Acute tryptophan depletion in accordance with body weight: influx of amino acids across the blood–brain barrier

Abstract

Acute tryptophan depletion (ATD) is a method of reducing central nervous serotonin (5-HT) synthesis in humans by administering an amino acid (AA) beverage lacking in tryptophan (TRP), the physiological precursor of 5-HT. However, to date, the use of conventional ATD protocols in children and adolescents was limited due to frequently observed side effects (e.g., vomiting and nausea). This study investigated the effects of diminished central nervous system 5-HT synthesis on plasma concentrations of relevant AAs and TRP influx into the brain in 24 healthy young adults using the ATD procedure Moja-De, a test protocol that has been used in preliminary research in youths. Twenty-four healthy participants received ATD and a TRP-balanced amino acid load (BAL) using a randomized double-blind within-subject crossover design. Plasma concentrations of the relevant AAs that compete with TRP on the same transport system were assessed at baseline and 90, 180, and 240 min after ATD/BAL intake. TRP influx across the blood–brain barrier was calculated using Michaelis–Menten kinetics with a correction for multiple substrate competition, indicating a significant decrease in TRP influx into the central nervous system under Moja-De. ATD Moja-De decreased TRP influx into the brain and central nervous system 5-HT synthesis safely and effectively and was well tolerated, allowing it to be used in children and adolescents. Future research into other secondary, compensatory effects induced by ATD in patients with neuropsychiatric disorders and healthy populations is needed. ATD Moja-De allows this type of research with a focus on a developmental viewpoint.Electronic supplementary materialThe online version of this article (doi:10.1007/s00702-012-0793-z) contains supplementary material, which is available to authorized users.

Effects of serotonin depletion on punishment processing in the orbitofrontal and anterior cingulate cortices of healthy women

“…Regarding the time-point of data acquisition, in a rodent model (Biskup et al, 2012) in all assessed brain regions at the particular time point of assessment used in the present study, 5-HT synthesis was substantially impaired as well as 5-Hydroxyindoleacetic acid (5-HIAA) content (an indirect measure of 5-HT release) was lowered following the administration of the used Moja-De ATD procedure. A recent study conducted in people in a comparable age cohort like the one in the present study cross-validated this procedure showing a robust decrease in total and free TRP influx over the blood-brain barrier after 90 min, remaining stable at this level 180 and 240 min later (Dingerkus et al, 2012). According to pilot data, the TRP-influx into the brain starts rising again after 6 h (Kewitz, 2002); hence, we ensured to measure in a time slot when TRP levels are still decreasing and not rising back to baseline.…”

“…ATD/BAL was administered at 0800 h and the fMRI measurement took place at 1100 h. The Moja-De ATD protocol (Biskup et al, 2012;Demisch et al, 2002;Dingerkus et al, 2012) includes administration of the relevant large neutral amino acids (LNAAs) in accordance with participants' body weights. Regarding the time-point of data acquisition, in a rodent model (Biskup et al, 2012) in all assessed brain regions at the particular time point of assessment used in the present study, 5-HT synthesis was substantially impaired as well as 5-Hydroxyindoleacetic acid (5-HIAA) content (an indirect measure of 5-HT release) was lowered following the administration of the used Moja-De ATD procedure.…”

“…However, the review demanded methodological improvement in future studies in terms of ATD administration and its efficacy to reduce basal 5-HT-release. Here we used the well established Moja-De ATD protocol (Demisch et al 2002;Kewitz, 2002), which was validated to reduce 5-HT synthesis in two strains of mice as well as in healthy human subjects (Biskup et al, 2012;Dingerkus et al, 2012). Furthermore, the reviewed studies contained notable limitations, e.g., they applied paradigms lacking reinforcement or punishment (Evers et al, 2006;Roiser et al, 2009;Rubia et al, 2005), which did not allow for investigation of serotonergic modulation of inhibition in light of negative consequences.…”

Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects

“…As pointed out by Hayward and colleagues, 80 in these circumstances the tryptophan-and histidine-deficient mixture might be probing the interaction between serotonin depletion and histamine depletion. The same criticism, a lack of histidine, applies to the original mixture used by Moja and colleagues, 12,81 which was subsequently changed somewhat by Stadler and colleagues, 82 and used in several subsequent studies (e.g., the study by Dingerkus and colleagues 83 ). A needed area of further research would be to study whether adding nonessential amino acids to a tryptophan-deficient amino acid mixture containing only essential amino acids would alter the lowering of plasma tryptophan levels and side effects.…”

“…While some studies use a mixture adjusted for body weight (e.g., the study by Dingerkus and colleagues 83 ), some studies have adopted the strategy of Ellenbogen and colleagues 91 of giving both men and women a fixed dose, with the dose for women adjusted for their lower average body weight. However, as discussed, the mechanism of action of ATD mixtures is to induce protein synthesis; therefore, presumably the correct adjustment would not be for body weight but for the mass of tissues (presumably mainly liver and muscle) responsible for the increase in protein synthesis.…”