reducing CPD (beta=0.01, t=1.97, p<0.05). The most common side effect reported during baclofen treatment is transient drowsiness, however there were no differences between groups in mild, moderate, or severe sedation. Craving was significantly lowered at end of treatment in all smokers (p<0.02). Retention did not differ between groups. In line with a multitude of preclinical studies examining the effects of baclofen on drug-motivated behavior, baclofen reduced CPD. In agreement with other studies examining craving and drug use, reductions in CPD were accompanied by a reduction in craving, a major motivator underlying continued smoking and relapse. These preliminary results demonstrate provisional evidence of the utility of baclofen to aid in smoking cessation and indicate further investigation.

DAT genotype modulates brain and behavioral responses elicited by cigarette cues.

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.