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; 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.

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

“…For example, research on reward sensitivity showed that BOLD during reward anticipation and delivery, as well as during presentation of reward-related stimuli is larger for 9R carriers than 10R hetero-and homozygotes (Dreher et al, 2009;Forbes et al, 2009;Franklin et al, 2009). Direct support of enhanced striatal DA release in 9R carriers was obtained following smoking in a [ 11 C]raclopride PET study (Brody et al, 2006), in agreement with studies suggesting the 9R allele to be associated with enhanced dopaminergic output.…”

Neuroimaging of cigarette cravings: individual differences matter

“…It therefore remains unclear whether the increased ACC activations reflect specific differences in cravings or differences in other withdrawal-related symptoms. A review of the studies included in the meta-analysis from Sayette & Wilson [1] reveals that only four of 11 studies that assessed the relationship showed significant associations between subjective cravings and ACC activations [3][4][5][6]. Although these results do not rule out a direct relationship between ACC activations and cravings, they do not offer a strong support for this assumption.…”

“…Thus, the neurobiology of craving has been examined principally via human neuroimaging studies. These studies have revealed that a diffuse network of brain regions is reliably engaged by drugrelated cues (for reviews, see [2][3][4][5][6]). …”

Impulse Control Disorders in Parkinson’s Disease: Crossroads between Neurology, Psychiatry and Neuroscience

“…This finding could be due to ventral striatal DA terminal loss, which seems unlikely given the reports of enhanced dopamine release in the ventral striatum of PD-ICD patients [48,49], or lower membrane expression determined functionally or genetically [55]. DAT gene variants have been consistently demonstrated in non-PD patients with ICDs and addiction [56][57][58][59][60], but a single study with PD-ICD patients found no association between the presence of ICDs and one particular DAT polymorphism [61].…”