DAT Genotype Modulates Brain and Behavioral Responses Elicited by Cigarette Cues

Department of Psychiatry, Addiction Treatment Research Center, University of Pennsylvania and Philadelphia VA Medical Center, Philadelphia, PA 19104, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 08/2008; 34(3):717-28. DOI: 10.1038/npp.2008.124
Source: PubMed


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.

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    • "Therefore, polymorphisms in the promoter region and 3 UTR represent good candidates in the context of linkage and association studies. Although the association between DAT1 and substance dependence has been examined previously (Franklin et al., 2009; Hong et al., 2003; Yeh et al., 2010), the role of DAT1 in the development of AD remains controversial and unclear. Prior studies on this topic have been limited to the investigation of only a few polymorphisms (Hamidovic et al., 2010; Hong et al., 2003; Ujike et al., 2003), and the limited results were unable to provide evidence of an existing association. "
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    ABSTRACT: A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and Alcohol Dependence 02/2015; 149. DOI:10.1016/j.drugalcdep.2015.01.030 · 3.42 Impact Factor
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    • "Cannabis craving prior to the imaging session was positively correlated with activation in the bilateral insula and pgACC. These findings are consistent with research indicating that drug-related cues activate the insula and that activity in the insula is positively correlated with drug craving (Bonson et al. 2002; Franklin et al. 2009b). The anterior cingulate cortex is involved in several monitoring, decisionmaking , and cognitive control processes (Isomura and Takada 2004; Rushworth et al. 2011), and the correlation between subliminal cannabis cue reactivity in the pgACC and cannabis craving may reflect interindividual variability in attempts to regulate responses to subliminal cannabis cues detected by the anterior insula. "
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    ABSTRACT: Addiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors. Using an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning). Twenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging. Participants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex. These data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.
    Psychopharmacology 11/2013; 231(7). DOI:10.1007/s00213-013-3342-z · 3.88 Impact Factor
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    • "Given that males and females respond differently to nicotine and nicotine-related factors, we hypothesized that they would also show differences in brain responses during SC exposure. Based on previous research suggesting greater behavioral and physiological responses to SCs among females relative to males [8,9,11,13], we hypothesized that females would show greater brain responses to SCs than males in brain regions that we have consistently shown to be associated with SC-reactivity (i.e., mOFC, VS/VP, hippocampus, amygdala, and insula) [16,21-23]. To test this hypothesis, we used the technique of pseudo-continuous arterial spin-labeled (pCASL) perfusion fMRI to acquire brain responses during SC (versus non-SC) exposure. "
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    ABSTRACT: Background Anecdotal and clinical theories purport that females are more responsive to smoking cues, yet few objective, neurophysiological examinations of these theories have been conducted. The current study examines the impact of sex on brain responses to smoking cues. Methods Fifty-one (31 males) cigarette-dependent sated smokers underwent pseudo-continuous arterial spin-labeled perfusion functional magnetic resonance imaging during exposure to visual smoking cues and non-smoking cues. Brain responses to smoking cues relative to non-smoking cues were examined within males and females separately and then compared between males and females. Cigarettes smoked per day was included in analyses as a covariate. Results Both males and females showed increased responses to smoking cues compared to non-smoking cues with males exhibiting increased medial orbitofrontal cortex and ventral striatum/ventral pallidum responses, and females showing increased medial orbitofrontal cortex responses. Direct comparisons between male and female brain responses revealed that males showed greater bilateral hippocampal/amygdala activation to smoking cues relative to non-smoking cues. Conclusions Males and females exhibit similar responses to smoking cues relative to non-smoking cues in a priori reward-related regions; however, direct comparisons between sexes indicate that smoking cues evoke greater bilateral hippocampal/amygdalar activation among males. Given the current literature on sex differences in smoking cue neural activity is sparse and incomplete, these results contribute to our knowledge of the neurobiological underpinnings of drug cue reactivity.
    Biology of Sex Differences 04/2013; 4(1):9. DOI:10.1186/2042-6410-4-9 · 4.84 Impact Factor
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