Summary
Central dopaminergic (DA) function in children and adults was assessed by monitoring plasma-free levels of the dopamine metabolite homovanillic acid (pHVA) before and after a single oral dose and chronic oral administration of debrisoquin. Debrisoquin inhibits peripheral metabolism of dopamine to HVA and does not cross the blood-brain barrier. By reducing peripheral formation of HVA through the use of debrisoquin, the remaining HVA in plasma more accurately reflects central DA activity. Debrisoquin administration resulted in marked reductions of pHVA in each of 12 patients studied. Eleven of the 12 subjects tolerated debrisoquin without physical or behavioral side effects. The debrisoquin administration method appears to be a safe and potentially valid technique for evaluating aspects of central dopaminergic function in children and adults.
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Abrams WB, Pocelinko R, Klausner M, Hanauer L, Whitman EN (1964) Clinical pharmacological studies with debrisoquin sulfate, a new antihypertensive agent. J New Drugs 4: 268–283
American Psychiatric Association (1980) Diagnostic and statistical manual of mental disorders, 3rd edn. APA task force on nomenclature and statistics, Washington, DC
Bacopoulos NG, Hattox SE, Roth RH (1979) 3,4-Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: possible indications of central dopaminergic activity. Eur J Pharmacol 56: 225–236
Baldessarini RJ, Tracy D (1978) Tardive dyskinesia. In: Lipton MA, DiMascio A, Killian KP (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 993–1004
Berger PA, Faull KF, Kilkowski J, Anderson PJ, Kraemer H, Davis K, Barchas JD (1980) CSF monoamine metabolites in depression and schizophrenia. Am J Psychiat 237: 174–180
Bowers MB Jr, Heninger GR, Sternberg D (1980) Clinical processes and central dopaminergic activity in psychotic disorders. Commun Psychopharm 4: 177–188
Bowers MB Jr, Swigar ME, Jatlow PI, Goicoechea N (1984) Plasma catecholamine metabolites and early response to haloperidol. J Clin Psychiat 45: 248–251
Brown WA, Laughren T (1981) Low serum prolactin and early relapse following neuroleptic withdrawal. Am J Psychiat 138: 237–239
Butler IJ, Koslow SH, Seifert WE, Caprioli RM, Singer HS (1979) Biogenic amine metabolism in Tourette syndrome. Ann Neurol 6: 37–39
Cohen DJ, Shaywitz BA, Young JG, Carbonari CM, Nathanson JA, Lieberman D, Bowers MB Jr, Maas JW (1979) Central biogenic amine metabolism in children with the syndrome of chronic multiple tics of Gilles de la Tourette syndrome: norepinephrine, serotonin, and dopamine. J Am Acad Child Psychiat 18: 320–341
Cutler NR, Jeste DV, Karoum F, Wyatt RJ (1982) Low-dose apomorphine reduces serum homovanillic acid concentrations in schizophrenic patients. Life Sci 30: 753–756
Davis KL, Davidson M, Mohs RC, Kendler KS, Davis BM, Johns CA, DeNigris Y, Horvath TB (1985) Plasma homovanillic acid concentration and the severity of schizophrenic illness. Science 227: 1601–1602
Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquin oxidation in a white British population. J Med Genet 17: 103–105
Flückinger E, del Pozo E, Von Werder K (1982) Prolactin: physiology, pharmacology and clinical findings. Springer, Berlin Heidelberg New York
Harcherik D, Leckman JF, Detlor J, Cohen DJ (1984) A new instrument for clinical studies of Tourette's syndrome. J Am Acad Child Psychiat 23: 153–160
Harris PQ, Brown SJ, Friedman MJ, Bacopoulos NG (1984) Plasma, drug and homovanillic acid levels in psychotic patients receiving neuroleptics. Biol Psychiat 19: 849–860
Hoeldtke R, Rogawski M, Wurtman RJ (1974) Effect of selective destruction of central and peripheral catecholamine-containing neurons with 6-hydroxydopamine on catecholamine excretion in the rat. Br J Pharmacol 50: 265–270
Johnstone EC, Crow TJ, Mashiter K (1977) Anterior pituitary hormone secretion in chronic schizophrenia-an approach to neurochemical mechanisms. Psychol Med 7: 223–228
Karoum F, Wyatt R, Costa E (1974) Estimation of the contribution of peripheral and central noradrenergic neurons to urinary 3-methoxy-4-hydroxyphenylglycol in the rat. Neuropharmacology 13: 165–176
Kendler KS, Heninger GR, Roth RH (1981) Brain contribution to the haloperidol-induced increase in plasma homovanillic acid. Eur J Pharmacol 71: 321–326
Kendler KS, Heninger GR, Roth RH (1982) Influence of dopamine agonists on plasma and brain levels of homovanillic acid. Life Sci 30: 2063–2069
Kendler KS, Mohs RC, Davis KL (1983) The effects of diet and physical activity on plasma homovanillic acid in normal human subjects. Psychiat Res 8: 215–223
Kleinman JE, Weinberger DR, Rogol AD, Bigelow LB, Klein ST, Gillen JC, Wyatt RJ (1982) Plasma prolactin concentrations and psychopathology in chronic schizophrenia. Arch Gen Psychiat 39: 655–657
Kopin I (1978) Measuring turnover of neurotransmitters in human brain. In: Lipton MA, DiMascio A, Killam KP (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 933–942
Laughren TP, Brown WA, Williams BW (1979) Serum prolactin and clinical state during neuroleptic treatment and withdrawal. Am J Psychiat 136, 108–110
Linnoila M, Ninan PT, Scheinin M, Waters RN, Chang WH, Bartko J, van Kammen DR (1983) Reliability of norepinephrine and major monoamine metabolite measurements in CSF of schizophrenic patients. Arch Gen Psychiat 40: 1290–1294
MacLeod RM, Scapagnini V (1980) (eds) Central and peripheral regulation of prolactin function. Raven Press, New York
Maas JW, Contreras SA, Bowden CL, Weintraub JE (1985) Effects of debrisoquin on CSF and plasma HVA concentrations in man. Life Sci 36: 2163–2170
Maas JW, Hattox SE, Greene NM, Landis DH (1980) Estimates of dopamine and serotonin synthesis by the awake human brain. J Neurochem 34: 1547–1549
Maas JW, Hattox SE, Landis DH (1979) Differential effects on brain catecholamines by debrisoquin. Biochem Pharmacol 28: 3153–3156
Maas JW, Hattox SE, Landis DH, Roth RH (1977) A direct method for studying 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) production by brain in awake animals. Eur J Pharmacol 46: 221–228
Maas JW, Hattox SE, Martin DM, Landis DH (1979) A direct method for determining dopamine synthesis and output of dopamine metabolites from brain in awake animals. J Neurochem 32: 839–843
Marsden CD (1981) Extrapyramidal disease. In: Davison AN, Thompson RHS (eds) The molecular basis of neuropathology. Edward Arnold, London, pp 345–383
Medina MA, Giachetti A, Shore PA (1969) On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquin. Biochem Pharmacol 18: 891–901
Moore DC, Glazer WM, Bowers MB Jr, Heninger GR (1983) Tardive dyskinesia and plasma homovanillic acid. Biol Psychiat 18: 1393–1401
Naber B, Pickar D, Davis GC, Cohen RM, Jimerson DC, Elchisak MA, DeFraites EG, Kalin NH, Risch SC, Buchsbaum MS (1981) Naloxone effects on B-endorphin, cortisol, prolactin, growth hormone, HVA and MHPG in plasma of normal volunteers. Psychopharmacology 74: 125–128
Pezzoli G, Panerai AE, DiGiulio A, Longo A, Passerini D, Carenzi A (1984) Methionine-enkephalin, substance P, and homovanillic acid in the CSF of parkinsonian patients. Neurology 34: 516–519
Pickar D, La Barca R, Linnoila M, Roy A, Hommer D, Everett D, Paul SM (1984) Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science 225: 954–957
Shaywitz SE, Shaywitz BA (1983) Biological influences in attentional disorders. In: Levine MD, Carey WB, Crocker AC, Gross RT (eds) Developmental-behavioral pediatrics. Saunders, Philadelphia, pp 746–755
Silas JH, Jones J, Tucker GT, Townsend MM, Phillips CA, Smith AJ (1979) Dissociation of biochemical and hypotensive effects of debrisoquin in hypertensive patients. Eur J Clin Pharmacol 16: 81–86
Singer HS, Butler IJ, Tune LE, Seifert WE, Coyle JT (1982) Dopaminergic dysfunction in Tourette Syndrome. Ann Neurol 12: 361–366
Sloan TP, Lancaster R, Shah RR, Idle JR, Smith RL (1983) Genetically determined oxidation capacity and the disposition of debrisoquin. Br J Clin Pharmacol 15: 443–450
Snyder SH (1982) Schizophrenia. Lancet ii: 970–974
Solomon HM, Ashley C, Spirt N, Abrams WB (1969) The influence of debrisoquin on the accumulation and metabolism of biogenic amines by the human platelet,in vivo andin vitro. Clin Pharm Therapeut 10: 229–238
Stahl SM, Berger PA (1982) Cholinergic and dopaminergic mechanisms in Tourette syndrome. In: Friedhoff AJ, Chase TN (eds) Gilles de la Tourette syndrome. Raven Press, New York, pp 141–150 (Advances in neurology, vol 35)
Sternberg EE, Heninger GR, Roth RH (1983) Plasma homovanillic acid as an index of brain dopamine metabolism: Enhancement with debrisoquin. Life Sci 32: 2447–2452
Swann AC, Maas JW, Hattox SE, Landis DH (1980) Catecholamine metabolites in human plasma as indices of brain function: Effects of debrisoquin. Life Sci 27: 1857–1863
Wilson RG, Hamilton JR, Boyd WD, Forrest APM, Cole EN, Boyns AR, Griffiths K (1975) The effect of long term phenothorazine therapy on plasma prolactin. Br J Psychiat 127: 71–74
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Riddle, M.A., Leckman, J.F., Cohen, D.J. et al. Assessment or central dopaminergic function using plasma-free homovanillic acid after debrisoquin administration. J. Neural Transmission 67, 31–43 (1986). https://doi.org/10.1007/BF01243357
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DOI: https://doi.org/10.1007/BF01243357