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

T J Gaber,V L S Dingerkus,S Bubenzer,K Helmbold,A Eisert,F D Zepf,C L Sánchez

doi:10.1007/s00702-012-0793-z

T J Gaber, V L S Dingerkus + Show 5 more

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https://doi.org/10.1007/s00702-012-0793-z

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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.

Highlights

The neurotransmitter serotonin (5-HT) plays an important role in many neuropsychiatric disorders and behavioral phenotypes, in particular, affective disorders, eating and attention disorders along with their changed cognitive processes, aggressive behavior and impulsivity
This study investigated the effects of diminished central nervous system 5-HT synthesis on plasma concentrations of relevant amino acid (AA) and TRP influx into the brain in 24 healthy young adults using the Acute tryptophan depletion (ATD) procedure MojaDe, a test protocol that has been used in preliminary research in youths
As outlined by Kewitz (2002), the affinity towards L-1 of different amino acids is correlated with the polarity of the molecules, and unipolar hydrophobic amino acids were shown to have the highest affinity with respect to L-1 as indexed by their rather low Km values

Summary

Introduction

The neurotransmitter serotonin (5-HT) plays an important role in many neuropsychiatric disorders and behavioral phenotypes, in particular, affective disorders, eating and attention disorders along with their changed cognitive processes, aggressive behavior and impulsivity. In order to determine influx-properties and affinity constants of different amino acids in order to be able to calculate influx rates several in vitro and in vivo methods were developed (e.g., in vitro measurements with isolated capillary endothelial cells of the blood–brain barrier, indicator-dilution technique, etc., see Kewitz 2002 and Pardridge 1998). The underlying concept of ATD, a physiological neurodietary method to lower central nervous 5-HT synthesis in humans, builds on the increase in plasma concentrations of other amino acids as achieved by their dietary administration (often after an overnight fasting period), which in turn impacts the transcapillary influx of TRP over the blood–brain barrier which follows the underlying principles of facilitated diffusion. This synthesis requires additional TRP from plasma stores and contributes to 5-HT depletion, in addition to the passive diffusion of amino acids across the blood–brain barrier (Zepf 2012)

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