title: The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration.
abstract: The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. cecilie.licht@childrens.harvard.edu
authors.forename: Cecilie L
authors.initials: CL
authors.lastname: Licht
authors.forename: Anders B
authors.initials: AB
authors.lastname: Marcussen
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.forename: David H
authors.initials: DH
authors.lastname: Overstreet
authors.forename: Susana
authors.initials: S
authors.lastname: Aznar
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015283:Citalopram / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D005464:Fluorobenzenes / Q000378:metabolism; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage*; D010880:Piperidines / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000172:deficiency; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013550:Swimming; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D010134:Fenclonine; D005277:Fenfluramine; D005464:Fluorobenzenes; D017374:Paroxetine; D010880:Piperidines; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; C534709:SB 207145; C079049:volinanserin