Genetic susceptibility to substance dependence

Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Molecular Psychiatry (Impact Factor: 14.5). 05/2005; 10(4):336-44. DOI: 10.1038/
Source: PubMed


Despite what is often believed, the majority of those who experiment with substances with a dependence potential do not develop dependence. However, there is a subpopulation of users that easily becomes dependent on substances, and these individuals exhibit pre-existing comorbid traits, including novelty seeking and antisocial behavior. There appears to be a genetic basis for the susceptibility to dependence and these comorbid traits. Animal studies have identified specific genes that can alter susceptibility to dependence and response to novelty. The mechanisms underlying the genetic susceptibility to dependence and response to novelty are complex, but genetic susceptibility plays a significant role in the transition from substance use to dependence and from chronic use to addiction. We discuss two models to explain how genetic variations alter dependence susceptibility. Identification of the specific genes involved in these processes would help to identify individuals that are vulnerable to dependence/addiction and to devise novel treatment strategies.

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Available from: Noboru Hiroi, Oct 05, 2015
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    • "pioid dependence is defined as compulsive seeking and taking of opioid drugs such as morphine and heroin and the occurrence of withdrawal syndrome when drug taking is stopped (Wise & Koob, 2014). Although many environmental elements such as stress and social factors are likely to affect drug addiction, genetic variations may also heavily influence the phenomenon (Hiroi & Agatsuma, 2005). In a study by Tsuang et al. (Tsuang et al., 1998), it has been reported that overall heritability for opioid addiction is 54% which could be bifurcated into a section accounting for sole genetic variance (38%) and another part for common liability (16%) with other substances. "
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    ABSTRACT: Introduction: X chromosome inactivation (XCI) is a process during which one of the two X chromosomes in female human is silenced leading to equal gene expression with males who have only one X chromosome. Here we have investigated XCI ratio in females with opioid addiction to see whether XCI skewness in women could be a risk factor for opioid addiction. Methods: 30 adult females meeting DSM IV criteria for opioid addiction and 30 control females with no known history of addiction were included in the study. Digested and undigested DNA samples which were extracted from blood were analyzed after amplification of the polymorphic androgen receptor (AR) gene located on the X chromosome. XCI skewness was studied in 3 ranges: 50:50-64:36 (random inactivation), 65:35-80:20 (moderately skewed) and >80:20 (highly skewed). Results: XCI from informative females in control group was 63% (N=19) random, 27% (N=8) moderately skewed and 10% (N=3) highly skewed. Addicted women showed 57%, 23% and 20%, respectively. The distribution and frequency of XCI status in women with opioid addiction was not significantly different from control group (P=0.55). Discussion: Our data did not approve our hypothesis of increased XCI skewness among women with opioid addiction or unbalanced (non-random) expression of genes associated with X chromosome in female opioid addicted subjects.
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    • "Alcohol dependence (AD) is substantially heritable with studies estimating that heritability is between 50 and 70 % (Heath et al. 1997; Hiroi and Agatsuma 2005; Ystrom et al. 2011; Young-Wolff et al. 2012). Genes associated with AD include those coding for enzymes involved in the absorption and elimination of ethanol such as alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and cytochrome P450 2E1 (CYP2E1) (Zakhari 2006; Edenberg 2007). "
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    ABSTRACT: Alcohol dependence (AD) has a large heritable component. Genetic variation in genes involved in the absorption and elimination of ethanol have been associated with AD. However, some of these polymorphisms are not present in an African population. Previous studies have reported that a type of AD which is characterized by anxious behaviour may be a genetically specific subtype of AD. We investigated whether variation in genes encoding cytochrome P450 2E1 (CYP2E1) or acetaldehyde-metabolising enzymes (ALDH1A1, ALDH2) might alter the risk of AD, with and without symptoms of anxiety, in a Cape population with mixed ancestry. Eighty case control pairs (one with AD, one without AD) were recruited and individually matched for potential confounders. Genotype data were available for 29 single-nucleotide polymorphisms (SNPs) across the three genes. Linkage disequilibrium D' values were evaluated for all pairwise comparisons. Allele and haplotype frequencies were compared between cases and controls using a χ (2) test. The ACAG haplotype in block 4 of the ALDH1A1 gene provided evidence of an association with AD (p = 0.03) and weak evidence of an association with AD without symptoms of anxiety (p = 0.06). When a genetic score was constructed using SNPs showing nominal evidence of association with AD, every extra risk allele increased the odds of AD by 35 % (OR 1.35, 95%CI 1.08, 1.68, p = 0.008) and the odds of having AD with anxiety symptoms increased by 53 % (OR 1.53, 95%CI 1.14, 2.05, p = 0.004). Although our results are supported by previous studies in other populations, they must be interpreted with caution due to the small sample size and the potential influence of population stratification.
    Metabolic Brain Disease 02/2014; 29(2). DOI:10.1007/s11011-014-9503-x · 2.64 Impact Factor
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    • "These traits can each be measured with different instruments, yet are highly overlapping conceptually and highly correlated empirically (Zuckerman and Cloninger, 1996). High novelty/sensation-seeking scores correlate with " impulsiveness " and " exploratory excitability " (Cloninger, 1987; Svrakic et al., 1993), as impulsive individuals are thought to gravitate to novel and risky situations and show less anxiety about them (Hiroi and Agatsuma, 2005). These combined traits lead an individual to rapidly respond to cues for rewards despite potential punishment (Zuckerman and Kuhlman, 2000), a hallmark of addictive behavior. "
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    ABSTRACT: Human genetic and epidemiological studies provide evidence that only a subset of individuals who experiment with potentially addictive drugs become addicts. What renders some individuals susceptible to addiction remains to be determined, but most would agree that there is no single trait underlying the disorder. However, there is evidence in humans that addiction liability has a genetic component, and that certain personality characteristics related to temperament (e.g. the sensation-seeking trait) are associated with individual differences in addiction liability. Consequently, we have used a selective breeding strategy based on locomotor response to a novel environment to generate two lines of rats with distinct behavioral characteristics. We have found that the resulting phenotypes differ on a number of neurobehavioral dimensions relevant to addiction. Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats exhibit increased exploratory behavior, are more impulsive, more aggressive, seek stimuli associated with rewards, and show a greater tendency to relapse. We therefore utilize this unique animal model to parse the genetic, neural and environmental factors that contribute to addiction liability. Our work shows that the glucocorticoid receptor (GR), dopaminergic molecules, and members of the fibroblast growth factor family are among the neurotransmitters and neuromodulators that play a role in both the initial susceptibility to addiction as well as the altered neural responses that follow chronic drug exposure. Moreover, our findings suggest that the hippocampus plays a major role in mediating vulnerability to addiction. It is hoped that this work will emphasize the importance of personalized treatment strategies and identify novel therapeutic targets for humans suffering from addictive disorders.
    Neuropharmacology 04/2013; 76. DOI:10.1016/j.neuropharm.2013.04.033 · 5.11 Impact Factor
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