A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity

Background: Genetic variation of the promoter for the serotonin transporter (5-HTT) gene has been associated with its functional capacity, In vitro, c arriers of a short allele (s-carriers) of the 5-HTT promoter display signif icant reduction? in 5-HTT capacity. Dysfunction of 5-HTT has been observed in alcoholic individuals. We assessed whether the allelic constitution of t he 5-HTT gene is associated with reduced serotonin transporter availability among alcoholic individuals, Methods: We genotyped the 5-HTT promoter region and measured the availabili ty of serotonin transporter protein with [I-123]beta-CIT SPECT in the raphe area in 14 abstinent male alcoholic subjects and 8 age-matched control sub jects of European American descent. Results: Among control subjects, the ratio of in vivo 5-HTT availability fo r 11-homozygous individuals relative to s-carriers was comparable to seroto nin uptake ratios measured in vitro. There was a significant interaction of diagnosis and 5-HTT promoter genotype on 5-HTT availability (p < .01), Amo ng controls, 11-homozygous individuals displayed a significant increase as compared with s-carriers. The availability of raphe 5-HTT was significantly reduced in 11-homozygous alcoholic individuals and was negatively correlat ed with their amount of alcohol consumption. Among s-carriers, 5-HTT availa bility did nor differ significantly between control and alcoholic subjects. Conclusions: Our preliminary findings suggest an association between 5-HTT allelic constitution and in vivo measurements of human serotonin transporte r availability, and a potentially selective susceptibility of 11-homozygous individuals to the neurotoxic effects of chronic excessive alcohol consump tion.