Association of Specific Haplotypes of D2 Dopamine ReceptorGene With Vulnerability to Heroin Dependence in 2 Distinct Populations

Xu, Ke; Lichtermann, Dirk; Lipsky, Robert H.; Franke, Petra; Liu, Xiehe; Hu, Yan; Cao, Liping; Schwab, Sibylle G.; Wildenauer, Dieter B.; Bau, Claiton H.D.; Ferro, Erica; Astor, Will; Finch, Thembi; Terry, Jeanietta; Taubman, Julie; Maier, Wolfgang; Goldman, David

doi:10.1001/archpsyc.61.6.597

Cited by 112 publications

(73 citation statements)

References 34 publications

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“…Of interest is the fact that Neville et al [2004] have localized the TaqI A polymorphism to a region approximately 9.5 kb upstream from the DRD2 gene in the Ankyrin (ANKK1) gene. Two studies found evidence for linkage disequilibrium between the TaqI A and the C957T polymorphisms [Duan et al, 2003;Xu et al, 2004] as was found in the present study. This suggests those previously reported positive associations between various addictions (e.g., alcohol dependence and nicotine dependence) and the TaqI A polymorphism may have been the result of variations in the C957T polymorphism which is known to have functional effects on dopaminergic availability.…”

Section: Discussionsupporting

confidence: 88%

“…Also, Lerman et al [2006] found that nicotine dependent individuals homozygous for the -141C Ins/Del showed an improved treatment response to buproprion. A significant case/control association between heroin dependence and allelic variation in both -141C Ins/Del and A-241G has been reported in a Chinese sample [Xu et al, 2004] though the results were not seen in a German sample studied by this group of investigators.…”

Section: Discussionmentioning

confidence: 64%

“…One of these SNPs, the C957T polymorphism, rather than being silent, alters mRNA folding leading to decreased mRNA stability and translation, and as a consequence dramatically changes dopamine-induced up-regulation of DRD2 expression. To date, this polymorphism has been studied in schizophrenics [Lawford et al, 2005], drug dependent individuals [Xu et al, 2004;Gelernter et al, 2006] and in nicotine dependent participants Jacobsen et al, 2006;Lerman et al, 2006]. To our knowledge, this mutation has not previously been studied in samples specifically recruited for multiplex alcohol dependent family status though alcohol dependence has been studied in the context of polysubstance abuse .…”

Section: Introductionmentioning

confidence: 99%

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Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Hill

Hoffman

Zezza

et al. 2008

American J of Med Genetics Pt B

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Animal and human studies of addiction indicate that the D2 dopamine receptor (DRD2) plays a critical role in the mechanism of drug reward. D2 receptor density in the brains of alcoholics has been shown to be reduced relative to controls. Previous studies of DRD2 in association with alcohol dependence using variation in the TaqI A locus were highly controversial. Recently, a synonymous mutation, C957T, in the coding region of the human DRD2 gene has been identified which appears to have functional effects including alteration in receptor availability. In order to determine if susceptibility to alcohol dependence (AD) within multiplex alcohol dependence families would be altered by the C957T in the coding region of the D2 gene, within-family association was studied in members of Caucasian multiplex alcohol dependence families. Members of control families with no personal alcohol or substance dependence history were included for case/control comparisons. Analyses performed to detect within-family association showed evidence favoring an association for the C957T polymorphism (P = 0.038). Linkage analyses of polymorphisms in this region showed that only the C957T locus remained of interest (P = 0.015). Evidence for the C957T T allele having a role in AD susceptibility at the population level using a case/control comparison was statistically marginal (P = 0.062), but was consistent with the family data results. These results support a role for DRD2 as a susceptibility gene for alcohol dependence within multiplex families at high risk for developing alcohol dependence.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Hill

Hoffman

Zezza

et al. 2008

American J of Med Genetics Pt B

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“…They were recruited from a study on genetic influences on vulnerability to heroin dependence (Xu et al, 2004). In conjunction with a five-year follow up, only subjects who were abstinent for at least one year were considered for the present study (mean abstinence duration (SD)=18.93 (±20.45) months).…”

Section: Participantsmentioning

confidence: 99%

Sustained incentive value of heroin-related cues in short- and long-term abstinent heroin users

Preller

Wagner

Sulzbach

et al. 2013

European Neuropsychopharmacology

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Models of addiction and addiction memory propose that drug-associated cues elicit incentive effects in drug users, which play an important role in maintenance of drug use and relapse. Incentive effects have been demonstrated for smoking and alcohol-related cues but evidence for heroin-related cues has been inconclusive. Furthermore, it is unknown whether appetitive effects of heroin-related cues persist after prolonged abstinence, although heroin addiction is known to have high relapse rates. Therefore, we investigated implicit and explicit valence of heroin-related cues in dependent users at different stages of abstinence using affective startle modulation. In Study I, 15 current heroin users were measured before and after detoxification. Correspondingly, 15 healthy control participants were tested twice at an interval of 14 days. In Study II, 14 long-term abstinent heroin users were additionally measured in a single session. Implicit processing of drug-related stimuli was assessed using affective startle modulation by pictures of heroin and smoking scenes. Explicit reactions were measured using ratings of valence and craving. In contrast to controls, heroin-dependent participants showed a clear reduction of startle response during heroin-related pictures (p<0.05). Detoxification did not significantly change their startle responses to heroin-cues. No difference between non-detoxified current and long-term abstinent heroin users was found in implicit reactions to heroin-cues, whereas explicit measures differed between both groups (all p<0.05). After detoxification and even after prolonged abstinence, heroin cues still exert implicit appetitive effects in heroin users. This implies that drug-induced adaptations of reward circuits are long-lasting, resulting in a highly stable addiction memory. AbstractModels of addiction and addiction memory propose that drug-associated cues elicit incentive effects in drug users, which play an important role in maintenance of drug use and relapse.Incentive effects have been demonstrated for smoking and alcohol-related cues but evidence for heroin-related cues has been inconclusive. Furthermore, it is unknown whether appetitive effects of heroin-related cues persist after prolonged abstinence, although heroin addiction is known to have high relapse rates. Therefore, we investigated implicit and explicit valence of heroin-related cues in dependent users at different stages of abstinence using affective startle modulation. In Study I, 15 current heroin users were measured before and after detoxification.Correspondingly, 15 healthy control participants were tested twice at an interval of 14 days.In Study II, 14 long-term abstinent heroin users were additionally measured in a single session. Implicit processing of drug-related stimuli was assessed using affective startle modulation by pictures of heroin and smoking scenes. Explicit reactions were measured using ratings of valence and craving. In contrast to controls, heroin-dependent participants showed a clear reduction o...

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“…[5][6][7][8][9] These include variants in genes coding for two receptors of the opioid system, the m 10-12 and k opioid receptors. 13 Other variants that have been found to be associated with opiate addiction are located in and around the dopamine D2 [14][15][16] and D4 receptors, [17][18][19][20] the serotonin transporter, 21,22 the serotonin 1B receptor 23 and genes for the enzyme catechol-O-methyltransferase. 24,25 Studies have provided evidence that several chromosomal regions are linked to the vulnerability to develop heroin, alcohol, nicotine or other drug abuse or addiction.…”

Section: Introductionmentioning

confidence: 99%

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

Nielsen

Yuferov

et al. 2008

Mol Psychiatry

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A genome-wide association study was conducted using microarray technology to identify genes that may be associated with the vulnerability to develop heroin addiction, using DNA from 104 individual former severe heroin addicts (meeting Federal criteria for methadone maintenance) and 101 individual control subjects, all Caucasian. Using separate analyses for autosomal and X chromosomal variants, we found that the strongest associations of allele frequency with heroin addiction were with the autosomal variants rs965972, located in the Unigene cluster Hs.147755 (experiment-wise q = 0.053), and rs1986513 (q = 0.187). The three variants exhibiting the strongest association with heroin addiction by genotype frequency were rs1714984, located in an intron of the gene for the transcription factor myocardin (P = 0.000022), rs965972 (P = 0.000080) and rs1867898 (P = 0.000284). One genotype pattern (AG-TT-GG) was found to be significantly associated with developing heroin addiction (odds ratio (OR) = 6.25) and explained 27% of the population attributable risk for heroin addiction in this cohort. Another genotype pattern (GG-CT-GG) of these variants was found to be significantly associated with protection from developing heroin addiction (OR = 0.13), and lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. Evidence was found for involvement of five genes in heroin addiction, the genes coding for the l opioid receptor, the metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 and cryptochrome 1 (photolyase-like). This approach has identified several new genes potentially associated with heroin addiction and has confirmed the role of OPRM1 in this disease.

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Association of Specific Haplotypes of D2 Dopamine ReceptorGene With Vulnerability to Heroin Dependence in 2 Distinct Populations

Abstract: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.

Cited by 112 publications

References 34 publications

Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Sustained incentive value of heroin-related cues in short- and long-term abstinent heroin users

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

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