title: 5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [(11)C]SB207145 PET in humans.
abstract: Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen O, Denmark.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fisher
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Holst
authors.forename: Brenda
authors.initials: B
authors.lastname: Mc Mahon
authors.forename: Mette E
authors.initials: ME
authors.lastname: Haahr
authors.forename: Karine
authors.initials: K
authors.lastname: Madsen
authors.forename: Nic
authors.initials: N
authors.lastname: Gillings
authors.forename: William F
authors.initials: WF
authors.lastname: Baaré
authors.forename: Peter S
authors.initials: PS
authors.lastname: Jensen
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D010880:Piperidines / Q000493:pharmacokinetics*; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; C534709:SB 207145; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin