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

Abstract

Serotonin transporter (5-HTT) activity is greater in carriers of the long (L) vs. short (S) alleles of the 5-HTT-linked polymorphic region (5'-HTTLPR) among healthy control subjects but not alcohol-dependent adults. In 198 alcoholics, we determined the relationship between current or lifetime drinking and platelet 5-HTT function and density among allelic variants of the 5'-HTTLPR. SS subjects were younger than L-carriers (LL and LS) (p<0.0085) and had fewer years of lifetime drinking. For L-carriers, the mean of Bmax for paroxetine binding, but not Vmax for serotonin (5-HT) uptake, was lower than that for SS subjects (p<0.05). More L-carriers than their SS counterparts had Vmax for 5-HT uptake below 200 nmol/10(7) platelets-min (p<0.05) and Bmax for paroxetine binding below 600 nmol/mg protein (p<0.06). Current drinking (drinks per day during the past 14 days) correlated positively with Km and Vmax of platelet 5-HT uptake (p<0.05) and negatively with Bmax, but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Years of lifetime drinking correlated negatively with Km and Vmax of platelet 5-HT uptake (p<0.05) and B(max), but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Among L-carriers alone, there were higher levels of platelet 5-HT uptake and lower levels of platelet paroxetine binding with increased drinking, and more lifetime drinking was associated with modestly lower levels of 5-HT uptake and paroxetine binding. Thus, 5-HTT expression varies with current and lifetime drinking in L-carriers alone.

Figure 1

Proportion of subjects within the L-carrier (Lx) and SS genotype groups with V_max for serotonin uptake less than 200 nmol/min−10⁷ platelets and B_max less than 600 nmol/mg protein. V_max for platelet serotonin uptake, B_max for platelet paroxetine binding, and genotype (LL, LS, SS) were determined as described in the Subjects and Methods section. Data of participants with LL and LS were combined (L-carriers) for comparison with SS participants. A greater percentage of L-carrier than SS alcoholics had V_max for 5-HT uptake below 200 nmol/10⁷ platelets-min (p < 0.05) and B_max for paroxetine binding below 600 nmol/mg protein (p < 0.06).

Figure 2

Correlation between V_max for platelet serotonin uptake and B_max for platelet paroxetine binding. V_max for platelet serotonin uptake and B_max for platelet paroxetine binding were determined as described in the Subjects and Methods section. The correlation was determined using natural logs (ln) of the platelet parameters. Dashed vertical and horizontal reference lines on the graph indicate positions on the x-axis of 600 nmol/mg protein and positions on the y-axis of 200 fmol/min−10⁷ platelets. The solid horizontal line is the regression line for the correlation (p > 0.05).