title: Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding.
abstract: Serotonergic neurotransmission is thought to underlie a dynamic interrelation between different key structures of the serotonin system. The serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft into the neuron, as well as the serotonin-1A (5-HT1A) and -1B (5-HT1B) receptors, inhibitory auto-receptors in the raphe region and projection areas, respectively, are likely to determine serotonin release. Thereby, they are involved in the regulation of extracellular serotonin concentrations and the extent of serotonergic effects in respective projection areas. Complex receptor interactions can be assessed in vivo with positron emission tomography (PET) and single-nucleotide-polymorphisms, which are thought to alter protein expression levels. Due to the complexity of the serotonergic system, gene × gene interactions are likely to regulate transporter and receptor expression and therefore subsequently serotonergic transmission. In this context, we measured 51 healthy subjects (mean age 45.5 ± 12.9, 38 female) with PET using [carbonyl-(11)C]WAY-100635 to determine 5-HT1A receptor binding potential (5-HT1A BPND). Genotyping for rs6296 (HTR1B) and 5-HTTLPR (SERT gene promoter polymorphism) was performed using DNA isolated from whole blood. Voxel-wise whole-brain ANOVA revealed a positive interaction effect of genotype groups (5-HTTLPR: LL, LS+SS and HTR1B: rs6296: CC, GC+GG) on 5-HT1A BPND with peak t-values in the bilateral parahippocampal gyrus. More specifically, highest 5-HT1A BPND was identified for individuals homozygous for both the L-allele of 5-HTTLPR and the C-allele of rs6296. This finding suggests that the interaction between two major serotonergic structures involved in serotonin release, specifically the SERT and 5-HT1B receptor, results in a modification of the inhibitory serotonergic tone mediated via 5-HT1A receptors.
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Pia
authors: P
authors: Baldinger
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Christoph
authors: C
authors: Kraus
authors: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors: Christina
authors: C
authors: Rami-Mark
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Gregor
authors: G
authors: Gryglewski
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Georg S
authors: GS
authors: Kranz
authors: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors: Daniela
authors: D
authors: Haeusler
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Andreas
authors: A
authors: Hahn
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Marie
authors: M
authors: Spies
authors: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors: Wolfgang
authors: W
authors: Wadsak
authors: Department of Biomedical Imaging und Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors: Markus
authors: M
authors: Mitterhauser
authors: Genetics Research Center, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Germany; Department of Psychiatry, Medical University of Halle, Germany.
authors: Dan
authors: D
authors: Rujescu
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria.
authors: Siegfried
authors: S
authors: Kasper
authors: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria. Electronic address: rupert.lanzenberger@meduniwien.ac.at.
authors: Rupert
authors: R
authors: Lanzenberger
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics*; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
chemical_list: D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide