Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study

Abstract

BackgroundThe catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport.MethodsFibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test.ResultsThe ADHD group had significantly decreased Vmax (p = 0.039) and Km (increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher Vmaxof alanine transport (p = 0.031), but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group.ConclusionsTryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder

“…These data are in line with the literature suggesting that fibroblasts could be a useful peripheral model for studying molecular processes in patients with neuropsychiatric disorders (Akin et al, 2004;Johansson et al, 2011;Auburger et al, 2012;Garbett et al, 2014;Kalman et al, 2014). In fact, fibroblasts are maintained in cultures in a controlled, reproducible environment, and after several rounds of cell division they are minimally affected by confounding factors (e.g., lifestyle or medication use) to which, in contrast, PBCs are exposed (Akin et al, 2004;Auburger et al, 2012;Garbett et al, 2014;Kalman et al, 2014).…”

Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters

“…Thus, the differential regulation observed in the present study is in agreement with earlier observations. Alterations in LAT functionality have been implicated in many neuronal disorders, including attention-deficit hyperactivity disorder, bipolar disorders and schizophrenia (Johansson et al, 2011;Logotheti et al, 2013). In addition, sex hormones are important for the development, modulation and protection of neuronal functions and have been implicated in the pathophysiology of mental diseases such as schizophrenia (Markham, 2012;Moore et al, 2013).…”

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

“…Decreased transport of tyrosine has been demonstrated by our group in fibroblasts obtained from patients with schizophrenia [19-21], autism [22], and bipolar disorder [23]. Furthermore, decreased transport of tryptophan has been observed in fibroblasts of children with ADHD in comparison to controls [24]. However, the reason for the disturbed amino acid transport in neuropsychiatric disorders is not completely understood.…”