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Aberrant amino acid transport in fibroblasts from patients with bipolar disorder
Stockholm County Council, Center for Dependency Disorder, Karolinska University Hospital Huddinge.
Örebro University, School of Health and Medical Sciences. (Neuropsychiatric Research Laboratory)
Örebro University, School of Health and Medical Sciences. (Neuropsychiatry Research Laboratory)
Stockholm County Council, Center for Dependency Disorder, Karolinska University Hospital Huddinge.
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2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 457, no 1, 49-52 p.Article in journal (Refereed) Published
Abstract [en]

Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n = 10) and healthy controls (n = 10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (Vmax) and affinity constant (Km) were determined. A significantly lower Vmax for tyrosine (p = 0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in Km for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low Vmax) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.

Place, publisher, year, edition, pages
Elsevier, 2009. Vol. 457, no 1, 49-52 p.
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-6392DOI: 10.1016/j.neulet.2009.03.095ISI: 000266360300012PubMedID: 19429160Scopus ID: 2-s2.0-67349103112OAI: oai:DiVA.org:oru-6392DiVA: diva2:213089
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-02-23Bibliographically approved
In thesis
1. Functional characterization of tyrosine and tryptophan transport in fibroblasts from healthy controls, patients with schizophrenia and bipolar disorder
Open this publication in new window or tab >>Functional characterization of tyrosine and tryptophan transport in fibroblasts from healthy controls, patients with schizophrenia and bipolar disorder
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2009. 65 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 30
Keyword
Fibroblasts, Tyrosine, Tryptophan, LAT1, Schizophrenia, Bipolar disorder
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-6393 (URN)978-91-7668-668-3 (ISBN)
Public defence
2009-05-29, Lokal HSM (Hörsal Musikhögskolan), Musikhögskolan, Örebro University, Örebro, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-28 Created: 2009-04-27 Last updated: 2011-05-02Bibliographically approved
2. Amino acid transport and receptor binding properties in neuropsychiatric disorders using the fibroblast cell model
Open this publication in new window or tab >>Amino acid transport and receptor binding properties in neuropsychiatric disorders using the fibroblast cell model
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Altered transport of the catecholamines and serotonin precursor amino acids tyrosine and tryptophan, might be one explanation for the dysfunctional neurotransmission implicated in the pathophysiology of bipolar disorder and Attention Deficit/Hyperactivity Disorder (ADHD). In previous studies, an altered amino acid transport has been found in schizophrenia and autism, when using the fibroblast cell model. The aim of this thesis was to investigate if the transport of precursor amino acids also may be altered in bipolar disorder and ADHD, and to relate the pre-synaptic activity (transport) with post-synaptic activity (receptors). A functional characterization of tryptophan transport in fibroblasts was also motivated, since the transport of tryptophan in fibroblast cells has not been fully explored.

Fibroblast cell lines from patients with bipolar type-1 disorder, from children with ADHD and from controls were included in the studies. The maximal transport capacity (Vmax) and affinity constant (Km) of tyrosine, tryptophan and alanine transport in bipolar patients and ADHD children were determined. Tryptophan transport characterization included; 1) measuring the uptake of tryptophan at high and low concentrations in the presence or absence of transporter selective inhibitors; 2) determination of Vmax and Km of tryptophan transport at high and low concentrations; 3) sodium dependency studies of tryptophan uptake. All transport studies were done using the cluster tray method. Furthermore, the maximal binding capacity (Bmax) and the equilibrium dissociation constant (KD) of muscarinic acetylcholine receptors (mAChRs) were determined in the ADHD children by a radioligand binding assay, using the mAChRs antagonist QNB.

In patients with bipolar disorder a decreased Vmax in the transport of tyrosine was observed (p=0.027), while the children with ADHD had a decreased Vmax of tryptophan transport (p=0.039) and an increased Vmax of alanine transport (p=0.031). Children with a hereditary ADHD also had a significantly decreased Bmax (p=0.01). The uptake of tryptophan at both high and low concentrations was partly sodium dependent and the inhibitors had different inhibitory effects on the tryptophan uptake. The uptake of tryptophan at high concentration had low affinity and high Vmax, whilst at low concentration the transport was with high affinity and low Vmax.

Altered amino acid transport was observed in fibroblasts of both bipolar disorder patients and ADHD children, which might indicate that the availability of precursor amino acid in the brain is altered. This could lead to disturbances, directly or indirectly, in the catecholaminergic and serotonergic systems. Children with hereditary ADHD might also have reduced levels of mAChRs in the CNS that could indirectly affect the dopaminergic activity. The uptake of tryptophan was through multiple transporters and was different at different substrate concentrations in terms of sodium dependency, affects of inhibitors and kinetic parameters.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2011. 68 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 57
Keyword
Fibroblasts, Bipolar disorder, ADHD, Tyrosine, Tryptophan, Alanine, Transport, mAChRs
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-17261 (URN)978-91-7668-818-2 (ISBN)
Public defence
2011-10-28, Örebro universitet, Prismahuset, hörsal P2, Fakultetsgatan 1, Örebro, 13:15
Opponent
Supervisors
Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2011-10-18Bibliographically approved

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