The Effects of Acute Tryptophan Depletion on Brain Activation During Cognition and Emotional Processing in Healthy Volunteers

Evers, Elisabeth A. T.; Sambeth, Anke; Ramaekers, Johannes G.; Riedel, Wim J.; Veen, Frederik M. van der

doi:10.2174/138161210791293060

Cited by 28 publications

(19 citation statements)

References 114 publications

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“…Furthermore, impaired reversal learning and perseveration have also been reported following acute tryptophan and 5-HT depletion in humans and other primates (Clarke et al, 2004;Evers et al, 2010). In line with this, the 5-HT precursor 5HTP or the 5HT 2C preferring receptor agonist CP809.101 improved cognitive flexibility and reversal learning in Tph2-KI mice (Supplementary Table S1).…”

Section: Discussionsupporting

confidence: 60%

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Del’Guidice

Lemay

Lemasson

et al. 2013

Neuropsychopharmacol

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Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT 2C receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT 2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

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Section: Discussionsupporting

confidence: 60%

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Del’Guidice

Lemay

Lemasson

et al. 2013

Neuropsychopharmacol

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“…An amino acid load devoid of tryptophan is administered, inducing hepatic protein synthesis which depletes circulating tryptophan. Furthermore, the increase in large neutral amino acids competes with the transport of reduced levels of tryptophan across the blood–brain barrier via the large neutral amino acid transporter (Hood et al ., ; Evers et al ., ). The control condition is identical except the amino acid load contains tryptophan.…”

Section: Methodsmentioning

confidence: 97%

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

Trotter

McGlone

McKie

et al. 2016

Eur J of Neuroscience

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C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4 h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. In addition, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were similar across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function.

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“…The principal source of serotonin is in the raphe nuclei in the midbrain. The influence of serotonin (5-HT) manipulation on emotional state and depression patients has been studied through tryptophan manipulation (Morris et al, 1999; Roiser et al, 2009; Evers et al, 2010). Following tryptophan depletion, habenula blood flow increases significantly in remitted major depressive disorder patients when subject to emotional stimuli (Roiser et al, 2009).…”

Section: Habenula and Behaviors Associated With Chronic Painmentioning

confidence: 99%

Unmasking the mysteries of the habenula in pain and analgesia

Shelton

Becerra

Borsook

2012

Progress in Neurobiology

104

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The habenula is a small bilateral structure in the posterior–medial aspect of the dorsal thalamus that has been implicated in a remarkably wide range of behaviors including olfaction, ingestion, mating, endocrine and reward function, pain and analgesia. Afferent connections from forebrain structures send inputs to the lateral and medial habenula where efferents are mainly projected to brainstem regions that include well-known pain modulatory regions such as the periaqueductal gray and raphe nuclei. A convergence of preclinical data implicates the region in multiple behaviors that may be considered part of the pain experience including a putative role in pain modulation, affective, and motivational processes. The habenula seems to play a role as an evaluator, acting as a major point of convergence where external stimuli is received, evaluated, and redirected for motivation of appropriate behavioral response. Here, we review the role of the habenula in pain and analgesia, consider its potential role in chronic pain, and review more recent clinical and functional imaging data of the habenula from animals and humans. Even through the habenula is a small brain structure, advances in structural and functional imaging in humans should allow for further advancement of our understanding of its role in pain and analgesia.

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The Effects of Acute Tryptophan Depletion on Brain Activation During Cognition and Emotional Processing in Healthy Volunteers

Cited by 28 publications

References 114 publications

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

Unmasking the mysteries of the habenula in pain and analgesia

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