title: Systemic inflammation alters central 5-HT function as determined by pharmacological MRI.
abstract: Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+15.9±2%) and a negative BOLD response in the dorsal raphe nucleus (-9.9±4.2%) and nucleus accumbens (-7.7±5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p<0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p<0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Rd, Oxford, OX1 3QT, UK; CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Martin
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Howarth
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Josie
authors.initials: J
authors.lastname: Raley
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Khrapitchev
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Stratford
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Rd, Oxford, OX1 3QT, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK. Electronic address: nicola.sibson@oncology.ox.ac.uk.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Rd, Oxford, OX1 3QT, UK.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005277:Fenfluramine / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D017551:Microdialysis; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D005277:Fenfluramine; D005464:Fluorobenzenes; D010880:Piperidines; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C079049:volinanserin