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Markers of dopamine depletion and compensatory response in striatum and cerebrospinal fluid

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Journal of Neural Transmission - Parkinson's Disease and Dementia Section

Summary

Though depletion of CSF homovanillic acid (HVA) concentration has often been regarded as a direct indicator of dopamine (DA) deficiency in Parkinson's Disease (PD), CSF HVA is normal in mildly affected patients. To explore why, we measured DA and its metabolites in striatum and CSF in rabbits receiving reserpine for 5 days. Reserpine, which depletes striatal DA by disrupting vesicular storage of the neurotransmitter, results in a compensatory increase of DA turnover. In response to a 96% depletion of striatal DA, its catabolic intermediates 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) decreased 64% and 92% in striatum, although the endproduct, HVA, was unchanged. In contrast, CSF concentrations of HVA and DOPAC increased significantly, though 3-MT and levodopa (LD) were unaltered. A 5-fold rise in striatal LD concentration after reserpine-induced DA depletion provided evidence for enhanced DA synthesis. As in PD, the compensatory increase of DA synthesis after reserpine administration confounds the ability of CSF HVA to reflect DA depletion.

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References

  • Ahlenius S, Ericson E, Wijkstrom A (1993) Stimulation of brain dopamine autoreceptors by remoxipride administration in reserpine-treated male rats. J Pharm Pharmacol 45: 237–239

    Google Scholar 

  • Algeri S, Achilli G, Calderini G, Perego C, Ponzio F, Toffano G (1987) Age-related changes in metabolic responses to chronic monoamine depletion in central dopaminergic and serotonergic systems of rats treated with reserpine. Neurobiol Aging 8: 61–66

    Google Scholar 

  • Andén N-E, Roos B-E, Werdinius B (1963) 3,4-Dihydroxphenylacetic acid in rabbit corpus striatum normally and after reserpine treatment. Life Sci 5: 319–325

    Google Scholar 

  • Andén N-E, Roos B-E, Werdinius B (1964) Effects of chlorpromazine, haloperidol, and reserpine on the levels of phenolic acids in rabbit corpus striatum. Life Sci 3: 149–158

    Google Scholar 

  • Beal MF, Matson WR, Swartz KJ, Gamache PH, Bird ED (1990) Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid. J Neurochem 55: 1327–1339

    Google Scholar 

  • Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455

    Google Scholar 

  • Bivin WS, Smith GD (1984) Techniques of experimentation. In: Fox JG, Cohen BJ, Loew FM (eds) Laboratory animal medicine. Academic Press, Orlando, pp 585–586

    Google Scholar 

  • Burns RS, LeWitt PA, Ebert MH, Pakkenberg H, Kopin IJ (1985) The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 312: 1418–1421

    Google Scholar 

  • Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180: 1200

    Google Scholar 

  • Carlsson A, Hillarp NA, Waldeck B (1962) A Mg++-ATP dependent storage mechanism in the amine granules of the adrenal medulla. Med Exp 6: 47–53

    Google Scholar 

  • Carlsson A (1972) Biochemical and pharmacological aspects of Parkinsonism. Acta Neurol Scand 48 [Suppl 51]: 11–42

    Google Scholar 

  • Chase TN, Eng N, Gordon EK (1976) Biochemical aids in the diagnosis of Parkinson's disease. Ann Clin Lab Sci 6: 4–10

    Google Scholar 

  • Chase TN (1980) Neurochemical alterations in Parkinson's disease. In: Wood JH (ed) Neurobiology of cerebrospinal fluid. Plenum Press, New York, pp 207–218

    Google Scholar 

  • Cunha L, Goncalves AF, Oliveira CV, Dinis M, Amaral R (1983) Homovanillic acid in the cerebrospinal fluid of Parkinsonian patients. Can J Neurol Sci 10: 43–46

    Google Scholar 

  • Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenschr 38: 1236–1239

    Google Scholar 

  • Ebinger G, Michotte Y, Herregodts P (1987) The significance of homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in human cerebrospinal fluid. J Neurochem 48: 1725–1729

    Google Scholar 

  • Elsworth JD, Deutch AY, Redmond DE Jr, Sladek JR Jr, Roth RH (1987) Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF. Brain Res 415: 293–299

    Google Scholar 

  • Elverfors A, Nissbrandt H (1991) Reserpine-insensitive dopamine release in the substantia nigra? Brain Res 557: 5–12

    Google Scholar 

  • Fekete MI, Szentendrei T, Herman JP, Kanyicska B (1980) Effects of reserpine and antidepressants on dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) concentrations in the striatum, olfactory tubercle and median eminence of rats. Eur J Pharmacol 64: 231–238

    Google Scholar 

  • Fine M, Masserano JM, Weiner N (1986) The effects of reserpine and haloperidol on tyrosine hydroxylase activity in the brains of aged rats. Life Sci 39: 235–241

    Google Scholar 

  • Fornstedt B, Carlsson A (1989) A marked rise in 5-S-cysteinyldopamine levels in guinea pig striatum following reserpine treatment. J Neural Transm 76: 155–161

    Google Scholar 

  • Gordon E, Perlow M, Oliver J, Kopin IJ (1975) Origin of catecholamine metabolites in monkey cerebrospinal fluid. J Neurochem 25: 347–349

    Google Scholar 

  • Hartikainen P, Reinikainen KJ, Soininen H, Sirvio J, Soikkeli R, Riekkinen PJ (1992) Neurochemical markers in cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls. J Neural Transm [P-D Sect] 4: 53–68

    Google Scholar 

  • Hornykiewicz O, Kish SJ (1986) Biochemical pathophysiology of Parkinson's disease. Adv Neurol 45: 19–34

    Google Scholar 

  • Hornykiewicz O (1993) Parkinson's disease and the adaptive capacity of the nigrostriatal dopamine system: possible neurochemical mechanisms. Adv Neurol 60: 140–147

    Google Scholar 

  • Hoshi H, Kuwabara H, Léger G, Cumming P, Guttman M, Gjedde A (1993) 6-[18F]fluoro-L-DOPA metabolism in living human brain: a comparison of six analytical methods. J Cereb Blood Flow Metab 13: 57–69

    Google Scholar 

  • Hutson PH, Curzon G (1986) Dopamine metabolites in rat cisternal cerebrospinal fluid: major contribution from extrastriatal dopamine neurones. J Neurochem 46: 186–190

    Google Scholar 

  • Kopin IJ (1985) Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev 37: 333–364

    Google Scholar 

  • LeWitt PA, Galloway MP (1990) Neurochemical markers of Parkinson's disease. In: Koller WC, Paulson G (eds) Therapy of Parkinson's disease. Marcel Dekker, New York, pp 63–93

    Google Scholar 

  • LeWitt PA, The Parkinson Study Group (1991) Deprenyl's protective effect against the progression of Parkinson disease: the DATATOP study. Acta Neurol Scand 84 [Suppl 136]: 79–86

    Google Scholar 

  • LeWitt PA, Galloway M, Matson W, Wilbury P, McDermott M, Oakes D, The Parkinson Study Group (1992a) Markers of endogenous dopamine synthesis in Parkinson's disease. Neurology 42 [Suppl 3]: 420

    Google Scholar 

  • LeWitt PA, Galloway MP, Matson W, Milbury P, McDermott M, Srivastava DK, Oakes D, The Parkinson Study Group (1992b) Markers of dopamine metabolism in Parkinson's disease. Neurology 42: 2111–2117

    Google Scholar 

  • Männistö PT, Ulmanen I, Lundstrom K, Taskinen J, Tenhunen J, Tilgmann C, Kaakkola S (1992) Characteristics of catechol O-methyl-transferase (COMT) and properties of selective COMT inhibitors. Prog Drug Res 39: 291–350

    Google Scholar 

  • Mogi M, Harada M, Kiuchi K, Kojima K, Kondo T, Narabayashi H, Rausch D, Riederer P, Jellinger K, Nagatsu T (1988) Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in Parkinson's disease. J Neural Transm 72: 77–81

    Google Scholar 

  • Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S, (1992) Kynurenic pathway abnormalities in Parkinson's disease. Neurology 42: 1702–1706

    Google Scholar 

  • The Parkinson Study Group (1993) The DATATOP study: cerebrospinal fluid homovanillic acid changes in patients with mild, early Parkinsonism. Mov Disord 8: 410–411

    Google Scholar 

  • Ponzio F, Achilli G, Calderini G, Ferretti P, Perego C, Toffano G, Algeri S (1984) Depletion and recovery of neuronal monoamine storage in rats of different ages treated with reserpine. Neurobiol Aging 5: 101–104

    Google Scholar 

  • Rutledge CO, Jonason J (1967) Metabolic pathways of dopamine and norepinephrine in rabbit brain in vitro. J Pharmacol Exp Ther 157: 493–502

    Google Scholar 

  • Snedecor GW, Cochrane WG (1980) Statistical methods, 7th ed. Iowa State University Press, Ames, p 97

    Google Scholar 

  • Wester P, Bergstrom U, Eriksson A, Gezelius C, Hardy J, Winblad B (1990) Ventricular cerebrospinal fluid monoamine transmitter and metabolite concentrations reflect human brain neurochemistry in autopsy cases. J Neurochem 54: 1148–1156

    Google Scholar 

  • Wolf ME, Zigmond MJ, Kapatos G (1989) Tyrosine hydroxylase content of residual striatal nerve terminals following 6-hydroxydopamine administration: a flow cytometric study. J Neurochem 53: 879–885

    Google Scholar 

  • Zigmond MJ, Acheson AL, Stachowiak MK, Stricker EM (1984) Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical Parkinsonism. Arch Neurol 41: 856–861

    Google Scholar 

  • Zubenko GS, Marquis IKD, Volicer L, Direnfeld LK, Langlais PJ, Nixon RA (1986) Cerebrospinal fluid levels of angiotensin-converting enzyme, acetylcholinesterase, and dopamine metabolites in dementia associated with Alzheimer's disease and Parkinson's disease: a correlative study. Biol Psychiatry 21: 1365–1381

    Google Scholar 

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Author notes

  1. D. A. Loeffler DVM, PhD

    Present address: Clinical Neuroscience Laboratory, Research Building, Room 209, Sinai Hospital, 6767 West Outer Drive, 48235, Detroit, Michigan, U.S.A.

Authors and Affiliations

  1. Clinical Neuroscience Laboratory, Research Building, Room 209, Sinai Hospital, 6767 West Outer Drive, 48235, Detroit, Michigan, U.S.A.

    P. A. LeWitt & A. J. DeMaggio

  2. Departments of Neurology and Psychiatry, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.

    P. A. LeWitt

  3. Cellular and Clinical Neuroscience Program, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.

    P. A. LeWitt

  4. Preclinical Biometrics, Warner Lambert Company, Ann Arbor, Michigan, U.S.A.

    P. L. Juneau

  5. ESA, Incorporated, Chelmsford, Massachusetts, U.S.A.

    P. E. Milbury & W. R. Matson

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  1. D. A. Loeffler DVM, PhD
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  3. A. J. DeMaggio
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  5. P. E. Milbury
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  6. W. R. Matson
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Loeffler, D.A., LeWitt, P.A., DeMaggio, A.J. et al. Markers of dopamine depletion and compensatory response in striatum and cerebrospinal fluid. J Neural Transm Gen Sect 9, 45–53 (1995). https://doi.org/10.1007/BF02252962

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  • DOI: https://doi.org/10.1007/BF02252962

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