Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), may depend on plasma concentrations of the essential amino acid L-tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36-h CSF collection via lumbar drain. Six subjects who were in good health were put on a low-TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP-deficient 15-amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5-HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at approximately 2 h following ingestion of the TRP-free amino acid drink and were lowest approximately 6 h after ATD; CSF TRP and 5-HIAA were decreased at 2.5 h and approximately 4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5-HIAA continued to decrease 14 h after the TRP-deficient amino acid drink was given.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.1999.721641.x

Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers.

Evidence that the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a role in the pathophysiology of mood disorders has been accumulating over the past three decades. Recent studies on this neurotransmitter have extended across the spectrum of psychiatric disorder, suggesting a role for 5-HT in psychosis, aggression, eating disorders and addiction. However, much of the evidence has come from post-mortem examination of the brain or measures of peripheral rather than central 5-HT function. The technique of tryptophan depletion allows investigation of brain 5-HT function in living subjects by examining the behavioural responses to this pharmacological challenge. This review considers the current status of tryptophan depletion as an experimental technique and discusses the implications of findings both in affective disorders and in a range of other psychiatric syndromes. MEDLINE and PSYCHLIT searches were completed for the years 1966 to November 1996 using the key words 'serotonin', '5-hydroxytryptamine', 'tryptophan' and 'depletion'. In addition relevant journals were hand-searched for the period from 1980 to December 1996. Forty-four double-blind studies in humans and three clinical case reports were identified; these cover a range of psychiatric disorders including mood disorders and psychoses, anxiety and eating disorders and specific behaviours such as appetite, aggression and craving. The studies reviewed utilized a variety of differing methodologies reducing the extent to which results can be generalized. A series of studies in depressed patients (before and after treatment with antidepressants) and their first-degree relatives have shown the importance of an intact 5-HT system in the action of antidepressants and offer new insights into the biology of affective disorder. The mood change induced by tryptophan depletion may predict those patients likely to respond to 5-HT-specific drugs. Rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals. Effects in other disorders are conflicting and further research is needed to clarify these findings.

Rapid depletion of plasma tryptophan: a review of studies and experimental methodology.

We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (−50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (−44%) and nucleus accumbens (−34%), areas with a predominantly dopaminergic innervation. Smaller decreases (−20–24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones.

https://link.springer.com/content/pdf/10.1007/s002130050823.pdf

Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release

Differential behavioral effects of plasma tryptophan depletion and loading in aggressive and nonaggressive men.

• Decreases in brain serotonin levels have been implicated in the pathogenesis of human depression. While circulating levels of tryptophan (TRP) might possibly reflect concentration of brain serotonin, a more relevant peripheral measure may be the ratio of plasma TRP to five other neutral amino acids (TRP/5aa ratio). In depressed subjects and normal controls, plasma TRP (free and total), phenylalanine (PHE), tyrosine (TYR), leucine, isoleucine, and valine were measured on three days. When depression was most severe, depressed patients had lower TRP/5aa ratios and total TRP levels and higher PHE and TYR levels. After the patients' conditions improved, these differences disappeared. As Hamilton depression scores improved, the plasma TRP/5aa ratios increased significantly. This finding tends to support the idea that changes in brain serotonin level reflect changes in depression severity.

Plasma Tryptophan and Five Other Amino Acids in Depressed and Normal Subjects

Changes in the synthesis rate of brain serotonin are positively correlated with changes in the concentration of brain tryptophan, indicating that the concentration of tryptophan in the whole brain reflects that at sites of serotonin synthesis. In turn, the concentration of brain tryptophan is positively correlated with that of free serum tryptophan (tryptophan is the only amino acid bound to serum proteins) and negatively to that of other amino acids competing with tryptophan for the same transport from blood to brain. Consistently, experiments in rats have shown that treatments which increase free tryptophan in serum (in respect to competing amino acids) also increase brain tryptophan and serotonin turnover. Conversely, the ingestion of diets containing all amino acids except tryptophan cause a dramatic fall in free serum tryptophan and a parallel decline in brain tryptophan and serotonin synthesis. In man the administration of an amino acid mixture lacking trytophan produces a marked depletion in serum tryptophan concentration.

Tryptophan-free diet: a new means for rapidly decreasing brain tryptophan content and serotonin synthesis.

Tryptophan hydroilase in brain, normally is not saturated by its substrate; therefore the rate of tryptophan hydroxilation in brain is controlled by the concentration of tryptophan. In the other hand, brain tryptophan content is controlled by the ratio of the concentration of free tryptophan (i.e. not bound to serum proteins) to that of the other circulating amino acids, wich compete for the same transport mechanism from blood to brain. The administration of an amino acid mixture, containing all essential amino acids but not tryptophan, caused a parallel depletion of total and free serum tryptophan and of tryptophan and serotonin in brain. The mechanism of the observed fall in serum tryptophan is a rapid removed of endogenous tryptophan from circulation, secondary to an increased incorporation of tryptophan into proteins by the liver. These results suggest the hypothesis that brain serotonin synthesis is controlled by a perpherical mechanism.

G Biggio

Papers

Tryptophan-free diet: a new means for rapidly decreasing brain tryptophan content and serotonin synthesis.

[Role of tryptophan in the physiological regulation of brain serotonin synthesis (author's transl)].

Urocortin: A Novel Player in Cardiac Control