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The influence of probenecid on the metabolism of serotonin, dopamine and their precursors in man

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Abstract

Probenecid inhibits the efflux of acid monoamine (MA) metabolites from the CNS. The probenecid-induced accumulation of these metabolites in the CSF in man supplies data on the central turnover of the corresponding amines. In this study an attempt was made to establish whether probenecid also exerts an influence on the metabolism of the MA precursors: tryptophan and tyrosine. The principal conclusions were the following.

  1. 1.

    Whereas in rats probenecid lowers the serum tryptophan level and elevates that in the brain (probably as a result of interference with the binding of tryptophan to serum albumins), the serum tryptophan level in human individuals is also lowered but the CSF concentration remains unchanged. After an oral tryptophan load, however, the CSF tryptophan concentration does increase.It is suggested that in man, endogenously released and exogenous tryptophan enter different metabolic pools in the brain.

  2. 2.

    After an oral load of 1-tryptophan, for the most part depressive patients showed a more rapid increase in CSF tryptophan concentration and a less marked rise of the CSF 5-HIAA level than did the psychologically undisturbed test subjects examined by Eccleston et al. It seems possible that, in the depressive patient, the tryptophan-metabolizing capacity is disturbed.

  3. 3.

    After an oral load of 1-tryptophan the CSF HVA concentration increased. Possibly, tryptophan is transformed to 5-HT in dopaminergic neurons, and this 5-HT may supersede the DA from the storage sites. This effect may well be of significance in the therapeutic application of 5-HT precursors.

  4. 4.

    The CSF concentrations of 5-HIAA, HVA, tryptophan and tyrosine show no systematic variations during the day.

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References

  • Barkai, A., Glusman, M., Rapport, M. M.: Serotonin turnover in the intact cat brain. J. Pharmacol. exp. Ther. 181, 28–35 (1972)

    Google Scholar 

  • Bowers, M. B., Jr.: 5-HT metabolism in psychiatric syndromes. Lancet 1970II, 1029

    Google Scholar 

  • Bowers, M. B., Jr.: Clinical measurements of central dopamine and 5-hydroxytryptamine metabolism: reliability and interpretation of cerebrospinal fluid acid monoamine metabolite measures. Neuropharmacology 11, 101–111 (1972)

    Google Scholar 

  • Butcher, L., Engel, J., Fuxe, K.: l-Dopa induced changes in central monoamine neurons after peripheral decarboxylase inhibition. J. Pharm. Pharmacol. 22, 313–316 (1970)

    Google Scholar 

  • Carroll, B. J.: Monoamine precursors in depression: Clinical trials and theoretical implications. Comm. Contemp. Psychiat. 1, 87–94 (1971)

    Google Scholar 

  • Dunner, D. L., Goodwin, F.K.: Effect of l-tryptophan on brain serotonin metabolism in depressed patients. Arch. gen. Psychiat. 26, 364–366 (1972)

    Google Scholar 

  • Eccleston, D., Ashcroft, G. W., Crawford, T. B. B., Stanton, J. B., Wood, D., McTurk, P. H.: Effect of tryptophan administration on 5-HIAA in cerebrospinal fluid in man. J. Neurol. Neurosurg. Psychiat. 33, 269–272 (1970)

    Google Scholar 

  • Fernstrom, J. D., Wurtman, R. J.: Brain serotonin content: Physiological dependence on plasma tryptophan levels. Science 173, 149–152 (1971)

    Google Scholar 

  • Goodwin,F. K.: State dependent as state independent biological variables in affective illness. Paper read for the 8th Congress of the Collegium Internationale Neuropsychopharmacologicum. Kopenhagen 1972

  • Goodwin, F. K., Dunner, D. L., Gershon, E. S.: Effect of l-dopa treatment on brain serotonin metabolism in depressed patients. Life Sci. 10, 751–759 (1971)

    Google Scholar 

  • Grahame-Smith, D. G.: Tryptophan hydroxylase and regulation of indole formation: In: Serotonin and behaviour. Ed. by J. Barches and S. Usdin. New York and London: Academic Press 1972

    Google Scholar 

  • Guldberg, H. C., Ashcroft, G. W., Crawford, T. B. B.: Concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid of the dog before and during treatment with probenecid. Life Sci. 5, 1571–1575 (1966)

    Google Scholar 

  • Korf, J.: Amine metabolism in the human brain: Evaluation of the probenecid test. Diss., Groningen 1971

  • Korf, J., Ottema, S., Veen, I. van der: Fluorimetric determination of homovanillic acid in biological material after isolation on sephadex G-10. Analyt. Biochem. 40, 187–191 (1971)

    Google Scholar 

  • Korf, J., Praag, H. M. van: Amine metabolism in human brain: further evaluation of the probenecid test. Brain Res. 35, 221–230 (1971)

    Google Scholar 

  • Korf, J., Praag, H. M. van, Sebens, J. B.: Effect of intravenously administrated probenecid in humans on the levels of 5-hydroxy-indoleacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in cerebrospinal fluid. Biochem. Pharmacol. 20, 659–668 (1971)

    Google Scholar 

  • Korf, J., Praag, H. M. van, Sebens, J. B.: Serum tryptophan decreased, brain tryptophan increased and brain serotonin synthesis unchanged after probenecid loading. Brain Res. 42, 239–242 (1972)

    Google Scholar 

  • Lakke, J. P. W. F., Korf, J., Hoorntje, S., Praag, H. M. van, Schut, T.: The probenecid test in Parkinson's disease. Psychiat. Neurol. Neurochir. (Amst.) 76, 139–146 (1973)

    Google Scholar 

  • Lakke, J. P. W. F., Korf, J., Praag, H. M. van, Schut, T.: The predictive value of the probenecid test for the effect of levodopa therapy in Parkinson's disease. Nature New Biol. 236, 208–209 (1972)

    Google Scholar 

  • Lichtensteiner, W., Mutzner, U., Langemann, H.: Uptake of 5-hydroxytryptamine and 5-hydroxytryptophan by neurons of the central nervous system normally containing catecholamines. J. Neurochem. 14, 489–497 (1967)

    Google Scholar 

  • Neff, N. H., Tozer, T. N., Brodie, B. B.: Application of steady-state kinetics to studies of the transfer of 5-hydroxyindoleacetic acid from brain to plasma. J. Pharmacol. exp. Ther. 158, 214–218 (1967)

    Google Scholar 

  • Ng, L. K. Y., Chase, T. N., Colburn, R. W., Kopin, I. J.: l-Dopa induced release of cerebral monoamines. Science 170, 76–77 (1970)

    Google Scholar 

  • Ng, L. K. Y., Chase, T. N., Colburn, R. W., Kopin, I. J.: Release of (3H)dopamine by l-5-hydroxytryptophan. Brain Res. 45, 499–505 (1972)

    Google Scholar 

  • Olsson, R., Roos, B.-E.: Concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid after treatment with probenecid in patients with Parkinson's disease. Nature (Lond.) 219, 502–503 (1968)

    Google Scholar 

  • Praag, H. M. van: Depressie en de stofwisseling van 5-hydroxytryptamine. Ned. T. Geneesk. 113, 2245–2247 (1969)

    Google Scholar 

  • Praag, H. M. van, Korf, J., Puite, J.: 5-Hydroxyindoleacetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature (Lond.) 225, 1259–1260 (1970)

    Google Scholar 

  • Praag, H. M. van, Korf, J.: A pilot study of some kinetic aspects of the metabolism of 5-hydroxytryptamine in depressive patients. Biol. Psychiat. 3, 105–112 (1971)

    Google Scholar 

  • Praag, H. M. van, Korf, J.: Endogenous depressions with and without disturbances in the 5-hydroxytryptamine metabolism: a biochemical classification? Psychopharmacologia (Berl.) 19, 148–152 (1971)

    Google Scholar 

  • Praag, H. M. van, Korf, J., Dols, L. C. W., Schut, T.: A pilot study of the predictive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant. Psychopharmacologia (Berl.) 25, 14–21 (1972)

    Google Scholar 

  • Praag, H. M. van, Korf, J., Schut, T.: Cerebral monoamines and depression. An investigation into their correlation with the aid of the probenecid technique. Arch. gen. Psychiat. 28, 827–831 (1973)

    Google Scholar 

  • Roos, B.-E., Sjöström, R.: 5-Hydroxyindoleacetic acid (and homovanillic acid) levels in the cerebrospinal fluid after probenecid application in patients with manic-depressive psychosis. Pharmacol. Clin. 1, 153–155 (1969)

    Google Scholar 

  • Schutte, H. H., Berg, C. J. van den, Jonkheid van der Veen, I.: The use of analogue Computer stimulation in the study of compartmentation and turnover of 5-hydroxytryptamine in rat brain after labelling plasma tryptophan. Psychopharmacologia (Berl.) 26, 47 (1972)

    Google Scholar 

  • Shields, P. J., Eccleston, D.: Effects of electrial stimulation of rat midbrain on 5-hydroxytryptamine synthesis as determined by a sensitive radioisotope method. J. Neurochem. 19, 265–272 (1972)

    Google Scholar 

  • Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., Stern, S.: Effect of psychotropic drugs on tryptophan concentration in the rat brain. J. Pharmacol. exp. Ther. 177, 475–480 (1971)

    Google Scholar 

  • Tamarkin, N. R., Goodwin, F. K., Axelrod, J.: Rapid elevation of biogenic amine metabolites in human CSF following probenecid. Life Sci. 9, 1397–1408 (1970)

    Google Scholar 

  • Werdinius, B.: Effect of probenecid on the levels of monoamine metabolites in the rat brain. Acta pharmacol. (Kbh.) 25, 18–23 (1967)

    Google Scholar 

Download references

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Authors and Affiliations

  1. Departments of Biological Psychiatry and Clinical Psychology, Psychiatric University Clinic, Groningen, The Netherlands

    H. M. van Praag, F. Flentge, J. Korf, L. C. W. Dols & T. Schut

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  1. H. M. van Praag
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  2. F. Flentge
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  3. J. Korf
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  4. L. C. W. Dols
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  5. T. Schut
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van Praag, H.M., Flentge, F., Korf, J. et al. The influence of probenecid on the metabolism of serotonin, dopamine and their precursors in man. Psychopharmacologia 33, 141–151 (1973). https://doi.org/10.1007/BF00429084

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  • DOI: https://doi.org/10.1007/BF00429084

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