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The Journal of Neuroscience, December 5, 2007, 27(49):13371-13375; doi:10.1523/JNEUROSCI.2398-07.2007

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Brief Communications
Heroin Abuse Is Characterized by Discrete Mesolimbic Dopamine and Opioid Abnormalities and Exaggerated Nuclear Receptor-Related 1 Transcriptional Decline with Age

Monika Cs. Horvath,¹ Gabor G. Kovacs,² Viktor Kovari,² Katalin Majtenyi,² Yasmin L. Hurd,^3 * and Eva Keller^1 *

¹Department of Forensic Medicine, Semmelweis University, H-1085, Budapest, Hungary, ²National Institute of Psychiatry and Neurology, H-1021, Budapest, Hungary, and ³Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029

Correspondence should be addressed to Yasmin L. Hurd, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1215, New York, NY 10029. Email: Yasmin.Hurd{at}mssm.edu

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 D₂ receptor, -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 -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 -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.

Key words: dopamine transporter; -synuclein; human; µ-opioid receptor; substantia nigra; periaqueductal gray

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Received May 25, 2007; revised Sept. 20, 2007; accepted Oct. 9, 2007.

Correspondence should be addressed to Yasmin L. Hurd, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1215, New York, NY 10029. Email: Yasmin.Hurd{at}mssm.edu

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