Indoleamine Metabolism in Rat Brain Studied Through Measurements of Tryptophan, 5‐Hydroxyindoleacetic Acid, and Indoleacetic Acid in Cerebrospinal Fluid

Abstract

Tryptophan, 5-hydroxyindoleacetic acid (SHIAA), and indoleacetic acid (IAA) were measured in rat cerebrospinal fluid (CSF) using highperformance liquid chromatography with fluorometric detection in order to study brain indoleamine metabolism. Previously we have shown that IAA in CSF is derived from tryptamine in the CNS. In this study our results indicated that the synthesis of both 5-hydroxytryptamine (5HT) and tryptamine varied with changes in brain tryptophan. After a tryptophan load, tryptamine synthesis increased much more than 5HT synthesis; under these circumstances, it can be of the same order of magnitude as 5HT synthesis. Studies with treatments that cause release of 5HT (reserpine and cold stress) indicated that tryptamine is not released with 5HT and is probably not stored in vesicles. Use of selective monoamine oxidase inhibitors suggested that results obtained in vitvo concerning the substrates for monoamine oxidase A and B apply in vivo. Thus, 5HT was acted on preferentially by the A enzyme, and tryptamine by the B enzyme. Measurement of IAA in brain, CSF, and plasma before and after probenecid indicated that there are active transport systems moving IAA from CSF and brain to blood, and from brain to CSF. Our data suggest that measurements of C S F IAA are a simple and convenient way of studying CNS tryptamine metabolism and should be applied clinically. Key words: Cerebrospinal fluid-5-Hydroxyindoleacetic acid-5-Hydroxytryptamine-Indoleacetic acid-Tryptamine-Tryptophan. Measurement of amine-related compounds inCSF is an important method for the study of biogenic amine metabolism in human CNS. Indoleamine metabolism has been studied through m e a s u r e m e n t s o f b o t h t r y p t o p h a n a n d 5hydroxyindoleacetic acid (5HIAA) in CSF. The concentration of tryptophan in CSF is a reasonably good index of its content in the CNS (Young et al., 1976) and brain tryptophan is an important determ i n a n t o f t h e r a t e o f s y n t h e s i s o f 5hydroxytryptamine (5HT) (Ashcroft et al., 1965).The CSF 5HIAA concentration reflects CNS 5HT turnover (Garelis et al., 1974;Ebert and Perlow, 1977) and many clinical studies have taken advan-tage of this fact. Recently, using a new highperformance liquid chromatographic (HPLC) method (Anderson and Purdy, 1979), we have shown that indoleacetic acid (IAA) in CSF is derived from another indoleamine, tryptamine, in the CNS (Young et al., 1979).The amount of information on IAA in CSF and the factors that might affect it is limited. One study reported its presence in human lumbar CSF using a gas chromatographic-mass spectrometric method (Bertilsson and Palmer, 1972). Another study showed that there was a significant positive correlation between IAA and SHIAA in lumbar CSF of depressed patients and that chronic treatment with From theThe present address of George M. Anderson is Child Study Center, Yale University, New Haven, Connecticut 065 10.Abbreviations used: SHIAA, 5-Hydroxyindoleacetic acid; HPLC, High-performance liquid chromatography; 5HT, 5-Hydroxytr...

CNS tryptamine metabolism in hepatic coma

“…The postprobenecid CSF tryptophan concentration was not significantly different between controls and cirrhotics; however, the sample sizes are small and the trend was for higher values in the cirrhotic group (Table 3). As in the rat (Young et al, 1980 a) probenecid caused accumulation of IAA; the CSF IAA values of the probenecid-treated controls were 6-fold higher (t = 3.08, p < 0.01) than in controls not given the drug (Table 3). Post-probenecid CSF IAA values were significantly higher in cirrhotics than in controls (Table 3).…”

“…Another difference between control and cirrhotic groups is that the control group contains some women as well as men. The mean lumbar CSF IAA concentration is higher in women than men (Young et al, 1980 c). However, this difference is small and does not prevent us seeing the large difference (nearly 7-fold) between the patients with and without liver disease.…”

“…In most cases the lumbar puncture was performed at 8 a.m. The patients remained recumbent from 12 midnight the preceding evening to avoid disturbing the gradient of IAA in CSF (Young et al, 1980 a). CSF was obtained from the orthopaedic controls during myelography; the initial 5 ml of CSF were taken.…”

“…Tryptamine metabolism increases with rising tissue tryptophan levels (Warsh et al, 1979;Young et al, 1980 b) and CSF tryptophan is high in patients with liver disease (Young et aI., 1975;Hutson et al, 1979). Therefore, we have looked at CNS tryptamine metabolism in patients with cirrhosis of the liver, by measuring IAA in their lumbar CSF.…”

The metabolism of l-tryptophan by isolated rat liver cells. Quantification of the relative importance of, and the effect of nutritional status on, the individual pathways of tryptophan metabolism

“…These are: (i) oxidation by tryptophan 2,3-dioxygenase [L-tryptophan-02 2,3-oxidoreductase (decyclizing), EC 1.13.11.111 to kynurenine and subsequently to acetyl-CoA (the 'glutarate' pathway) or nicotinamide nucleotides (the 'NAD' pathway); (ii) transamination to yield indol-3-ylpyruvic acid, which may then be oxidized to indol-3-ylacetic acid; (iii) decarboxylation to yield the neurotransmitter tryptamine (Saavedra & Axelrod, 1973;Young et al, 1980) (Young et al, 1978). Several methods have been used to investigate the control of tryptophan oxidation by the kynurenine pathway in intact isolated liver preparations.…”