title: Brain serotonin 4 receptor binding is associated with the cortisol awakening response.
abstract: Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of hypothalamic-pituitary-adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR. Thirty healthy volunteers (25 males, age range 20-56 years) underwent 5-HT4r PET imaging with [(11)C]-SB207145, genotyping of the SERT-linked polymorphic region (5-HTTLPR), and performed serial home sampling of saliva (5 time points from 0 to 60min from awakening) to assess CAR. The association between 5-HT4r binding in 4 regions of interest (prefrontal cortex, anterior cingulate cortex, pallidostriatum, and hippocampus) and CAR was tested using multiple linear regression with adjustment for age and 5-HTTLPR genotype. Finally, an exploratory voxel-based analysis of the association was performed. CAR was negatively associated with 5-HT4r binding in pallidostriatum (p=0.01), prefrontal cortex (p=0.03), and anterior cingulate cortex (p=0.002), respectively, but showed no association in hippocampus. The results remained significant when taking into account other potentially relevant covariates. In conclusion, our finding reinforces an association between HPA-axis function and serotonin signaling in vivo in humans. We suggest that higher synaptic serotonin concentration, here indexed by lower 5-HT4r binding, supports HPA-axis dynamics, which in healthy volunteers is reflected by a robust CAR.
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Gustav R
authors.initials: GR
authors.lastname: Jakobsen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fisher
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark.
authors.forename: Agnete
authors.initials: A
authors.lastname: Dyssegaard
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark; Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark.
authors.forename: Brenda
authors.initials: B
authors.lastname: McMahon
authors.affiliation: Department of Biostatistics, University of Copenhagen, DK-1014 Copenhagen, Denmark.
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Holst
authors.affiliation: PET and Cyclotron Unit, DK-2100 Copenhagen, Denmark.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Svarer
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Jensen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, DK-2100 Copenhagen, Denmark; Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark. Electronic address: vibe@nru.dk.
authors.forename: Vibe G
authors.initials: VG
authors.lastname: Frokjaer
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D010880:Piperidines / Q000378:metabolism; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D014851:Wakefulness; D055815:Young Adult
chemical_list: D010880:Piperidines; C534709:SB 207145; D050486:Serotonin Plasma Membrane Transport Proteins; D044422:Receptors, Serotonin, 5-HT4; D006854:Hydrocortisone
keywords: 5-HT4; Brain imaging; Cortisol; HPA-axis; Human; Neuroendocrinology; PET; Serotonin