title: Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans.
abstract: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.
authors.affiliation: Sackler Institute of Psychobiological Research, Institute of Health and Wellbeing, University of Glasgow, United Kingdom. Electronic address: rajeev.krishnadas@glasgow.ac.uk.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Krishnadas
authors.affiliation: Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Nicol
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: Jen
authors.initials: J
authors.lastname: Sassarini
authors.affiliation: Sackler Institute of Psychobiological Research, Institute of Health and Wellbeing, University of Glasgow, United Kingdom.
authors.forename: Navesh
authors.initials: N
authors.lastname: Puri
authors.affiliation: Department of Dermatology, Western Infirmary, Glasgow, United Kingdom.
authors.forename: A David
authors.initials: AD
authors.lastname: Burden
authors.affiliation: Department of Dermatology, Western Infirmary, Glasgow, United Kingdom.
authors.forename: Joyce
authors.initials: J
authors.lastname: Leman
authors.affiliation: School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: Emilie
authors.initials: E
authors.lastname: Combet
authors.affiliation: West of Scotland Radionuclide Dispensary, Greater Glasgow and Clyde NHS Trust, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Pimlott
authors.affiliation: Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom.
authors.forename: Donald
authors.initials: D
authors.lastname: Hadley
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: Sackler Institute of Psychobiological Research, Institute of Health and Wellbeing, University of Glasgow, United Kingdom. Electronic address: jonathan.cavanagh@glasgow.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cavanagh
mesh_terms: D015535:Arthritis, Psoriatic / Q000000981:diagnostic imaging / Q000378:metabolism*; D001933:Brain Stem / Q000000981:diagnostic imaging / Q000378:metabolism*; D003863:Depression / Q000378:metabolism; D000068800:Etanercept / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008875:Middle Aged; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
keywords: Cytokines; Depression; Inflammation; SPECT; Serotonin transporter; Tumor necrosis factor