Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice
Open Access
- 3 May 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 17 (7), 694-704
- https://doi.org/10.1038/mp.2011.50
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.Keywords
This publication has 79 references indexed in Scilit:
- 5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to AntidepressantsNeuron, 2010
- Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporterCellular Signalling, 2009
- Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to AntidepressantsPLOS ONE, 2008
- Role of GSK3β in behavioral abnormalities induced by serotonin deficiencyProceedings of the National Academy of Sciences of the United States of America, 2008
- Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivoProceedings of the National Academy of Sciences of the United States of America, 2008
- Serotonin-1A receptor imaging in recurrent depression: replication and literature reviewNuclear Medicine and Biology, 2007
- Serotonin and Depression: A Disconnect between the Advertisements and the Scientific LiteraturePLoS Medicine, 2005
- Changes of body temperature and extracellular serotonin level in the preoptic area and anterior hypothalamus after thermal or serotonergic pharmacological stimulation of freely moving ratsLife Sciences, 2004
- Neurotransmitters and Suicidal BehaviorAnnals of the New York Academy of Sciences, 1997
- Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysisLife Sciences, 1991