Differential Effects of Tryptophan Challenge on Mood and Coping with Stress in Subjects with Genetic (5-HTTLPR) or Chronic Stress-Induced Brain 5-HT Vulnerabilities

Abstract

Background Brain serotonin (5-HT) dysfunction is a relevant pathophysiological factor contributing to stress proneness and hence to stress-related affective disturbances. Susceptibility to 5-HT dyfunction, 5-HT vulnerability, is not only promoted by cognitive proneness (frequent stress perceptions and experiences) but also by genetic vulnerabilities. A commonly recognized 5-HT vulnerable genotype involves a polymorphism in the 5-HT transporter-linked promoter region (5-HTTLPR). This region encodes the 5-HT transporter protein (5-HTT), controls 5-HT reuptake and function, and is the target mechanism for antidepressant drugs. The short-allele (S) variant 5-HTTLPR is associated with lower 5-HTT mRNA concentrations than the long-allele (L) variant and is thought to promote 5-HT vulnerability for the negative affective effects of stress. Brain 5-HT vulnerabilities are often explored by tryptophan depletion (ATD). This intervention reduces brain 5-HT by lowering the plasma dietary amino acid tryptophan, the precursor of 5-HT, which competes with other large neutral amino acids (TRP/LNAA ratio) for uptake into the brain. Yet, because 5-HT vulnerable subjects may exhibit enhanced post-synaptic sensitization, as a compensatory response to reduced 5-HT availability and/or lower pre-synaptic 5HTT expression, they may be particularly susceptible for the beneficial effects of tryptophan challenge. Data showing that cognitive and/or genetically 5-HT vulnerable subjects are indeed less affected by the negative effects of acute stress exposure following dietary tryptophan augmentation will be presented.