Plasma tryptophan and clinical phenotypes in alcohol addicted males during acute tryptophan depletion depend on 5HTTPR-polymorphism

Background and aims: Dysfunction of the serotoninergic system may play a role in craving and relapse in alcohol dependence. The 44-bp insertion/deletion polymorphism (5-HTTLPR) of the serotonin transporter (5-HTT) modifies serotonin reuptake und presynaptic 5-HTT expression. We asked how the 5-HTTLPR affects mood, craving and peripheral blood serotoninergic neurotransmitter concentrations in acute tryptophan depletion. Methods: In a controlled double-blind design, the effects of tryptophan depletion were tested in 24 non-drinking men with alcohol dependence without a previous diagnosis of major depression. Depressive symptoms, anxiety, and craving were assessed prior to and 5 h after a tryptophan-depleted amino acid drink compared with tryptophan supplemented placebo. The 5-HTTLPR and 5-HTT mRNA were analyzed from peripheral blood. L-tryptophan, 5-hydroxy-tryptamine, 5-hydroxyindole acetic acid, and homovanillinic acid were quantified in serum before and after depletion. Results: High individual constancy in L-tryptophan, serotonin, and homovanillic acid was observed (r-square 74.0%, 69.6%, and 81.9%) indicating a strong genetic background behind the inter-individual variation in serotoninergic neurotransmitters. Baseline L-tryptophan was higher in carriers of an s-allele of 5-HTTLPR than in l/l (p = 0.002). Baseline plasma homovanillic acid was also significantly dependent on the 5-HTTLPR (p < 0.001). Scores for depression and craving were significantly higher in carriers of the ll genotype than in the ls genotype. Upon placebo (with tryptophan supplementation) there was a decrease in depressive symptoms. Conclusions: In non drinking subjects with alcohol dependence, the 5-HTTLPR polymorphism modulated baseline plasma concentrations of homovanillic acid and possibly of L-tryptophan depletion. Craving was higher in carriers of the l/l genotype and tryptophan supplementation decreased depressive symptoms.