Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice.
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| Title: | Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. |
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| Authors: | Jacobsen, J P R, Siesser, W B, Sachs, B D, Peterson, S, Cools, M J, Setola, V, Folgering, J H A, Flik, G, Caron, M G |
| Source: | Molecular Psychiatry. Jul2012, Vol. 17 Issue 7, p694-704. 11p. 4 Graphs. |
| Subjects: | Serotonin uptake inhibitors, Neurotransmitters, Neural transmission, Biomarkers, Tryptophan, Hydroxylases |
| Abstract: | Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HTExt). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT1A receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT2A receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT2A receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT1A receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HTExt. Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT1A agonist-induced hypothermia and increased 5-HT2A receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy. [ABSTRACT FROM AUTHOR] |
| Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 77195571 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Jacobsen%2C+J+P+R%22">Jacobsen, J P R</searchLink><br /><searchLink fieldCode="AR" term="%22Siesser%2C+W+B%22">Siesser, W B</searchLink><br /><searchLink fieldCode="AR" term="%22Sachs%2C+B+D%22">Sachs, B D</searchLink><br /><searchLink fieldCode="AR" term="%22Peterson%2C+S%22">Peterson, S</searchLink><br /><searchLink fieldCode="AR" term="%22Cools%2C+M+J%22">Cools, M J</searchLink><br /><searchLink fieldCode="AR" term="%22Setola%2C+V%22">Setola, V</searchLink><br /><searchLink fieldCode="AR" term="%22Folgering%2C+J+H+A%22">Folgering, J H A</searchLink><br /><searchLink fieldCode="AR" term="%22Flik%2C+G%22">Flik, G</searchLink><br /><searchLink fieldCode="AR" term="%22Caron%2C+M+G%22">Caron, M G</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Molecular+Psychiatry%22">Molecular Psychiatry</searchLink>. Jul2012, Vol. 17 Issue 7, p694-704. 11p. 4 Graphs. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Serotonin+uptake+inhibitors%22">Serotonin uptake inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Neurotransmitters%22">Neurotransmitters</searchLink><br /><searchLink fieldCode="DE" term="%22Neural+transmission%22">Neural transmission</searchLink><br /><searchLink fieldCode="DE" term="%22Biomarkers%22">Biomarkers</searchLink><br /><searchLink fieldCode="DE" term="%22Tryptophan%22">Tryptophan</searchLink><br /><searchLink fieldCode="DE" term="%22Hydroxylases%22">Hydroxylases</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HTExt). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT1A receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT2A receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT2A receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT1A receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HTExt. Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT1A agonist-induced hypothermia and increased 5-HT2A receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/mp.2011.50 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 11 StartPage: 694 Subjects: – SubjectFull: Serotonin uptake inhibitors Type: general – SubjectFull: Neurotransmitters Type: general – SubjectFull: Neural transmission Type: general – SubjectFull: Biomarkers Type: general – SubjectFull: Tryptophan Type: general – SubjectFull: Hydroxylases Type: general Titles: – TitleFull: Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Jacobsen, J P R – PersonEntity: Name: NameFull: Siesser, W B – PersonEntity: Name: NameFull: Sachs, B D – PersonEntity: Name: NameFull: Peterson, S – PersonEntity: Name: NameFull: Cools, M J – PersonEntity: Name: NameFull: Setola, V – PersonEntity: Name: NameFull: Folgering, J H A – PersonEntity: Name: NameFull: Flik, G – PersonEntity: Name: NameFull: Caron, M G IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 07 Text: Jul2012 Type: published Y: 2012 Identifiers: – Type: issn-print Value: 13594184 Numbering: – Type: volume Value: 17 – Type: issue Value: 7 Titles: – TitleFull: Molecular Psychiatry Type: main |
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