A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity

Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests that a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on reactivity towards angry, neutral and happy faces were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). An a priori genotype stratification approach of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex (vmPFC) reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in vmPFC activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.