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

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, ␣-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 ϭ Ϫ0.8268, p Ͻ 0.001 vs controls, r ϭ Ϫ0.6204, p ϭ 0.0746). TH and ␣-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D 2 receptor. Evaluating midbrain -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.

Nurr1 Expression and Its Modulation in Microglia

“…The distribution of Nurr1 in both the cytoplasm and the nucleus of cultured microglia showed by immunofluorescent staining is different from that of the neuron [30,31] . The apparent translocation of Nurr1 from the cytoplasm to the nucleus after the LPS-activation implicates a close interaction between Nurr1 expression and microglial activation.…”

Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia

“…Previous evidence suggests segregated regulation of dopaminergic neurons in frontal cortical (FEF is located here) compared to mesocortical regions. For instance, Horvath and colleagues (2007) demonstrated significant downregulation of DAT1 mRNA and protein in nigrostriatal, but not mesolimbic regions. Interestingly, there were complementary alterations in DAT1 transcriptional regulators, α-synuclein (SNCA) and Nurr1 (alias, NR4A2) in these regions (Horvath et al, 2007).…”

“…For instance, Horvath and colleagues (2007) demonstrated significant downregulation of DAT1 mRNA and protein in nigrostriatal, but not mesolimbic regions. Interestingly, there were complementary alterations in DAT1 transcriptional regulators, α-synuclein (SNCA) and Nurr1 (alias, NR4A2) in these regions (Horvath et al, 2007). Notably, their brain tissue samples were from heroin abusers and were analyzed with immunohistochemistry.…”

Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons

“…Human specimens were obtained from the Forensic Medicine Departments of Semmelweis University (Budapest, Hungary) and of Karolinska Institutet (Stockholm, Sweden) under approved local protocols (Horvath et al, 2007). Fresh-frozen brain sections (20 μm) were analyzed from control or heroin-overdose subjects.…”