Central Serotonin Transporter Availability Measured With [¹²³I]β-CIT SPECT in Relation to Serotonin Transporter Genotype

OBJECTIVE: A functional polymorphism has been described in the promoter region of the gene (SLC6A4) coding for the serotonin transporter protein (SERT). This polymorphism has two common alleles, designated as long and short. Each allele has been linked with a number of human clinical phenotypes, including neuropsychiatric diseases associated with dysregulation of serotonin transmission. In vitro studies of nonneural cells have suggested that the long allele may have higher transcriptional activity than the short allele. However, the relevance of these findings for SERT levels in the brain remains unclear. METHOD: The authors assessed genotypes at the SLC6A4 promoter polymorphism in 96 healthy European American subjects who underwent single photon emission computed tomography scanning with [¹²³I]2β-carbomethoxy-3β-(4-iodophenyl) tropane ([¹²³I]β-CIT) for measurement of central SERT availability. A ratio of specific to nondisplaceable brain uptake (i.e., V₃′′=[brainstem-diencephalon – occipital]/occipital), a measure proportional to the binding potential (B_max/K_D), was derived. RESULTS: The results showed that the main effect of genotype was significant. Post hoc Tukey pairwise comparisons revealed that the short-short homozygotes had significantly greater SERT availability than the long-short heterozygotes. There was a nonsignificant tendency for the long-long homozygotes to have greater SERT availability than the heterozygotes, but no difference was observed between the long-long homozygotes and the short-short homozygotes. The effect of age was significant in the analysis of covariance model. CONCLUSIONS: These results do not suggest higher central SERT levels in association with the long allele in European American subjects but point to a more complex relationship between SLC6A4 genotype and protein availability.