Summary
Fusaric acid (FA) administration to the rats promoted one hour later a large decrease in plasma total tryptophan (TRP), without affecting either plasma free TRP or lipolysis, as measured by plasma non esterified fatty acid concentration. The previous change was associated with hypoinsulinemia, hyperglycemia and increased plasma corticosterone level. Regression analysis revealed a significant correlation between brain TRP and the percentage of plasma TRP which was free (i.e. unbound to albumin), both increased by FA injection. The increase in brain TRP promoted an increased brain serotonin synthesis, as measured by the enhanced brain and CSF 5-HIAA levels. Valine pretreatment, which blocks TRP entry into the brain, completely prevented FA-induced brain TRP and brain 5-HIAA increases.
These results suggest that the increased brain serotonergic turnover following FA treatment was due to a peripheral action of the drug upon TRP disposition. The latter effect may be caused (i) byin vivo peripheral alterations in catecholaminergic metabolism and (ii) by FA chemical structure sincein vitro experiments revealed that FA was able to displace TRP binding to albumin, thus increasing the plasma free TRP pool.
Similar content being viewed by others
References
Axelrod, J., Reisine, T. D.: Stress hormones: their interaction and regulation. Science224, 452–459 (1984).
Badawy, A. A. B.: The functions and regulation of tryptophan pyrrolase. Life Sci.21, 755–768 (1977).
Baraban, J. M., Aghajanian, G. K.: Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography. Brain Res.204, 1–11 (1981).
Bonnay, M. M., Guerinot, F., Bohuon, C. J.: Evidence for a peripheral effect of fusaric acid, a dopamineΒ-hydroxylase inhibitor, on serotonin metabolism. Biochem. Pharmacol.23, 2770–2773 (1974).
Bourgoin, S., Faivre-Bauman, A., Benda, P., Glowinski, J., Hamon, M.: Plasma tryptophan and 5-HT metabolism in the CNS of the newborn rat. J. Neurochem.23, 319–327 (1974).
Carlsson, A., Davis, J. N., Kehr, W., Lindqvist, M., Atack, C. V.: Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brainin vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn-Schmiedebergs Arch. Pharmacol.275, 153–168 (1972).
Chaouloff, F., Laude, D., Mignot, E., Kamoun, P., Elghozi, J. L.: Tryptophan and serotonin turnover rate in the brain of genetically hyperammonemic mice. Neurochem. Int.7, 143–153 (1985 a).
Chaouloff, F., Elghozi, J. L., Guezennec, Y., Laude, D.: Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. Br. J. Pharmac.86, 33–41 (1985 b).
Curzon, G., Knott, P. J.: Effects on plasma and brain tryptophan in the rat of drugs and hormones that influence the concentration of unesterified fatty acid in the plasma. Br. J. Pharmac.50, 197–204 (1974).
Echizen, H., Freed, C. R.:In vivo electrochemical detection of extraneuronal 5-hydroxyindole acetic acid and norepinephrme in the dorsal raphe nucleus of urethane-anesthetized rats. Brain Res.277, 55–62 (1983).
Elghozi, J. L., Mignot, E., Le Quan-Bui, K. H.: Probenecid sensitive pathway of elimination of dopamine and serotonin metabolites in CSF of the rat. J. Neural Transm.57, 85–94 (1983).
Elghozi, J. L., Laude, D., Chaouloff, F.: Fusaric acid-induced elevation of homovanillic acid in the CSF as an index of brain noradrenaline synthesis. Eur. J. Pharmacol.117, 363–367 (1985).
Fain, J. N.: Biochemical aspects of drug and hormone action on adipose tissue. Pharmacol. Rev.25, 67–118 (1973).
Fernando, J. C. R., Knott, P. J., Curzon, G.: The relevance of both plasma free tryptophan and insulin to rat brain tryptophan concentration. J. Neurochem.27, 343–345 (1976).
Fernstrom, J. D., Wurtman, R. J.: Brain serotonin content: physiological regulation by plasma neutral amino acids. Science178, 414–416 (1972).
Fiorelli, G., Piolanti, P., Forti, C., Sorio, M.: Determination of plasma corticosteroids and urinary cortisol by a competitive protein binding method using dextran coated charcoal. Clin. Chim. Acta37, 179–187 (1972).
Friedman, P. A., Kappelman, A. M., Kaufman, S.: Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain. J. Biol. Chem.247, 4165–4173 (1972).
Girard, J. R., Cuendet, G. S., Marliss, E. B., Kervran, A., Rieutort, M., Assan, R.: Fuels, hormones and liver metabolism at term and during the early postnatal period in the rat. J. Clin. Invest.52, 3190–3200 (1973).
Guerinot, F., Poitou, P., Bohuon, C.: Serotonin synthesis in the rat brain after acetylsalicylic acid administration. J. Neurochem.22, 191–192 (1974).
Hidaka, H.: Fusaric (5-butylpicolinic) acid, an inhibitor of dopamineΒ-hydroxylase, affects serotonin and noradrenaline. Nature231, 54–55 (1971).
Hutson, P. H., Knott, P. J., Curzon, G.: Effect of isoprenaline infusion on the distribution of tryptophan, tyrosine and isoleucine between brain and other tissues. Biochem. Pharmacol.29, 509–516 (1980).
Johnson, G. A., Kim, E. G., Boukma, S. J.: 5-hydroxyindole levels in rat brain after inhibition of dopamineΒ-hydroxylase. J. Pharmacol. Exp. Ther.180, 539–546 (1972).
Johnson, G. A., Kim, E. G.: Increase of brain levels of tryptophan induced by inhibition of dopamineΒ-hydroxylase (EC 1.14.2.1). J. Neurochem.20, 1761–1764 (1973).
Jones, M. T., Hillhouse, E. W., Burden, J.: Effect of various putative neurotransmitters on the secretion of corticotrophin-releasing hormone from the rat hypothalamusin vitro. A model of the neurotransmitters involved. J. Endocrinol.69, 1–20 (1976).
Joseph, M. H., Young, S. N., Curzon, G.: The metabolism of a tryptophan load in rat brain and liver. The influence of hydrocortisone and allopurinol. Biochem. Pharmacol.25, 2599–2604 (1976).
Knott, P. J., Curzon, G.: Free tryptophan in plasma and brain tryptophan metabolism. Nature239, 452–453 (1972).
Lambert, A. E.: The regulation of insulin secretion. Rev. Physiol. Biochem. Pharmacol.75, 97–159 (1976).
McMenamy, R. H.: Binding of indole analogues to human serum albumin. Effects of fatty acids. J. Biol. Chem.24, 4235–4243 (1965).
Moir, A. T. B.: Interaction in the cerebral metabolism of the biogenic amines: effect of intravenous infusion of L-tryptophan on the metabolism of dopamine and 5-hydroxyindoles in brain and cerebrospinal fluid. Br. J. Pharmac.43, 715–723 (1971).
Nagatsu, T., Hidaka, H., Kuzuya, H., Takeya, K.: Inhibition of dopamineΒ-hydroxylase by fusaric acid (5-butylpicolinic acid)in vitro andin vivo. Biochem. Pharmacol.19, 35–44 (1970).
Pardridge, W. M.: Kinetics of competitive inhibition of neutral amino acid transport across the blood brain barrier. J. Neurochem.28, 103–108 (1977).
Racz, K., Küchel, O., Buu, N. T.:In vivo release of adrenal catecholamines in rats by fusaric acid. Eur. J. Pharmacol.109, 1–7 (1985).
Reinhard, J. F., Roth, R. H.: Noradrenergic modulation of serotonin synthesis and metabolism. I. Inhibition by clonidinein vivo. J. Pharmacol. Exp. Ther.221, 541–546 (1981).
Sadler, E., Weiner, M., Buterbaugh, G. G.: Effect of streptozotocin-induced diabetes on tryptophan oxygenase activity and brain tryptophan levels in rats. Res. Comm. Chem. Path. Pharmac.42, 37–50 (1983).
Slein, M. W.: D-glucose determination with hexokinase and glucose phosphate dehydrogenase. In: Methods of Enzymatic Analysis (Bergmeyer, H., ed.), pp. 117–123. New York-London: Academic Press. 1963.
Spano, P. F., Szyszka, K., Galli, C. L., Ricci, A.: Effect of clofibrate on free and total tryptophan in serum and brain tryptophan metabolism. Pharmacol. Res. Comm.6, 163–173 (1974).
Steffens, A. B., Damsma, G., van der Gugten, J., Luiten, P. G. M.: Circulating free fatty acids, insulin, and glucose during chemical stimulation of hypothalamus in rats. Am. J. Physiol.247, E765-E771 (1984).
Stoner, H. B., Cunnigham, V. J., Elson, P. M., Hunt, A.: The effects of diet, lipolysis and limb ischaemia on the distribution of plasma tryptophan in the rat. Biochem. J.146, 659–666 (1975).
Svensson, T. H., Bunney, B. S., Aghajanian, G. K.: Inhibition of both noradrenergic and serotoninergic neurons in brain by theα-adrenergic agonist clonidine. Brain Res.92, 291–306 (1975).
Turtle, J. R., Littleton, G. K., Kipnis, D. M.: Stimulation of insulin secretion by theophylline. Nature213, 727–728 (1967).
Young, S. N., Oravec, M., Sourkes, T. L.: The effect of theophylline on tryptophan pyrrolase in the hypophysectomized rat and some observations on the validity of tryptophan pyrrolase assays. J. Biol. Chem.249, 3932–3936 (1974).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chaouloff, F., Laude, D., Merino, D. et al. Peripheral and central short-term effects of fusaric acid, a DBH inhibitor, on tryptophan and serotonin metabolism in the rat. J. Neural Transmission 65, 219–232 (1986). https://doi.org/10.1007/BF01249084
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01249084