Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics

Abstract

Expression rates of long (L) and short (S) alleles of the serotonin (5-HT) transporter (5-HTT) gene have been shown to differ under various circumstances. We compared 5-HTT uptake (function) level and paroxetine binding (density) in platelets of alcoholics as indices of 5-HTT expression rate among LL, LS, and SS genotypes. Concentration curves of [ 3 H]5-HT and [ 3 H]paroxetine were used to quantify the equilibrium constant (Km) and maximum 5-HT uptake rate (Vmax) for 5-HTT uptake into intact platelets and the dissociation constant (Kd) and maximum specific binding density (Bmax) for paroxetine binding to platelet membranes, respectively. Genotypes were determined using electrophoresis with fluorescent markers. Vmax for 5-HTT uptake did not correlate with Bmax for paroxetine binding (r=−0.095, P=0.415). Means of Vmax and Bmax did not differ in a statistically significant manner among LL, LS, and SS genotypes in these alcoholic subjects. However, Vmax for LL and SS appeared to have a bimodal distribution, so the percentage of subjects with Vmax <200 fmol/min-10 7 platelets was statistically significantly higher in LL than in SS (51.5% vs. 22.7%, respectively), with an odds ratio of 3.6 (P<0.05). The percentage of Vmax <200 fmol/min-10 7 platelets for LS was 39.3% (not significant vs. LL or SS). Previous studies of healthy human controls have shown that 5-HTT density in raphe nuclei and 5-HTT uptake in platelets are higher in the LL genotype than in S carriers. Our findings in currently drinking alcoholics support the hypothesis that those with the LL genotype of the 5′-HTTLPR region of the 5-HTT gene have reduced 5-HTT function.

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

“…Before BLT, 5-HTT turnover numbers and E TYR correlated significantly in patients achieving full remission (r ¼ 0.624, p ¼ 0.002), at a trend level in partial responders (r ¼ 0.482, p ¼ 0.069), while there was no correlation in nonresponders (r ¼ 0.083, p ¼ 0.729). The 5-HTTLPR polymorphism was not associated with any of the functional 5-HTT parameters, and in contrast to some (Greenberg et al, 1999;Patkar et al, 2003), but not other findings (Javors et al, 2005), our data failed to show an influence of 5-HTTLPR on seasonal variations in V max or other 5-HTT parameters.…”

Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking?

“…The current study is the first to show that the reduced activity of the 5-HTT in human alcoholics is related to drinking patterns and that this can be demonstrated in platelet preparations. We previously reported reduced 5-HT uptake in the platelets of a smaller sample of LL alcoholics (Javors et al, 2005). The current study substantially expands those findings, clearly showing reduced functional 5-HTT uptake in L-carriers, and adds the findings of reduced paroxetine binding as well.…”

“…The observed lack of correlation between V max and B max in our study probably is due in part to this lack of specificity of paroxetine binding. However, our unpublished results have indicated that only about 20% of the 5-HTTs are located at the surface of platelets, which may further account for the observed lack of correlation between V max and B max (Javors et al, 2005). Although the density of paroxetine binding (B max ) is certainly an indicator of the expression rate of the 5-HTT, the mechanism by which the majority of transporters are internalized is unknown, but it is likely to include phosphorylation, glycosylation, and other cellular signaling mechanisms involved with 5-HTT uptake and turnover.…”

“…First, while healthy subjects with the LL genotype showed greater β-CIT neuronal binding in the raphe nucleus than did subjects with SS alleles, alcoholics with the LL genotype had reduced β-CIT neuronal binding compared with controls (Heinz et al, 2000). Second, our laboratory recently found no mean difference among the LL, LS, and SS genotypes in the platelet 5-HT uptake measures of alcohol-dependent outpatients, but compared with SS homozygotes, a higher percentage of LL alcoholics had unusually low platelet 5-HT uptake (<200 nmol/10 −7 platelets-min) (Javors et al, 2005). Though these reduced measures of functional 5-HT uptake in platelets are consistent with Heinz et al's (2000) finding that the 5-HTT may be decreased in LL alcoholics, it is important to determine the basis for this finding.…”

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…has not been addressed unequivocally, even though a dominant s allele effect has been repeatedly reported [34][35][36] other studies did not confirm this model 37 and SNPs are usually supposed to have a codominant effect. 38 Our results favour the view of a dominant s effect, as indicated on response and early response.…”