Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression

Andrej Nikoshkov, Katarina Drakenberg, Xinyu Wang, Monika Cs Horvath, E. Keller, Yasmin L. Hurd

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3′ UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH)mRNAexpression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.

Original languageEnglish
Pages (from-to)786-791
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number2
DOIs
Publication statusPublished - Jan 15 2008

Fingerprint

Heroin Dependence
Neuropeptides
Opioid Analgesics
Dopamine
Genotype
Corpus Striatum
Heroin
Reward
Nucleus Accumbens
Methyltransferases
Tyrosine 3-Monooxygenase
Messenger RNA
Catecholamines
Opiate Alkaloids
Alleles
Dinucleotide Repeats
Dynorphins
proenkephalin
Enkephalins
Dopaminergic Neurons

Keywords

  • Catecholamine-O-methyltransferase
  • Drug abuse
  • Mu opioid receptor
  • Nucleus accumbens
  • Prodynorphin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Opioid neuropeptide genotypes in relation to heroin abuse : Dopamine tone contributes to reversed mesolimbic proenkephalin expression. / Nikoshkov, Andrej; Drakenberg, Katarina; Wang, Xinyu; Horvath, Monika Cs; Keller, E.; Hurd, Yasmin L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 2, 15.01.2008, p. 786-791.

Research output: Contribution to journalArticle

@article{f7712f88b6d141878faac46596e6d061,
title = "Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression",
abstract = "Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3′ UTR dinucleotide (CA) repeats; 79{\%} of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH)mRNAexpression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.",
keywords = "Catecholamine-O-methyltransferase, Drug abuse, Mu opioid receptor, Nucleus accumbens, Prodynorphin",
author = "Andrej Nikoshkov and Katarina Drakenberg and Xinyu Wang and Horvath, {Monika Cs} and E. Keller and Hurd, {Yasmin L.}",
year = "2008",
month = "1",
day = "15",
doi = "10.1073/pnas.0710902105",
language = "English",
volume = "105",
pages = "786--791",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - Opioid neuropeptide genotypes in relation to heroin abuse

T2 - Dopamine tone contributes to reversed mesolimbic proenkephalin expression

AU - Nikoshkov, Andrej

AU - Drakenberg, Katarina

AU - Wang, Xinyu

AU - Horvath, Monika Cs

AU - Keller, E.

AU - Hurd, Yasmin L.

PY - 2008/1/15

Y1 - 2008/1/15

N2 - Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3′ UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH)mRNAexpression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.

AB - Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3′ UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH)mRNAexpression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.

KW - Catecholamine-O-methyltransferase

KW - Drug abuse

KW - Mu opioid receptor

KW - Nucleus accumbens

KW - Prodynorphin

UR - http://www.scopus.com/inward/record.url?scp=38649097175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38649097175&partnerID=8YFLogxK

U2 - 10.1073/pnas.0710902105

DO - 10.1073/pnas.0710902105

M3 - Article

C2 - 18184800

AN - SCOPUS:38649097175

VL - 105

SP - 786

EP - 791

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -