Neurochem. Int. Vol. 7, No. 1, pp. 143-153, 1985 0197-0186/85 $3.00+0.00 Printed in Great Britain. All rights reserved Copyright © 1985 Pergamon Press Ltd TRYPTOPHAN AND SEROTONIN TURNOVER RATE IN THE BRAIN OF GENETICALLY HYPERAMMONEMIC MICE F. CHAOULOFF, D. LAUDE, E. MIGNOT, P. KAMOUN* and J. L. ELGHOZI Laboratoire de Pharmacologie, INSERM U7, Facult6 de Mrdecine Necker-Enfants Malades, 156 rue de Vaugirard, 75015 Paris and *Laboratoire de BiochimieG/mrtique, Hopital des Enfants Malades, 149-rue de Srvres, 75015 Paris, France (Received 14 April 1984; accepted 25 June 1984) Abstract--An investigation was made into the effects of hyperammonemia on the metabolism of brain serotonin (5-HT). The animal model used was the sparse fur (spf) mouse, which possesses an inborn error of the urea cycle, i.e. an abnormal form of ornithine transcarbamylase. Several indoles were measured in brain and plasma using liquid chromatography with electrochemical detection coupled to an u.v. detection (LCEC-u.v.). In the mutant mice, plasma total tryptophan (TRP) was higher when compared with the controls, while plasma free-TRP portion was unchanged. In these animals, brain TRP was increased whilst the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantlyhigher in the hypothalamus and midbrain. Experiments with NSD-1015 (100mg/kg i.p.) indicated that the 5-hydroxytryptophan (5-HTP) synthesis rate was increased in the hyperammonemic mice. Pargyline experiments (100 mg/kg i.p.) confirmed the enhanced brain 5-HT turnover rate in the spfmice. In addition, these experiments led to the conclusion that hyperammonemia does not affect the various rate constants. After administration of NSD-1015, TRP level slightly increased in the spf mouse brains, while it was stationary in those of the controls. This result could indicate an increased activity of hepatic TRP- pyrrolase in the hyperammonemic mice. Valine (VAL) administration (200 mg/kg i.p.) reduced brain TRP content in the two kinds of mice, but its effect was of shorter duration in the spf when compared with the control. Comparison of brain tryptamine level indicated a slight but not significant increase in the mutant mice. The data reported here indicate that hyperammonemia may affect peripheral TRP metabolism with consequences upon brain 5-HT synthesis, which could promote certain neurologic disorders. Tryptophan (TRP), the precursor of serotonin (5-HT), is unique among amino-acids. It is the only one bound to albumin in the blood of adult animals (McMenamy and Oncley, 1958). This binding site is shared by non esterified fatty acids (NEFA), which can displace the TRP and thus raise the level of the free form (McMenamy, 1965). In many circum- stances, plasma free TRP rather than the total (free and bound) appears to influence 5-HT biosynthesis in the brain (Knott et al., 1972; Tagliamonte et al., 1973; Bourgoin et al., 1974; Bloxam and Curzon, 1978). Most of the neutral amino-acids, including TRP, are transported across the blood-brain barrier (BBB) by a saturable and stereospecific common carrier (Pardridge, 1977; James and Fischer, 1981). Con- sequently, TRP entry and thus 5-HT biosynthesis may partly depend upon the relative blood levels of the competing amino-acids, chiefly valine, leucine, isoleucine, phenylalanine and tyrosine (Oldendorf, 1971; Fernstrom and Wurtman 1972a; Pardridge, 1977; Pardridge, 1979; Bloxam et al., 1980; Sarna et al., 1982). In addition, there is another transport component which is non saturable, i.e. by diffusion which increases in importance when plasma TRP level is elevated (Pratt, 1979; Sourkes, 1979). Brain 5-HT metabolism depends on the concentration of its precursor, TRP, since TRP-hydroxylase, the rate limiting enzyme of 5-HT pathway, is not saturated (Friedman et al., 1972; Carlsson and Lindqvist, 1972a,b). Several of the parameters described above are modified in human hepatic encephalopathy and also in the animal models for such liver impairment, which are produced by portacaval anastomosis (PCA), or hepatectomy. The plasma levels of the aromatic amino-acids and methionine are enhanced, while those of branched-chain amino-acids (BCAA) are decreased (James et al., 1978; Bloxam and Cur- zon, 1978; James et al., 1979). To date in all experi- ments, a common feature found is an increase of free TRP level in plasma (Curzon et al., 1973; Knell et al., 1974; James et al., 1978; Bloxam and Curzon, 1978). 143 NC.I, 7/1 J