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Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice

Molecular Psychiatry volume 17, pages 694–704 (2012)Cite this article

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.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health MH79201 and MH60451 (MGC), the NIMH Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (VS). Support from the Lennon Family Foundation to MGC for the initial part of this work is also greatly appreciated. WBS was the recipient of a NRSA postdoctoral fellowship (F32-MH-083404) and BDS is the recipient of a Minority Supplement award from the National Institutes of Health (MH79201-03S1). JPRJ is the grateful recipient of an individual grant from The Lundbeck Foundation of Denmark. We thank Wendy Roberts for skillful technical assistance and Dr Thomas Cremers for advice and making the SymDAQ HPLC-MS technology available. We thank Dr Garth Brown of Perkin-Elmer and Dr Hank F Kung of the University of Pennsylvania for advice and supplying [125I]p-MPPI.

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  1. Department of Cell Biology, Duke University, Durham, NC, USA

    J P R Jacobsen, W B Siesser, B D Sachs, S Peterson, M J Cools & M G Caron

  2. Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

    V Setola

  3. BrainsOnline, Groningen, The Netherlands

    J H A Folgering & G Flik

  4. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

    M G Caron

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  1. J P R Jacobsen
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Jacobsen, J., Siesser, W., Sachs, B. et al. Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Mol Psychiatry 17, 694–704 (2012). https://doi.org/10.1038/mp.2011.50

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