Gene X Abstinence Effects on Drug Cue Reactivity in Addiction: Multimodal Evidence

Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Medical Department, Brookhaven National Laboratory, Upton, New York 11973, Department of Psychology, Stony Brook University, Stony Brook, New York 11794, National Institute on Drug Abuse, Bethesda, Maryland 20892, and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2013; 33(24):10027-36. DOI: 10.1523/JNEUROSCI.0695-13.2013
Source: PubMed


Functional polymorphisms in the dopamine transporter gene (DAT1 or SLC6A3) modulate responsiveness to salient stimuli, such that carriers of one 9R-allele of DAT1 (compared with homozygote carriers of the 10R-allele) show heightened reactivity to drug-related reinforcement in addiction. Here, using multimodal neuroimaging and behavioral dependent variables in 73 human cocaine-addicted individuals and 47 healthy controls, we hypothesized and found that cocaine-addicted carriers of a 9R-allele exhibited higher responses to drug cues, but only among individuals who had used cocaine within 72 h of the study as verified by positive cocaine urine screens (a state characterized by intense craving). Importantly, this responsiveness to drug cues was reliably preserved across multimodal imaging and behavioral probes: psychophysiological event-related potentials, self-report, simulated cocaine choice, and fMRI. Because drug cues contribute to relapse, our results identify the DAT1R 9R-allele as a vulnerability allele for relapse especially during early abstinence (e.g., detoxification).

Download full-text


Available from: Muhammad Parvaz, Oct 24, 2014
  • Source
    • "Over the many years to come since the 1990 finding, laboratories all across the globe including NIDA and NIAAA not only confirmed this early work [2] but extended the magnitude of many other candidate genes, especially genes and second messengers located in the reward circuitry of the brain [18]. Examples include, Moeller et al. [19] suggested that drug cues contribute to relapse, and their neurogenetic results have identified the DAT1R 9R-allele as a vulnerability allele for relapse especially during early abstinence (e.g., detoxification). The DAT1 9 allele influences the fast acting transport of dopamine sequestered from the synapse leading to a hypodopaminergic trait. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors as well as altered pain tolerance. While there are many studies claiming a genetic association with addiction and other behavioral infractions, defined as Reward Deficiency Syndrome (RDS), not all are scientifically accurate and in some case just wrong. Albeit our bias, we discuss herein the facts and fictions behind molecular genetic testing in RDS (including pain and addiction) and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one’s genetic risk for RDS.
    Full-text · Article · Jan 2015
  • Source
    • "Prior to analysis, and following the literature linking risk variants of 5-HTTLPR and MAOA to negative emotionality, each participant's neutral (baseline) LPP was subtracted from the unpleasant LPP, yielding the contrast unpleasant > neutral. [For results exploring the parallel pleasant > neutral contrast, which did not result in any significant results and therefore establishes specificity to the unpleasant > neutral contrast, see Supplementary Materials 5 ; also note that results of the cocaine-related contrasts are reported elsewhere (Moeller et al., 2013).] We then performed two-way analyses of covariance (ANCOVAs) (three total ANCOVAs), with diagnosis (CUD, control) as the first between-group factor and genetics as the second between-group factor; cigarette smoking history (yes/no) and race (African-American/Other) were included in these ANCOVAs as dummy covariates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Gene polymorphisms that affect serotonin signaling modulate reactivity to salient stimuli and risk for emotional disturbances. Here, we hypothesized that these serotonin genes, which have been primarily explored in depressive disorders, could also have important implications for drug addiction, with the potential to reveal important insights into drug symptomatology, severity, and/or possible sequelae such as dysphoria. Methods Using an imaging genetics approach, the current study tested in 62 cocaine abusers and 57 healthy controls the separate and combined effects of variations in the serotonin transporter (5-HTTLPR) and monoamine oxidase A (MAOA) genes on processing of aversive information. Reactivity to standardized unpleasant images was indexed by a psychophysiological marker of stimulus salience (i.e., the late positive potential (LPP) component of the event-related potential) during passive picture viewing. Depressive symptomatology was assessed with the Beck Depression Inventory (BDI). Results Results showed that, independent of diagnosis, the highest unpleasant LPPs emerged in individuals with MAOA-Low and at least one ‘Short’ allele of 5-HTTLPR. Uniquely in the cocaine participants with these two risk variants, higher unpleasant LPPs correlated with higher BDI scores. Conclusions Taken together, these results suggest that a multilocus genetic composite of monoamine signaling relates to depression symptomatology through brain function associated with the experience of negative emotions. This research lays the groundwork for future studies that can investigate clinical outcomes and/or pharmacogenetic therapies in drug addiction and potentially other psychopathologies of emotion dysregulation.
    Full-text · Article · Jul 2014 · Drug and Alcohol Dependence
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.
    Full-text · Article · Mar 2014 · Translational Psychiatry
Show more