Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis?

Abstract

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.

The Human BNST: Functional Role in Anxiety and Addiction

“…Initial attempts to validate these findings in humans have been encouraging; for example, Grillon et al (2006) showed that benzodiazepine administration (alprazolam) reduced unpredictable context-enhanced startle but not fear-potentiated startle. In another study from the same lab (Robinson et al, 2012), reduced serotonin via acute tryptophan depletion enhanced startle in the long-duration threat periods but had no effect in the short-duration threat periods. Although more research is needed in this area, the preliminary results in both rodents and humans are encouraging.…”

Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

“…There is evidence that serotonin acts in the BNST to affect anxiety behavior in humans, non-human primates, and rodents alike. Acute tryptophan depletion, causing a reduction in serotonin levels in the brain, significantly increases long-duration anxiety-potentiated startle in humans while having no effect on short-duration fear-potentiated startle (Robinson et al, 2012). The possible role for serotonin in long-duration anxiety and not the phasic fear response implicates the BNST, as it is specifically involved in long-but not short-duration responses (Walker et al, 2009).…”

Exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging

“…Connectivity in various brain circuits can change due to experience as well (Saibeni et al, 2005). For example, exposure to early life stress is associated with impaired connectivity between the amygdala and the right ventrolateral PFC (Robinson et al, 2012b). Such structural and functional brain changes are relevant for health because they can impair the regulation of central and peripheral responses to threat, promoting the sustained threat perception that may drive chronic inflammation.…”