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Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

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References

  • Aksenova MV, Silvers JM, Aksenov MY, Nath A, Ray PD, Mactutus CF, Booze RM (2006) HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: changes in dopamine transporter binding and immunoreactivity. Neurosci Lett 395:235–239

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shachar D, Zuk R, Glinka Y (1995) Dopamine neurotoxicity: inhibition of mitochondrial respiration. J Neurochem 64:718–723

    CAS  PubMed  Google Scholar 

  • Berger JR, Nath A (1997) HIV dementia and the basal ganglia. Intervirology 40:122–131

    Article  CAS  PubMed  Google Scholar 

  • Berger J, Kumar M, Kumar A, Fernandez J, Levin B (1994) Cerebrospinal fluid dopamine in HIV-1 infection. AIDS 8:67–71

    Article  CAS  PubMed  Google Scholar 

  • Czub S, Koutsilieri E, Sopper S, Czub M, Stahl-Hennig C, Muller JG, Pedersen V, Gsell W, Heeney JL, Gerlach M, Gosztonyi G, Riederer P, ter Meulen V (2001) Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs. Acta Neuropathol (Berl) 101:85–91

    CAS  Google Scholar 

  • Czub S, Czub M, Koutsilieri E, Sopper S, Villinger F, Muller JG, Stahl-Hennig C, Riederer P, Ter Meulen V, Gosztonyi G (2004) Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs. Acta Neuropathol (Berl) 107:216–226

    Article  CAS  Google Scholar 

  • di Rocco A, Bottiglieri T, Dorfman D, Werner P, Morrison C, Simpson D (2000) Decreased homovanillic acid in cerebrospinal fluid correlates with impaired neuropsychologic function in HIV-1-infected patients. Clin Neuropharmacol 23:190–194

    Article  CAS  PubMed  Google Scholar 

  • Gelman BB, Spencer JA, Holzer CE 3rd, Soukup VM (2006) Abnormal striatal dopaminergic synapses in National NeuroAIDS Tissue Consortium subjects with HIV encephalitis. J Neuroimmune Pharmacol 1:410–420

    Article  PubMed  Google Scholar 

  • Hersh BP, Rajendran PR, Battinelli D (2001) Parkinsonism as the presenting manifestation of HIV infection: improvement on HAART. Neurology 56:278–279

    CAS  PubMed  Google Scholar 

  • Hutson PH, Sarna GS, Kantamaneni BD, Curzon G (1984) Concurrent determination of brain dopamine and 5-hydroxytryptamine turnovers in individual freely moving rats using repeated sampling of cerebrospinal fluid. J Neurochem 43:151–159

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Mehraein P, Weis S (2000) Neuronal damage of the substantia nigra in HIV-1 infected brains. Acta Neuropathol (Berl) 99:376–384

    Article  CAS  Google Scholar 

  • Jenuwein M, Scheller C, Neuen-Jacob E, Sopper S, Tatschner T, ter Meulen V, Riederer P, Koutsilieri E (2004) Dopamine deficits and regulation of the cAMP second messenger system in brains of simian immunodeficiency virus-infected rhesus monkeys. J Neurovirol 10:163–170

    Article  CAS  PubMed  Google Scholar 

  • Khanlou N, Moore DJ, Chana G, Cherner M, Lazzaretto D, Dawes S, Grant I, Masliah E, Everall IP (2009) Increased frequency of alpha-synuclein in the substantia nigra in human immunodeficiency virus infection. J Neurovirol 15:131–138

    Article  CAS  PubMed  Google Scholar 

  • Koutsilieri E, Gotz ME, Sopper S, Stahl-Hennig C, Czub M, ter Meulen V, Riederer P (1997) Monoamine metabolite levels in CSF of SIV-infected rhesus monkeys (Macaca mulatta). Neuroreport 8:3833–3836

    Article  CAS  PubMed  Google Scholar 

  • Koutsilieri E, ter-Meulen V, Riederer P (2001) Neurotransmission in HIV associated dementia: a short review. J Neural Transm 108:767–775

    Article  CAS  PubMed  Google Scholar 

  • Koutsilieri E, Sopper S, Scheller C, ter Meulen V, Riederer P (2002) Parkinsonism in HIV dementia. J Neural Transm 109:767–775

    Article  CAS  PubMed  Google Scholar 

  • Kuhn DM, Francescutti-Verbeem DM, Thomas DM (2006) Dopamine quinones activate microglia and induce a neurotoxic gene expression profile: relationship to methamphetamine-induced nerve ending damage. Ann N Y Acad Sci 1074:31–41

    Article  CAS  PubMed  Google Scholar 

  • Kumar AM, Fernandez J, Singer EJ, Commins D, Waldrop-Valverde D, Ownby RL, Kumar M (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains. J Neurovirol 1–18

  • Kure K, Weidenheim KM, Lyman WD, Dickson DW (1990) Morphology and distribution of HIV-1 gp41-positive microglia in subacute AIDS encephalitis. Pattern of involvement resembling a multisystem degeneration. Acta Neuropathol 80:393–400

    Article  CAS  PubMed  Google Scholar 

  • Larsson M, Hagberg L, Forsman A, Norkrans G (1991) Cerebrospinal fluid catecholamine metabolites in HIV-infected patients. J Neurosci Res 28:406–409

    Article  CAS  PubMed  Google Scholar 

  • LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491

    CAS  PubMed  Google Scholar 

  • Meisner F, Scheller C, Kneitz S, Sopper S, Neuen-Jacob E, Riederer P, Meulen VT, Koutsilieri E (2008) Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacology 33(9):2228–2236

    Article  CAS  PubMed  Google Scholar 

  • Obermann M, Kuper M, Kastrup O, Yaldizli O, Esser S, Thiermann J, Koutsilieri E, Arendt G, Diener HC, Maschke M (2009) Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV. J Neurol 256:948–953

    Article  CAS  PubMed  Google Scholar 

  • Rottenberg D, Sidtis J, Strother S, Schaper K, Anderson J, Nelson M, Price R (1996) Abnormal cerebral glucose metabolism in HIV-1 seropositive subjects with and without dementia. J Nucl Med 37:1133–1141

    CAS  PubMed  Google Scholar 

  • Sardar A, Czudek C, Reynolds G (1996) Dopamine deficits in the brain: the neurochemical basis of parkinsonian symptoms in AIDS. Neuroreport 7:910–912

    Article  CAS  PubMed  Google Scholar 

  • Scheller C, Sopper S, Jenuwein M, Neuen-Jacob E, Tatschner T, Grunblatt E, ter Meulen V, Riederer P, Koutsilieri E (2005) Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. J Neurochem 95:377–387

    Article  CAS  PubMed  Google Scholar 

  • Theodore S, Cass WA, Nath A, Maragos WF (2007) Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res 5:301–313

    Article  CAS  PubMed  Google Scholar 

  • Thomas DM, Francescutti-Verbeem DM, Kuhn DM (2006) Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage. FASEB J 20:515–517

    CAS  PubMed  Google Scholar 

  • Wallace DR, Dodson S, Nath A, Booze RM (2006) Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function. Synapse 59:51–60

    Article  CAS  PubMed  Google Scholar 

  • Wang GJ, Chang L, Volkow ND, Telang F, Logan J, Ernst T, Fowler JS (2004) Decreased brain dopaminergic transporters in HIV-associated dementia patients. Brain 127:2452–2458

    Article  PubMed  Google Scholar 

  • Wiley C, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann S, Dailey P, Achim C (1998) Distribution of brain HIV load in AIDS. Brain Pathol 8:277–284

    Article  CAS  PubMed  Google Scholar 

  • Zauli G, Secchiero P, Rodella L, Gibellini D, Mirandola P, Mazzoni M, Milani D, Dowd DR, Capitani S, Vitale M (2000) HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells. J Biol Chem 275:4159–4165

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study was supported by grants from the “Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie”, Germany (BMBF KI 0211 Competence Network HIV/AIDS) and “Deutsche Forschungsgemeinschaft” (GRK 1522/1). We are grateful for the excellent technical assistance of Rainer Burger and Ingeborg Euler-König.

Conflict of interest statement

The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Virology and Immunobiology, University of Würzburg, Versbacherstr. 7, 97078, Würzburg, Germany

    C. Scheller, F. Meisner, V. ter Meulen & E. Koutsilieri

  2. Department of Neurology, University Hospital of Düsseldorf, Düsseldorf, Germany

    G. Arendt & T. Nolting

  3. Department of Nuclear Medicine, University of Düsseldorf, Düsseldorf, Germany

    C. Antke & H. W. Müller

  4. German Primate Center, Göttingen, Germany

    S. Sopper

  5. Department of Neurology, University Hospital of Duisburg-Essen, Duisburg-Essen, Germany

    M. Maschke, M. Obermann & A. Angerer

  6. Department of Neurology, University Hospital of Münster, Münster, Germany

    I. W. Husstedt

  7. Institute of Neuropathology, University of Düsseldorf, Düsseldorf, Germany

    E. Neuen-Jacob

  8. Department of Psychiatry, Stellenbosch University, Cape Town, South Africa

    P. Carey

  9. Clinical Neurochemistry, National Parkinson Foundation Center of Excellence Research Laboratory, Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    P. Riederer

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  1. C. Scheller
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  2. G. Arendt
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  3. T. Nolting
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  4. C. Antke
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  5. S. Sopper
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  6. M. Maschke
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  7. M. Obermann
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  8. A. Angerer
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  9. I. W. Husstedt
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  10. F. Meisner
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  11. E. Neuen-Jacob
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  12. H. W. Müller
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  13. P. Carey
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  14. V. ter Meulen
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  15. P. Riederer
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  16. E. Koutsilieri
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Corresponding author

Correspondence to E. Koutsilieri.

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Scheller, C., Arendt, G., Nolting, T. et al. Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses. J Neural Transm 117, 699–705 (2010). https://doi.org/10.1007/s00702-010-0415-6

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  • DOI: https://doi.org/10.1007/s00702-010-0415-6

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