A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans

被引:206
作者
David, SP
Murthy, NV
Rabiner, EA
Munafó, MR
Johnstone, EC
Jacob, R
Walton, RT
Grasby, PM
机构
[1] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Med Res Council Clin Sci Ctr, London W12 0NN, England
[2] Univ Oxford, Canc Res UK Gen Practice Res Grp, Dept Clin Pharmacol, Oxford OX2 6HE, England
[3] Brown Univ, Ctr Primary Care & Prevent, Pawtucket, RI 02860 USA
[4] Addenbrookes Ctr Clin Invest, GlaxoSmithKline, Cambridge CB2 2GG, England
关键词
serotonin; 5-HT1A receptor; serotonin transporter; genetics; polymorphisms; positron emission tomography;
D O I
10.1523/JNEUROSCI.3769-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 [C-11] 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.
引用
收藏
页码:2586 / 2590
页数:5
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