Association between heroin dependence and prodynorphin gene polymorphisms

Wei, Shuguang; Zhu, Yan; Lai, Jianghua; Xue, Hao; Chai, Z.Q.; Li, S.B.

doi:10.1016/j.brainresbull.2011.02.010

Cited by 34 publications

(38 citation statements)

References 37 publications

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“…On basis on the 1000 Genome data analysis of the PDYN gene (+/ − 10 kb), rs2235749 was in strong LD with several 3′ UTR SNPs including rs910080 and was thus a good proxy for the 3′UTR (Supplementary Figure S3). As there was a near complete overlap of the rs2235749 and rs910080 polymorphisms in each subject consistent with the strong LD (D'40.9) between these SNPs (Wei et al, 2011), only the genotype data of the rs2235749 variant are presented below for the postmortem and clinical cohorts. Racial composition did not differ among the different genotypes and self-reported race showed a complete overlap with ancestry informative markers.…”

Section: ′Utr Polymorphisms Of the Pdyn Gene Are Associated With Behmentioning

confidence: 98%

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

Egervári

Jutras‐Aswad

Landry

et al. 2016

Neuropsychopharmacol

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Genetic factors impact behavioral traits relevant to numerous psychiatric disorders and risk-taking behaviors, and different lines of evidence have indicated that discrete neurobiological systems contribute to such individual differences. In this study, we explored the relationship of genetic variants of the prodynorphin (PDYN) gene, which is enriched in the striatonigral/striatomesencephalic pathway, a key neuronal circuit implicated in positive 'Go' behavioral choice and action. Our multidisciplinary approach revealed that the single nucleotide polymorphism (SNP) rs2235749 (in high linkage disequilibrium with rs910080) modifies striatal PDYN expression via impaired binding of miR-365, a microRNA that targets the PDYN 3′-untranslated region (3′UTR), and is significantly associated to novelty-and reward-related behavioral traits in humans and translational animal models. Carriers of the rs2235749G allele exhibited increased levels of PDYN 3′UTR in vitro and had elevated mRNA expression in the medial nucleus accumbens shell (NAcSh) and caudate nucleus in postmortem human brains. There was an association of rs2235749 with novelty-seeking trait and a strong genotype-dose association with positive reinforcement behavior in control subjects, which differed in cannabis-dependent individuals. Using lentiviral miRZip-365 constructs selectively expressed in Pdyn-neurons of the NAcSh, we demonstrated that the Pdyn-miR365 interaction in the NAcSh directly influences novelty-seeking exploratory behavior and facilitates self-administration of natural reward. Overall, this translational study suggests that genetically determined miR-365-mediated epigenetic regulation of PDYN expression in mesolimbic striatonigral/striatomesencephalic circuits possibly contributes to novelty seeking and positive reinforcement traits.

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Section: ′Utr Polymorphisms Of the Pdyn Gene Are Associated With Behmentioning

confidence: 98%

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

Egervári

Jutras‐Aswad

Landry

et al. 2016

Neuropsychopharmacol

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“…While several functions have been associated with the striatum, the medial orbitofrontal cortex (mOFC) and the amygdala, it is widely accepted that they play a dominant role in processes related to reward anticipation and consumption, in the control of mood, and motivation, as well as in stimulus-response learning [14], [15], [16], [17], [18], [19]. In line with these functions, there is evidence that increases in PDYN neurotransmission may contribute to the pathogenesis of depression, anxiety-like behavior, dysphoria, and drug addiction [20], [21], [22], [23].…”

Section: Introductionmentioning

confidence: 99%

“…While several studies observed that individuals with a higher number of alleles (and hence higher dynorphin levels) showed increased susceptibility to the development of cocaine [25], methamphetamine [22] and heroin [21] dependency, others did not find such a relationship between genotype and drug abuse [26], [27]. Numerous psychopharmacological studies indicate, though, that chronic drug abuse as well as KOPr agonists enhance the expression of dynorphin, lead to adaptations in KOPr’s second-messenger signaling in the mesolimbic reward system, and therefore are able to influence and regulate the brain’s reward system (for review, see [28]).…”

Section: Introductionmentioning

confidence: 99%

A Genetic Polymorphism of the Endogenous Opioid Dynorphin Modulates Monetary Reward Anticipation in the Corticostriatal Loop

et al. 2014

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The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.

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“…There have been several reports that have examined the relationship between this tandem repeat element polymorphism and substance use disorders (SUDs) but results are mixed, with some studies showing that high PDYN expressing alleles are more common among people with SUDs (Nomura et al, 2006; Dahl et al, 2005; Wei et al, 2011, Williams et al, 2007), others showing low expression alleles in association with dependence (Chen et al 2002) and still others reporting no association (Ray et al, 2005; Nikoshkov et al, 2008; Zimprich, 2000). The inconsistent results across studies can be attributed to a variety of factors, including small sample sizes, variation in ethnic background of the samples and the examination of different SUDs (e.g., heroin, cocaine, and methamphetamine).…”

Section: Introductionmentioning

confidence: 99%

Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene

Flory

Pytte

Hurd

et al. 2011

Biological Psychology

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The results of the current analyses present preliminary evidence of an association between putatively functional variation in the prodynorphin (PDYN) gene and a dimensional measure of disinhibited behavior. A 68 bp sequence in the core promoter region of the PDYN gene was genotyped in a community sample of 1021 adults aged 30–54. Participants were interviewed for lifetime history of DSM-IV alcohol dependence and completed two self-report measures of sensation seeking and impulsiveness. Fifteen percent (n=151) of the sample met DSM-IV criteria for alcohol dependence and while results did not support an association between the PDYN polymorphism and the diagnosis of alcohol dependence, we did observe an association between the “low” expressing L allele of the PDYN gene and a preference for engaging in disinhibited behavior. Additionally, people who had both a history of alcohol dependence and higher scores on this Disinhibited Behavior scale were most likely to carry an L allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors (e.g., drug use, sexual activity).

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Association between heroin dependence and prodynorphin gene polymorphisms

Cited by 34 publications

References 37 publications

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

A Genetic Polymorphism of the Endogenous Opioid Dynorphin Modulates Monetary Reward Anticipation in the Corticostriatal Loop

Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene

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