Journal of Neuroimmune Pharmacology

, Volume 1, Issue 4, pp 410–420 | Cite as

Abnormal Striatal Dopaminergic Synapses in National NeuroAIDS Tissue Consortium Subjects with HIV Encephalitis

  • Benjamin B. Gelman
  • Jeffrey A. Spencer
  • Charles E. HolzerIII
  • Vicki M. Soukup
Original Article

Abstract

People with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) have neurological problems that overlap with diseases associated with abnormal dopaminergic (DAergic) synaptic transmission, including subcortical dementia, motor slowing, psychosis, and drug addiction. Previous study has suggested that DAergic tone may be decreased in HIV/AIDS, but biochemical confirmation of that tenet is still lacking. To that end, this study addresses the neurochemical interaction between HIV infection and DAergic synaptic transmission in human brain specimens. Protein markers of DAergic synapses were characterized in homogenates of the corpus striatum from individuals with HIV encephalitis (HIVE) and seronegative controls from the autopsy cohort of the National NeuroAIDS Tissue Consortium. Striatal DAergic markers were abnormal in HIVE. Abnormal presynaptic markers included decreased tyrosine hydroxylase (TH) protein and decreased phosphorylated TH. The presynaptic dopamine reuptake transporter (DAT) was increased reciprocally. Postsynaptic abnormalities included decreased dopamine receptor type 2 (D2R) and increased D3R. There was preferential loss of the alternatively spliced long isoform of D2R relative to the short isoform. Abnormal DAergic synapse proteins were significantly correlated with the HIV Gag mRNA transcripts amplified in striatal extracts. These synaptic changes resemble shifts that occur when DAergic tone is increased experimentally. Increased DAergic tone leads to heightened salience for drugs of abuse, increases behaviors that increase the risk of HIV transmission, and might decrease compliance with antiretroviral medication regimens.

Key words

addiction autopsy dementia dopamine dopaminergic dopamine receptor dopamine transporter dopamine reuptake HIV encephalitis national neuroAIDS tissue consortium synaptic transmission tyrosine hydroxylase 

References

  1. Baldwin GC, Roth MD, Tashkin DP (1998) Acute and chronic effects of cocaine on the immune system and the possible link to AIDS. J Neuroimmunol 83:133–138CrossRefGoogle Scholar
  2. Berger JR, Nath A (1997) HIV dementia and the basal ganglia. Intervirology 40:122–131PubMedGoogle Scholar
  3. Berger JR, Arendt G (2000) HIV dementia: the role of the basal ganglia and dopaminergic systems. J Psychopharmacol 14:214–221PubMedCrossRefGoogle Scholar
  4. Bezard E, Devero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatial degeneration in a progressive MPTP-lesioned macaque model of Parkinson's disease. J Neurosci 21:6853–6861PubMedGoogle Scholar
  5. Blanchard V, Raisman-Vozari R, Vyas S, Michel PP, Javoy-Agid F, Uhl G, Agid Y (1994) Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon. Brain Res Mol Brain Res 22:29–38PubMedCrossRefGoogle Scholar
  6. Budka H (1991) Neuropathology of human immunodeficiency virus infection. Brain Pathol 1:163–175PubMedGoogle Scholar
  7. Burt DR, Creese I, Snyder SH (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326–328PubMedCrossRefGoogle Scholar
  8. Centonze D, Usiello A, Gubellini P, Pisani A, Borrelli E, Bernardi G, Calabresi P (2002) Dopamine D2 receptor-mediated inhibition of dopaminergic neurons in mice lacking D2L receptors. Neuropsychopharmacology 27:723–726PubMedCrossRefGoogle Scholar
  9. Chen L, Segal DM, Moraes CT, Mash DC (1999) Dopamine transporter mRNA in autopsy studies of chronic cocaine users. Brain Res Mol Brain Res 73:181–185PubMedCrossRefGoogle Scholar
  10. Chiasson MA, Stoneburner RL, Hildebrandt DS, Ewing WE, Telzak EE, Jaffe HW (1991) Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack). AIDS 5:1121–1126PubMedCrossRefGoogle Scholar
  11. Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM, Niznik HB, Levey AI (1995) The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 15:1714–1723PubMedGoogle Scholar
  12. Creese I, Snyder SH (1979) Nigrostriatal lesions enhance striatal [3H]apomorphine and [3H]spiroperidol binding. Eur J Pharmacol 56:277–281PubMedCrossRefGoogle Scholar
  13. Czub S, Koutsilieri E, Soppers S, Czub M, Stahl-Hennig C, Müller 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 101:85–91PubMedGoogle Scholar
  14. Dal Toso R, Sommer B, Ewert M, Herb A, Prichett D, Bach A, Shivers B, Seeburg PH (1989) The dopamine D2 receptor: two molecular forms generated by alternative splicing. EMBO J 8:4025–4034Google Scholar
  15. Dickinson SD, Sabeti J, Larson GA, Giardina K, Rubinstein M, Kelly MA, Grandy DK, Low MJ, Gerhardt GA, Zahniser NR (1999) Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum. J Neurochem 72:148–156PubMedCrossRefGoogle Scholar
  16. Esch T, Stefano GB (2004) The neurobiology of pleasure, reward processes, addiction and their health implications. Neuroendocrinology Lett 25:235–251CrossRefGoogle Scholar
  17. Fossom LH, Sterling CR, Tank AW (1992) Regulation of tyrosine hydroxylase gene transcription rate and tyrosine hydroxylase mRNA stability by cyclic AMP and glucocorticoid. Mol Pharmacol 42:908–989Google Scholar
  18. Gatley SJ, Volkow ND, Fowler JS, Dewey SL, Logan J (1995) Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine. Synapse 20:137–144PubMedCrossRefGoogle Scholar
  19. Gatley SJ, Volkow ND, Gifford AN, Ding YS, Logan J, Wang GJ (1997) Model for estimating dopamine transporter occupancy and subsequent increases in synaptic dopamine using positron emission tomography and carbon-11-labeled cocaine. Biochem Pharmacol 53:43–52PubMedCrossRefGoogle Scholar
  20. Gelman BB, Soukup VM, Keherly MJ, Holzer CE, Richey FJ, Lahart CJ (2004) Acquired neuronal channelopathies in HIV-associated dementia. J Neuroimmunol 157:111–119PubMedCrossRefGoogle Scholar
  21. Gelman BB, Soukup VM, Holzer CE III, Fabian RH, Schuenke KW, Keherly MJ, Richey FJ, Lahart CJ (2005) Lysosome expansion in white matter: potential correlate of altered membrane turnover in HIV-associated dementia. J AIDS 39:422–425Google Scholar
  22. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 253:1429–1432CrossRefGoogle Scholar
  23. Grassi MP, Perin C, Clerici F, Zocchetti C, Borella M, Cargnel A, Mangoni A (1997) Effects of HIV seropositivity and drug abuse on cognitive function. Eur Neurol 37:48–52PubMedGoogle Scholar
  24. Haavik J, Schellilng D, Campbell DG, Andersson KK, Flatmark T, Cohen P (1989) Identification of protein phosphatase 2A as the major tyrosine hydroxylase phophatase in adrenal medulla and corpus striatum: evidence from the effects of okadaic acid. FEBS Lett 251:36–42PubMedCrossRefGoogle Scholar
  25. Harrington KA, Augwood SJ, Kingsbury AE, Foster OJ, Emson PC (1996) Dopamine transporter (DAT) and synaptic vesicle amine transporter (VMAT2) gene expression in the substantia nigra of control and Parkinson's disease. Brain Res Mol Brain Res 36:157–162PubMedCrossRefGoogle Scholar
  26. Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor M, Kelly MD, Ellis RJ, Wolfson T, Velin R, Marcotte TD, Hesselink JR, Jernigan TL, Chandler J, Wallace M, Abramson I, The HNRC Group (1995) The HNRC 500—neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1:231–251PubMedCrossRefGoogle Scholar
  27. Herrero MT, Augood SJ, Asensi H, Agid Y, Obeso JA, Emson PC (1996) Effects of l-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys. Brain Res Mol Brain Res 42:149–155PubMedCrossRefGoogle Scholar
  28. Hriso E, Kuhn T, Masdeu JC, Grundman M (1991) Extrapyramidal symptoms due to dopamine-blocking agents in patients with AIDS encephalopathy. Am J Psychiatry 148:1558–1561PubMedGoogle Scholar
  29. Joyce JN, Smutzer G, Whitty CJ, Myers A, Bannon M (1997) Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with Parkinson's, Alzheimer's with parkinsonism, and Alzheimer's Disease. Mov Disord 12:885–897PubMedCrossRefGoogle Scholar
  30. Kandel ER, Schwartz JH, Jessell TM (1991) Disorders of mood, depression, mania, and anxiety disorders. In Principles of Neuroscience, 3rd edition. Appleton and Lange, Norwalk, CT, pp 869–886Google Scholar
  31. Kansy JW, Daubner SC, Nishi A, Sotogaku N, Lloyd MD, Nguyen C, Lu L, Haycock JW, Hope BT, Fitzpatrick PF, Bibb JA (2004) Identification of tyrosine hydroxylase as a physiological substrate for Cdk5. J Neurochem 91:374–384PubMedCrossRefGoogle Scholar
  32. Khan ZU, Mrzljak L, Gutierrez A, DeLa Calle A, Goldman-Rakic PS (1998) Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci U S A 95:7731–7736PubMedCrossRefGoogle Scholar
  33. Kimmel HL, Joyce AR, Carroll FI, Kuhar MJ (2001) Dopamine D1 and D2 receptors influence dopamine transporter synthesis and degradation in the rat. J Pharmacol Exp Ther 298:129–140PubMedGoogle Scholar
  34. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58PubMedCrossRefGoogle Scholar
  35. Koutsilieri E, Sopper S, Scheller C, ter Meulen V, Riederer P (2002) Involvement of dopamine in the progression of AIDS Dementia Complex. J Neural Transm 109:399–410PubMedCrossRefGoogle Scholar
  36. Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev 71: 155–234PubMedGoogle Scholar
  37. Lewis EJ, Harrington CA, Chikaraishi DM (1987) Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP. Proc Natl Acad Sci U S A 84:3550–3554PubMedCrossRefGoogle Scholar
  38. Lindgren N, Xu ZQ, Lindskog M, Herrera-Marschitz M, Goiny M, Haycock J, Goldstein M, Hokfelt T, Fisone G (2000) Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum. J Neurochem 74:2470–2477PubMedCrossRefGoogle Scholar
  39. Lindgren N, Xu ZQ, Herrera-Marschitz M, Haycock J, Hokfelt T, Fisone G (2001) Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum. Eur J Neurosci 13:773–780PubMedCrossRefGoogle Scholar
  40. Little KY, McLaughlin DP, Zhang L, McFinton PR, Dalack GW, Cook EH Jr, Cassin BJ, Watson SJ (1998) Brain dopamine transporter mRNA and binding sites in cocaine users: a post mortem study. Arch Gen Psychiatry 55:793–799PubMedCrossRefGoogle Scholar
  41. Little KY, Zhang L, Desmond T, Frey KA, Dalack GW, Cassin BJ (1999) Striatal dopaminergic abnormalities in human cocaine users. Am J Psychiatry 156:238–245PubMedGoogle Scholar
  42. Lopez OL, Smith G, Meltzer CC, Becker JT (1999) Dopamine systems in human immunodeficiency virus-associated dementia. Neuropsych Neuropsychol Behav Neurol 12:184–192Google Scholar
  43. Marcario JF, Manaye KF, Santa Cruz KS, Mouton PR, Berman NE, Cheney PD (2004) Severe subcortical degeneration in macaques infected with neurovirulent simian immunodeficiency virus. J Neurovirol 10:387–399PubMedGoogle Scholar
  44. Mash DC, Staley JK (1999) D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Ann N Y Acad Sci 877:507–522PubMedCrossRefGoogle Scholar
  45. Mayfield RD, Zahniser NR (2001) Dopamine 2 receptor regulation of the dopamine transporter expressed in Xenopus laevis oocytes is voltage-dependent. Mol Pharmacol 59:113–121PubMedGoogle Scholar
  46. Melikian HE (2004) Neurotransmitter transporter trafficking: endocytosis, recycling and regulation. Pharmacol Ther 104:17−27PubMedCrossRefGoogle Scholar
  47. Meller E, Bohmaker K, Namba Y, Friedhoff AJ, Goldsteint M (1987) Relationship between receptor occupancy and response at striatal dopamine autoreceptors. Mol Pharmacol 31:592–598PubMedGoogle Scholar
  48. Mirsattari SM, Power C, Nath A (1998) Parkinsonism with HIV dementia. Mov Disord 13:684–689PubMedCrossRefGoogle Scholar
  49. Morgello S, Gelman BB, Kozlowski PB, Vinters HV, Masliah E, Cornford M, Cavert W, Marra C, Grant I, Singer E (2001) The national neuroAIDS tissue consortium. Neuropathol Appl Neurobiol 27:326–335PubMedCrossRefGoogle Scholar
  50. Nader MA, Czoty PW (2005) PET Imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic predisposition versus environmental modulation. Am J Psychiatry 162:1473–1482PubMedCrossRefGoogle Scholar
  51. Nath A, Hauser KF, Wojna V, Booze RM, Maragos W, Prendergast M, Cass W, Turchan JT (2002) Molecular basis for interactions of HIV and drugs of abuse. J AIDS 31(Suppl 2):S62–S69Google Scholar
  52. Quik M, Police S, He L, DiMonte DA, Langston JW (2000) Expression of D(3) receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment. Neuroscience 98: 263–273PubMedCrossRefGoogle Scholar
  53. Reyes MG, Faraldi F, Senseng CS, Flowers C, Fariello R (1991) Nigral degeneration in acquired immune deficiency syndrome (AIDS). Acta Neuropathol (Berl) 82:39–44CrossRefGoogle Scholar
  54. Robbins TW (2003) Dopamine and cognition. Curr Opin Neurol 16(suppl 2):S1–S2PubMedCrossRefGoogle Scholar
  55. Roth MD, Tashkin DP, Choi R, Jamieson BD, Zack JA, Baldwin GC (2002) Cocaine enhances human immunodeficiency virus replication in a model of severe combined immunodeficient mice implanted with human peripheral blood leukocytes. J Infect Dis 185:701–705PubMedCrossRefGoogle Scholar
  56. Rudnick G, Clark J (1993) From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta 1144:249–263PubMedCrossRefGoogle Scholar
  57. Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32:229–313PubMedGoogle Scholar
  58. Segal DM, Moraes CT, Mash DC (1997) Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Brain Res Mol Brain Res 45:335–339PubMedCrossRefGoogle Scholar
  59. Staley JK, Hearn L, Ruttenber AJ, Wetli CV, Mash DC (1994) High affinity cocaine recognition sites on the dopamine transporter are elevated in fatal cocaine overdose victims. J Pharmacol Exp Ther 271:1678–1685PubMedGoogle Scholar
  60. Staley JK, Mash DC (1996) Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci 16:6100–6106PubMedGoogle Scholar
  61. Tank AW, Curella P, Ham L (1986a) Induction of mRNA for tyrosine hydroxylase by cyclic AMP and glucocorticoids in a rat pheochromocytoma cell line: evidence for the regulation of tyrosine hydroxylase synthesis by multiple mechanisms in cells exposed to elevated levels of both inducing agents. Mol Pharmacol 30: 497–503PubMedGoogle Scholar
  62. Tank AW, Ham L, Curella P (1986b) Induction of tyrosine hydroxylase by cyclic AMP and glucocorticoids in a rat pheochromocytoma cell line: effect of the inducing agents alone or in combination on the enzyme levels and rate of synthesis of tyrosine hydroxylase. Mol Pharmacol 30:486–496PubMedGoogle Scholar
  63. Thobois S, Vingerhoets F, Fraix V, Xie-Brustolin J, Mollion H, Costes N, Mertens P, Benabid AL, Pollak P, Broussolle E (2004) Role of dopaminergic treatment in dopamine receptor down-regulation in advanced Parkinson disease. A positron emission tomographic study. Arch Neurol 61:1705–1709PubMedCrossRefGoogle Scholar
  64. Uhl GR, Walther D, Mash D, Faucheux B, Javoy-Agid F (1994) Dopamine transporter messenger RNA in Parkinson's disease and control substantia nigra. Ann Neurol 35:494–498PubMedCrossRefGoogle Scholar
  65. Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004) Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 9:557–569PubMedCrossRefGoogle Scholar
  66. Volkow ND, Wang GJ, Fowler JS, Ding Y-S (2005) Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1410–1415PubMedCrossRefGoogle Scholar
  67. Wade TV, Rothblat DS, Schneider JS (2001) Changes in striatal dopamine D3 receptor regulation during expression of and recovery from MPTP-induced parkinsonism. Brain Res 905:111–119PubMedCrossRefGoogle Scholar
  68. 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 127:2452–2458PubMedCrossRefGoogle Scholar
  69. White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51:141–153PubMedCrossRefGoogle Scholar
  70. Wiley CA, Achim CL (1994) HIV encephalitis is the pathologic correlate of dementia in AIDS. Ann Neurol 36:673–676PubMedCrossRefGoogle Scholar
  71. Wilson JM, Levey AI, Bergeron C, Kalasinsky K, Ang L, Peretti F, Adams VI, Smialek J, Anderson WR, Shannak K, Deck J, Niznik HB, Kish SJ (1996) Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users. Ann Neurol 40:428–439PubMedCrossRefGoogle Scholar
  72. Wolf ME, Roth RH (1990) Autoreceptor regulation of dopamine synthesis. Ann N Y Acad Sci 604:323–343PubMedGoogle Scholar
  73. Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, Hinkin CH, Lazzaretto D, Cherner M, Marcotte TD, Gelman BB, Morgello S, Singer EJ, Grant, I, Heaton RK (2004) Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 26:759–778PubMedCrossRefGoogle Scholar
  74. Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21−55PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Benjamin B. Gelman
    • 1
    • 2
  • Jeffrey A. Spencer
    • 1
  • Charles E. HolzerIII
    • 3
  • Vicki M. Soukup
    • 4
  1. 1.Department of Pathology, Route 0785University of Texas Medical BranchGalvestonUSA
  2. 2.Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonUSA
  3. 3.Department of PsychiatryUniversity of Texas Medical BranchGalvestonUSA
  4. 4.Department of NeurologyUniversity of Texas Medical BranchGalvestonUSA

Personalised recommendations