Oxytocinergic modulation of stress-associated amygdala-hippocampus pathways in humans is specially mediated by serotonergic mechanisms

Background: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting state fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. Methods: We employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD+) or the corresponding placebo-control protocols (ATD-) before the administration of intranasal OXT or placebo intranasal spray, respectively. Results: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD+. In the absence of OXT or 5-HT modulation this pathway was associated with self-reported stress perception in everyday life, while an OXT-induced modulation of this pathway was following ATD- pre-treatment. Conclusions: Together, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.

Perseverative behavior under uncertainty is enhanced by tryptophan depletion but diminished with subclinical obsessive–compulsive symptoms

Serotonin is critically involved in flexible decision-making, yet the preponderance of evidence comes from non-human studies. Many insights about the serotonin's function have come from the technique of dietary acute tryptophan depletion (ATD). However, it is unclear whether ATD modulates choice behavior during probabilistic reversal learning (PRL), a widely used model of behavioral flexibility with significant translational and clinical value. To determine whether ATD affects latent choice tendencies, we applied computational models of reinforcement learning to PRL data from healthy human volunteers (n = 62; 29 females) who had received either ATD or placebo in a randomized, double-blind, placebo-controlled procedure. A secondary objective was to ascertain how model parameters related to clinically relevant self-report questionnaires. ATD did not affect the updating ("learning rates") or deployment ("reinforcement sensitivity") of value representations driving choice. However, ATD increased "stimulus stickiness", the tendency to choose a previously chosen visual stimulus again, regardless of reinforcement--a pattern seen in stimulant use disorder (SUD). Greater subclinical obsessive-compulsive symptoms were associated with lower stimulus stickiness, a pattern seen in clinically diagnosed obsessive-compulsive disorder (OCD). Low reinforcement sensitivity was instead related to intolerance of uncertainty and symptoms of depression and anxiety. Individuals with higher trait impulsivity showed lower reward and higher punishment learning rates, which parallels findings in SUD. Collectively, these results point to a role for serotonin in compulsive tendencies. They underscore the utility of computational modelling in illuminating the microstructure of behavior, which could point towards new markers of vulnerability to psychopathology.

Acute tryptophan depletion in healthy subjects increases preferences for negative reciprocity

Reciprocity motivates to reward those who are kind (= positive reciprocity) and to punish those who are unkind (= negative reciprocity). The neurotransmitter serotonin (5-HT) modulates human behavior in numerous social situations, such as retaliation in response to perceived unfairness. In a placebo-controlled study, we used acute tryptophan depletion (ATD) to investigate the influence of available serotonin on choice behavior and reciprocity in the Hawk-Dove game. This game illustrates a conflict situation and incorporates two potential strategies: the cooperative Dove strategy and the uncooperative, more aggressive Hawk strategy. After strategic choices, we elicited the subjects’ expectations (= beliefs) regarding the opponent’s choices and controlled for risk preferences and current mood. We defined strategy choices as negative reciprocity when the participants opted for Hawk in response to an expected Hawk. We hypothesized that the ATD-induced reduction of 5-HT availability would increase participants’ preferences for negative reciprocity. Generalized estimating equations reveal no significant main effect of ATD on assessed belief, mood, or risk attitude. But assessment of ATD’s marginal effects over beliefs suggests that ATD significantly increases the tendency for negative reciprocity, whereas positive reciprocity (Dove in response to an expected Dove) is unaffected. We could therefore demonstrate that 5-HT availability mediates (negative) reciprocal behavior in social decision-making.

Effects of tryptophan depletion on anxiety, a systematic review

Vulnerability markers for onset of anxiety disorders are scarce. In depression, patients at risk tend to respond with a negative mood to ‘acute tryptophan depletion’ (ATD), while healthy volunteers and current patients do not. The serotonergic system thus provides indications for vulnerability for depression. It is unknown whether ATD reveals vulnerability in anxiety too. This study systematically reviews the effects of ATD on anxiety and assesses whether challenging anxiety modifies the response. PubMed, Embase and PsychInfo were systematically searched up to April 2019 for studies in which (1) healthy volunteers or patients with a (remitted) anxiety disorder underwent ATD and (2) levels of anxiety were reported. In total, 21 studies were included. Studies conducted in healthy volunteers (n = 13), and patients with a remitted (n = 6) or current (panic, social or generalised) anxiety disorder (n = 4). Studies were mostly of poor quality and heterogeneous regarding population, challenge test used and outcome measures. ATD did not consistently affect anxiety in any of the groups. Moreover, a challenge test after ATD (n = 17 studies) did not consistently provoke anxiety in healthy volunteers or remitted patients. A 35% CO2 challenge did consistently increase anxiety in patients with a current panic disorder (PD). To conclude, this systematic review found no clear indications that ATD provokes anxiety in those at risk for anxiety disorders. Hence, unlike in depression, ATD does not indicate vulnerability to develop an anxiety disorder. Because included studies were heterogeneous and mostly of poor quality, there is an urgent need for high quality research in homogeneous samples.

The Tryptophan System in Cocaine-Induced Depression

Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in cocaine use disorder (CUD). The comorbid MDD might be primary-MDD (CUD-primary-MDD) or cocaine-induced MDD (CUD-induced-MDD), and their accurate diagnoses and treatment is a challenge for improving prognoses. This study aimed to assess the tryptophan/serotonin (Trp/5-HT) system with the acute tryptophan depletion test (ATD), and the kynurenine pathway in subjects with CUD-primary-MDD, CUD-induced-MDD, MDD and healthy controls. The ATD was performed with a randomized, double-blind, crossover, and placebo-controlled design. Markers of enzymatic activity of indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase, kynurenine aminotransferase (KAT) and kynureninase were also established. Following ATD, we observed a decrease in Trp levels in all groups. Comparison between CUD-induced-MDD and MDD revealed significant differences in 5-HT plasma concentrations (512 + 332 ng/mL vs. 107 + 127 ng/mL, p = 0.039) and the Kyn/5-HT ratio (11 + 15 vs. 112 + 136; p = 0.012), whereas there were no differences between CUD-primary-MDD and MDD. Effect size coefficients show a gradient for all targeted markers (d range 0.72–1.67). Results suggest different pathogenesis for CUD-induced-MDD, with lower participation of the tryptophan system, probably more related to other neurotransmitter pathways and accordingly suggesting the need for a different pharmacological treatment approach.

Effects of Acute Tryptophan Depletion on Human Taste Perception

Taste perception has been reported to vary with changes in affective state. Distortions of taste perception, including blunted recognition thresholds, intensity and hedonic ratings have been identified in those suffering from depressive disorders. Serotonin is a key neurotransmitter implicated in the aetiology of anxiety and depression; systemic and peripheral manipulations of serotonin signalling have previously been shown to modulate taste detection. However, the specific effects of central serotonin function on taste processing have not been widely investigated. Here, in a double-blind placebo-controlled study, acute tryptophan depletion was used to investigate the effect of reduced central serotonin function on taste perception. 25 female participants aged 18-28 attended the laboratory on 2 occasions at least 1 week apart. On one visit they received a tryptophan depleting drink and on the other a control drink was administered. Approximately 6 hours after drink consumption they completed a taste perception task which measured detection thresholds and supra-threshold perceptions of the intensity and pleasantness of four basic tastes (sweet, sour, bitter and salt). While acutely reducing central levels of serotonin had no effect on the detection thresholds of sweet, bitter or sour tastes it significantly enhanced detection of salt. For supra-threshold stimuli, acutely reduced serotonin levels significantly enhanced the perceived intensity of both bitter and sour tastes and blunted pleasantness ratings of bitter quinine. These findings show manipulation of central serotonin levels can modulate taste perception and are consistent with previous reports that depletion of central serotonin levels enhances neural and behavioural responsiveness to aversive signals.

Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine

BackgroundAutism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occuring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved in both regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) ‘normalizes’ differences in brain function during performance of EF tasks. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. MethodWe conducted a pharmacological magnetic resonance imaging (phMRI) study to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during during two EF tasks (of response inhibition and sustained attention) in 38 adult males; 19 with ASD and 19 matched controls. ResultsUnder placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibtion regions including inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were ‘normalized’ during response inhibition in inferior frontal and premotor cortices.LimitationsOur sample only consisted of high functioning male adults. Therefore, our findings may not be generalizable to other autistic subgroups (e.g. children or women). ConclusionsOur findings provide the first evidence that tianeptine can ‘normalize’ atypical brain activation during EF in adults with ASD. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine; and if it improves clinical symptoms.

Oxytocinergic modulation of threat-specific amygdala sensitization in humans is critically mediated by serotonergic mechanisms

BackgroundOverarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems. Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking.MethodsTo determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/ desensitization, we conducted a parallel-group randomized placebo-controlled double-blind experiment during which n = 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD, TRYP-) or the corresponding placebo-control protocols before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threat-specific amygdala reactivity towards threatening stimuli (angry faces) as assessed by fMRI served as the primary outcome.ResultsNo treatment main or interaction effects on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with TRYP-.ConclusionsThe present findings provide the first evidence for a role of OXT in threat-specific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system. OXT may have a therapeutic potential to facilitate amygdala desensitization and adjunct up-regulation of 5-HT neurotransmission may facilitate OXT’s anxiolytic potential.The trial was preregistered on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03426176, ID NCT03426176)