Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age

Monika Cs Horvath, Gabor G. Kovacs, Viktor Kovari, K. Majtényi, Yasmin L. Hurd, E. Keller

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Dysfunction of mesocorticolimbic dopaminergic neurons is considered a common feature of all drugs of abuse, yet few investigations have evaluated the dopamine (DA) system in nonstimulant human abusers. We examined mRNA expression levels of DA transporter (DAT), tyrosine hydroxylase (TH), dopamine D 2 receptor, α-synuclein, and nuclear receptor-related 1 (Nurr1) in discrete mesocorticolimbic and nigrostriatal subpopulations of heroin users and control subjects. The chronic use of heroin was significantly associated with decreased DAT mRNA expression localized to the paranigral nucleus (PN) and the mesolimbic division of the ventral tegmental area (VTA) with no alterations in nigrostriatal populations. Consistently, the density of DAT immunoreactivity was significantly reduced in the nucleus accumbens but not in dorsal striatum, mesolimbic and nigrostriatal efferent targets, respectively. Significant alteration of the mRNA expression of Nurr1, a transcription factor that regulates DAT expression, was also confined to the PN. Moreover, the results revealed an exaggerated reduction of Nurr1 expression with age in heroin users (r = -0.8268, p <0.001 vs controls, r = -0.6204, p = 0.0746). TH and α-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D2 receptor. Evaluating midbrain μ- and κ-opioid receptors, relevant for the action of heroin and regulation of DA neurons, revealed dysregulation of G-protein coupling selective to the VTA PN. Altogether the current findings provide direct neurobiological evidence that midbrain reward circuits have the most prominent DA and opioid impairments in human heroin abusers and that abnormal Nurr1 transcription with opiate use may exacerbate limbic dysfunction with age.

Original languageEnglish
Pages (from-to)13371-13375
Number of pages5
JournalJournal of Neuroscience
Volume27
Issue number49
DOIs
Publication statusPublished - Dec 5 2007

Fingerprint

Heroin Dependence
Heroin
Cytoplasmic and Nuclear Receptors
Opioid Analgesics
Dopamine
Ventral Tegmental Area
Synucleins
Messenger RNA
Dopaminergic Neurons
Tyrosine 3-Monooxygenase
Mesencephalon
Opiate Alkaloids
Dopamine Plasma Membrane Transport Proteins
Nucleus Accumbens
Street Drugs
Opioid Receptors
Reward
GTP-Binding Proteins
Transcription Factors
Population

Keywords

  • α-synuclein
  • μ-opioid receptor
  • Dopamine transporter
  • Human
  • Periaqueductal gray
  • Substantia nigra

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age. / Horvath, Monika Cs; Kovacs, Gabor G.; Kovari, Viktor; Majtényi, K.; Hurd, Yasmin L.; Keller, E.

In: Journal of Neuroscience, Vol. 27, No. 49, 05.12.2007, p. 13371-13375.

Research output: Contribution to journalArticle

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abstract = "Dysfunction of mesocorticolimbic dopaminergic neurons is considered a common feature of all drugs of abuse, yet few investigations have evaluated the dopamine (DA) system in nonstimulant human abusers. We examined mRNA expression levels of DA transporter (DAT), tyrosine hydroxylase (TH), dopamine D 2 receptor, α-synuclein, and nuclear receptor-related 1 (Nurr1) in discrete mesocorticolimbic and nigrostriatal subpopulations of heroin users and control subjects. The chronic use of heroin was significantly associated with decreased DAT mRNA expression localized to the paranigral nucleus (PN) and the mesolimbic division of the ventral tegmental area (VTA) with no alterations in nigrostriatal populations. Consistently, the density of DAT immunoreactivity was significantly reduced in the nucleus accumbens but not in dorsal striatum, mesolimbic and nigrostriatal efferent targets, respectively. Significant alteration of the mRNA expression of Nurr1, a transcription factor that regulates DAT expression, was also confined to the PN. Moreover, the results revealed an exaggerated reduction of Nurr1 expression with age in heroin users (r = -0.8268, p <0.001 vs controls, r = -0.6204, p = 0.0746). TH and α-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D2 receptor. Evaluating midbrain μ- and κ-opioid receptors, relevant for the action of heroin and regulation of DA neurons, revealed dysregulation of G-protein coupling selective to the VTA PN. Altogether the current findings provide direct neurobiological evidence that midbrain reward circuits have the most prominent DA and opioid impairments in human heroin abusers and that abnormal Nurr1 transcription with opiate use may exacerbate limbic dysfunction with age.",
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AU - Hurd, Yasmin L.

AU - Keller, E.

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