title: Evidence that increased 5-HT release evokes region-specific effects on blood-oxygenation level-dependent functional magnetic resonance imaging responses in the rat brain.
abstract: This study aimed to determine the potential of in vivo functional magnetic resonance imaging (fMRI) methods as a non-invasive means of detecting effects of increased 5-HT release in brain. Changes in blood-oxygenation level-dependent (BOLD) contrast induced by administration of the 5-HT-releasing agent, fenfluramine, were measured in selected brain regions of halothane-anesthetized rats. Initial immunohistochemical measurements of the marker of neural activation, Fos, confirmed that in halothane-anesthetized rats fenfluramine (10 mg/kg i.v.) evoked cellular responses in cortical regions which were attenuated by pre-treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (300 mg/kg i.p. once daily for 2 days). Fenfluramine-induced Fos was demonstrated in numerous glutamatergic pyramidal neurons (Fos/excitatory amino acid carrier 1 (EAAC1) co-labeled), but also a small number of GABA interneurons (Fos/glutamic acid decarboxylase (GAD)(67) colabeled). Fenfluramine (10 mg/kg i.v.) evoked changes in BOLD signal intensity in a number of cortical and sub-cortical regions with the greatest effects being observed in the nucleus accumbens (-13.0%+/-2.7%), prefrontal cortex (-10.1%+/-3.2%) and motor cortex (+2.3%+/-1.0%). Pre-treatment with p-chlorophenylalanine, significantly attenuated the response to fenfluramine (10 mg/kg i.v.) in all regions with the exception of the motor cortex which showed a trend. These experiments demonstrate that increased 5-HT release evokes region-specific changes in the BOLD signal in rats, and that this effect is attenuated in almost all regions by 5-HT depletion. These findings support the use of fMRI imaging methods as a non-invasive tool to study 5-HT function in animal models, with the potential for extension to clinical studies.
authors.affiliation: Department of Pharmacology, Mansfield Road, Oxford, UK. m.preece@kingston.ac.uk
authors.forename: M A
authors.initials: MA
authors.lastname: Preece
authors.forename: M J
authors.initials: MJ
authors.lastname: Taylor
authors.forename: J
authors.initials: J
authors.lastname: Raley
authors.forename: A
authors.initials: A
authors.lastname: Blamire
authors.forename: T
authors.initials: T
authors.lastname: Sharp
authors.forename: N R
authors.initials: NR
authors.lastname: Sibson
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010100:Oxygen / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D050580:Excitatory Amino Acid Transporter 3; D010134:Fenclonine; D005277:Fenfluramine; D016761:Oncogene Proteins v-fos; D010100:Oxygen; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C493398:Slc1a1 protein, rat