Introduction: In mice, disruption of 5-HTT function via knockout of the 5-HTT gene reduces 5-HT1A receptor density. In humans, the short allele (S) of the serotonin transporter (5-HTTLPR) gene has been associated with decreased transcriptional activity and reduced 5-HTT function. Furthermore, a promoter polymorphism in the 5-HT1A receptor gene (–1018 C>G) inhibits the repression of transcription, which may lead to increased 5-HT1A autoreceptor expression. We therefore investigated the effects of polymorphisms of the 5-HTTLPR and 5-HT1A receptor (–1018 C>G) genes on 5-HT1A receptor density in humans using PET and [11C] WAY 100635 (a specific ligand for 5-HT1A receptors).

Methods: Thirty-five healthy volunteers [27 males, mean (SD) age: 46 (13) years], who had previously undergone PET scans with [11C] WAY 100635, underwent blood collection for genotyping (i) the 5-HT1A receptor gene single nucleotide polymorphism at the site -1018 C>G, (ii) the common 44 bp insertion/deletion polymorphism (∼ 1 kb from initiation site) in the upstream regulatory region of 5-HTTLPR. PET scans were undertaken using the ECAT 953 and 966 scanners. Binding potential (BP) values were obtained using a simplified reference tissue model with a standard PET template. We carried out multivariate repeated measures ANOVA with 21 regions of interest as within-subject factors and genetic polymorphisms, scanner, and gender as between-subject factors.

Results: Genotype frequencies of all the polymorphisms conformed to the Hardy-Weinberg equilibrium. The “S” allele of 5-HTTLPR gene showed significantly lower 11C WAY 100635 BP values when compared to the “L” allele (F = 4.8, df 1.27, P= .037) and this was independent of the scanner and gender effects. The 5-HT1A receptor gene (–1018 c>g) did not show any significant genetic (allelic or genotypic) effects on 11C WAY 100635 BP values (F = .002, df 1.28, P= .9).

Conclusions: This study demonstrates for the first time that a genetic polymorphism of the 5-HT transporter gene indirectly affects 5-HT1A receptor density in vivo. This may be mediated by a persistently increased 5-HT tone associated with the “S” allele of 5-HTTLPR causing a downregulation of 5-HT1A receptors.

Comment: This PET imaging study, so far available only in abstract form, was done in a group of volunteers and elegantly demonstrates how genetic polymorphism of the 5-HT transporter gene can modify central 5-HT1A activity. This is potentially important in migraine and depression, where serotonin levels may be reduced. Could this be another gene locus that may have relevance to migraineurs?—David S. Millson