??-Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

Bönsch, Dominikus; Greifenberg, Verena; Bayerlein, Kristina; Biermann, Teresa; Reulbach, Udo; Hillemacher, Thomas; Kornhuber, Johannes; Bleich, Stefan

doi:10.1097/01.alc.0000164360.43907.24

Cited by 74 publications

(69 citation statements)

References 20 publications

(20 reference statements)

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“…␣-Synuclein also regulates DAT (Wersinger et al, 2003), and the increased expression of ␣-synuclein mRNA in our heroin subjects is comparable with other substance abuse human studies showing elevated ␣-synuclein mRNA and protein levels in cocaine abusers (Mash et al, 2003;Qin et al, 2005) and alcoholics (Bonsch et al, 2004(Bonsch et al, , 2005. Increased midbrain ␣-synuclein is characteristic of neurodegeneration of DA pigmented cells (elAgnaf and Irvine, 2002) within the substantia nigra.…”

Section: Discussionsupporting

confidence: 86%

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

Horváth¹,

Kovács²,

Kovari³

et al. 2007

J. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 86%

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

Horváth¹,

Kovács²,

Kovari³

et al. 2007

J. Neurosci.

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“…21 a-Synuclein inhibits the enzyme tyrosine hydroxylase, thereby downregulating the synthesis of dopamine (DA). 22,23 a-Synuclein is implicated in neurodegenerative disorders 24 such as Parkinson's disease, [25][26][27][28] and high levels of a-synuclein mRNA have been associated with alcoholism in humans 29,30 and alcohol preference in rats. 31 Since anxiety is a common feature in Parkinson's patients, 32 and also in alcoholics, 33,34 a-synuclein may also be important in anxiety.…”

Section: Introductionmentioning

confidence: 99%

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

et al. 2008

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A genomic region neighboring the a-synuclein gene, on rat chromosome 4, has been associated with anxiety-and alcohol-related behaviors in different rat strains. In this study, we have investigated potential molecular and physiological links between a-synuclein and the behavioral differences observed between Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rats, a genetic model of anxiety. As expected, LEW rats appeared more fearful than SHR rats in three anxiety models: open field, elevated plus maze and light/dark box. Moreover, LEW rats displayed a higher preference for alcohol and consumed higher quantities of alcohol than SHR rats. a-Synuclein mRNA and protein concentrations were higher in the hippocampus, but not the hypothalamus of LEW rats. This result inversely correlated with differences in dopamine turnover in the hippocampus of LEW and SHR rats, supporting the hypothesis that a-synuclein is important in the downregulation of dopamine neurotransmission. A novel single nucleotide polymorphism was identified in the 3 0 -untranslated region (3 0 -UTR) of the asynuclein cDNA between these two rat strains. Plasmid constructs based on the LEW 3 0 -UTR sequence displayed increased expression of a reporter gene in transiently transfected PC12 cells, in accordance with in-vivo findings, suggesting that this nucleotide exchange might participate in the differential expression of a-synuclein between LEW and SHR rats. These results are consistent with a novel role for a-synuclein in modulating rat anxiety-like behaviors, possibly through dopaminergic mechanisms. Since the behavioral and genetic differences between these two strains are the product of independent evolutionary histories, the possibility that polymorphisms in the a-synuclein gene may be associated with vulnerability to anxiety-related disorders in humans requires further investigation.

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“…Later work demonstrated a correlation between the levels of alpha synuclein in serum with the intensity of alcohol craving in addicted patients during withdrawal (Bonsch et al, 2005a;Bonsch et al, 2004). Monkeys that chronically selfadminstered ethanol for 18 months had 3-fold higher peripheral blood levels of alpha synuclein mRNA, suggesting that peripheral alpha synuclein upregulates with chronic exposure to alcohol (Walker and Grant, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…This region has been associated with drug abuse through a genome-wide SNP genome scan (Uhl et al, 2001). Genomic variation in SNCA has been associated with susceptibility to alcohol (Bonsch et al, 2005b), methamphetamine psychosis/dependence (Kobayashi et al, 2004) and alcohol craving (Bonsch et al, 2005a;Bonsch et al, 2005b;Foroud et al, 2000;Foroud et al, 2007). Using a family based test of association in multiplex alcoholic pedigrees, analyses in the 3′ end of SNCA identified a haplotype overestimated in European-American individuals who crave alcohol and a different haplotype, which was preferentially transmitted to noncravers (Foroud et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Alpha synuclein is elevated in rats whose alcohol preference is inbred (Liang et al, 2003) and high levels are associated with an increase in alcohol craving in patients during withdrawal (Bonsch et al, 2005a;Bonsch et al, 2004). Peripheral blood alpha synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol (Walker and Grant, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

Mash

Adi

Duque

et al. 2008

Drug and Alcohol Dependence

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Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha-synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p < 0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r = 0.60, p < 0.001) and frequency (r = 0.64. p < 0.001) of cocaine craving and with thirty days of cocaine use in the prior month before entry to treatment (r = 0.56, p < 0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.

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??-Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

Cited by 74 publications

References 20 publications

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

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

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

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