A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans.
In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.
David
Sean P
SP
Department of Clinical Pharmacology, Cancer Research United Kingdom General Practice Research Group, University of Oxford, Oxford OX2 6HE, United Kingdom.
Murthy
Naga Venkatesha
NV
Rabiner
Eugenii A
EA
Munafó
Marcus R
MR
Johnstone
Elaine C
EC
Jacob
Robyn
R
Walton
Robert T
RT
Grasby
Paul M
PM
D000328:Adult; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011725:Pyridines / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology
D010879:Piperazines; D011725:Pyridines; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide