Dietary Tryptophan Depletion Research Articles

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers

An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.

Dietary tryptophan depletion according to body weight – A new treatment option in acute mania?

Decreased neurotransmission of serotonin (5-HT) was shown to be related to the development of depressive symptoms, whereas recent preliminary evidence suggests that acute mania may be related to a hyperserotonergic state. The reduction of central nervous 5-HT synthesis achieved by a new modification of the dietary rapid tryptophan depletion technique, with the relevant amino acids dosed according to body weight, is hypothesized by the authors to be a further option of treatment during acute mania, in particular in view of a decrease in adverse reactions, a reduced amount of amino acids needed for sufficient depletion, but also improved tolerability. However, ethical issues may limit such studies investigating this relationship in acutely manic patients, in particular in view of informed consent.

Low-Serotonin Levels Increase Delayed Reward Discounting in Humans

Previous animal experiments have shown that serotonin is involved in the control of impulsive choice, as characterized by high preference for small immediate rewards over larger delayed rewards. Previous human studies under serotonin manipulation, however, have been either inconclusive on the effect on impulsivity or have shown an effect in the speed of action-reward learning or the optimality of action choice. Here, we manipulated central serotonergic levels of healthy volunteers by dietary tryptophan depletion and loading. Subjects performed a "dynamic" delayed reward choice task that required a continuous update of the reward value estimates to maximize total gain. By using a computational model of delayed reward choice learning, we estimated the parameters governing the subjects' reward choices in low-, normal, and high-serotonin conditions. We found an increase of proportion in small reward choices, together with an increase in the rate of discounting of delayed rewards in the low-serotonin condition compared with the control and high-serotonin conditions. There were no significant differences between conditions in the speed of learning of the estimated delayed reward values or in the variability of reward choice. Therefore, in line with previous animal experiments, our results show that low-serotonin levels steepen delayed reward discounting in humans. The combined results of our previous and current studies suggest that serotonin may adjust the rate of delayed reward discounting via the modulation of specific loops in parallel corticobasal ganglia circuits.

P.1.a.007 Decision-making behaviour is influenced by tryptophan hydroxylase 2 gene

Introduction: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin (5-HT). There are two main subtypes, the TPH2 subtype which is involved in neuronal serotonin synthesis and the TPH1 subtype which is involved in serotonin synthesis in the periphery. Polymorphisms in the TPH2 gene and distinct haplotypes (combinations of single nucleotide polymorphisms (SNPs) which are inherited together) with functional effects on the TPH enzyme activity may represent risk factors for serotonergic system related psychiatric disorders. However, genetic studies of TPH2 related to depression, schizophrenia, alcoholism, drug abuse, aggression and suicidality have produced conflicting results. One possible explanation of this is that TPH2 function might relate to a more basic behavioural feature, or endophenotype, involved in many psychiatric disorders. Decision making may be defined as the ability to select an advantageous response from a range of available options. Impaired decision making, attributed to a 5-HT deficit in orbitofrontal cortex (OFC), is one candidate endophenotype for many psychiatric conditions. Previous studies demonstrated that rapid dietary tryptophan depletion – leading to reduced central serotonin function – altered the decision-making of healthy volunteers. In our study, we tested the hypothesis that TPH2 haplotype will affect decision making, in a large sample using a simple paper-pencil task. Methods: From the NewMood population study cohort we present interim data on 864 subjects who completed a pencil and paper decision making task, the 53-item Brief Symptom Checklist and for whom we have TPH2 genetic haplotype data. The task consisted of choosing between two ‘wheel of fortunelike’ alternatives: ‘A’ which provided a smaller but more likely ‘win’ and ‘B’ which gave a ‘win’ 2 times the amount with lower probability that was systematically varied. We used a repeated measure design with 4 different probability levels of winning on ‘A’. The probability of winning on ‘B’ at which the subjects valued the two trials equally (indifference point) was determined as a measure of willingness to take a risk. The HaploView software package was employed to identify htSNPs based on the genotype data of CEPH population (International HapMap Project). The chosen SNPs were genotyped using Sequenom’s massarray technology and haplotypes were generated by HelixTree. Results: TPH2 haplotypes (p = 0.003) and Anxiety scores (p = 0.001) had an independent significant effect on decision making, with more anxious subjects making less risky choices. There was no interaction between TPH2 haplotypes and Anxiety scores. Depression scores had no effect on decision making. Discussion: This study supports the role of TPH2 gene, and the 5-HT system, in risk taking behaviour. This genetic effect is independent of mood state and might be an additive factor contributing to psychiatric disorders.

Serotonin 1A Receptor Activation and Hypothermia in Humans: Lack of Evidence for a Presynaptic Mediation

The hypothermia produced by 5-HT1A agonists had initially been claimed to be caused by the activation of cell body 5-HT1A autoreceptors resulting in decreased 5-HT transmission in laboratory animals. In order to address this issue in humans, 12 healthy volunteers underwent a dietary tryptophan depletion paradigm to decrease 5-HT availability, under double-blind conditions, during which body temperature was monitored following oral administration of the 5-HT1A agonist buspirone (30 mg). In addition, plasma prolactin and growth hormone evaluations, two responses that are mediated via the direct activation of postsynaptic 5-HT1A receptors, were determined. The hypothesis was that if responses are mediated by decreased transmission at postsynaptic 5-HT1A receptors, resulting from dampened 5-HT release as a consequence of 5-HT1A autoreceptors activation, then responses to the exogenous 5-HT1A agonist should be attenuated when 5-HT availability has been markedly decreased beforehand. Buspirone produced the same significant increase in prolactin and growth hormone in the tryptophan-depleted state as in the control condition. Similarly, the degree of hypothermia produced by buspirone was not significantly different in the two experimental conditions. In conclusion, these results strongly suggest that the hypothermia and the increases in prolactin and growth hormone produced by buspirone are attributable to the enhanced activation of postsynaptic 5-HT1A receptors, and not to a decrease in 5-HT transmission resulting from the activation of the 5-HT1A cell body autoreceptors on 5-HT neurons.

Chemical neuromodulation of frontal-executive functions in humans and other animals.

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

The effects of a low tryptophan diet on brain 5 -HT metabolism and 5-HT-mediated neuroendocrine responses in the male rat

The study was undertaken to assess the effects of periods of dietary tryptophan (TRP) depletion on (i) plasma total and free TRP together with brain TRP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5- HIAA) and (ii) the prolactin (PRL) responses to the 5-HT releasing agent, D-fenfluramine (FEN), and the 5-HT agonist, m-chlorophenylpiperazine (mCPP). The TRP-deficient diet caused significant reductions in plasma total and free TRP for a short-lived period; however, it caused longer lasting and significant reductions in brain TRP, 5-HT and 5-HIAA content. Following periods of dietary TRP depletion, plasma PRL responses to FEN were significantly reduced for 14 days but had normalised by day 21. In contrast, the PRL responses to mCPP were significantly enhanced after 6 and 21 days, the response at 14 days being similar to control. The result suggests that periods of dietary invoked TRP depletion cause a deficiency of brain TRP content which subsequently leads to a fall in brain 5-HT. This is associated with a reduced PRL response to FEN and an enhanced PRL response to mCPP, the latter possibly resulting from functional up-regulation of post-synaptic 5-HT receptors.

The effects of acute dietary tryptophan depletion on schizophrenic positive and negative symptoms

Neuroactive metabolites in the kynurenine pathway of tryptophan catabolism are associated with neurodegenerative disorders. Tryptophan is transported across the blood–brain barrier and converted via the kynurenine pathway to N-formyl-l-kynurenine, which is further degraded to l-kynurenine. This metabolite can then generate a group of metabolites called kynurenines, most of which have neuroactive properties.The association of tryptophan catabolic pathway alterations with various central nervous system (CNS) pathologies has raised interest in analytical methods to accurately quantify kynurenines in body fluids. We here describe a rapid and sensitive reverse-phase HPLC–MS/MS method to quantify l-kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxy-l-kynurenine (3HK) and anthranilic acid (AA) in rat plasma. Our goal was to quantify these metabolites in a single run; given their different physico-chemical properties, major efforts were devoted to develop a chromatography suitable for all metabolites that involves plasma protein precipitation with acetonitrile followed by chromatographic separation by C18 RP chromatography, detected by electrospray mass spectrometry. Quantitation range was 0.098–100 ng/ml for 3HK, 9.8–20,000 ng/ml for KYN, 0.49–1000 ng/ml for KYNA and AA. The method was linear (r > 0.9963) and validation parameters were within acceptance range (calibration standards and QC accuracy within ±30%).

PET Studies of Presynaptic Monoamine Metabolism in Depressed Patients and Healthy Volunteers

No deranged presynaptic monoamine metabolism in the brain has been directly demonstrated in mood disorders, in spite of the rich but indirect pharmacological evidence for a decreased efficacy of monoaminergic synaptic transmission in depression, especially as for serotonin. The availability of 11C-labelled 5-hydroxytryptophan (5-HTP) and L-DOPA, the direct precursors in the synthetic pathways to serotonin and dopamine, has allowed positron emission tomographic (PET) studies in 8 healthy volunteers and 6 patients suffering from unipolar depression. Main results indicate (1) decreased uptake of [11C]5-HTP and [11C]L-DOPA over the blood-brain barrier in depression (which is not altered by dietary tryptophan depletion in healthy volunteers), and (2) an increased utilization of [11C]5-HTP (but not [11C]L-DOPA), in the lower region of the medial prefrontal cortex, mainly of the left side. This phenomenon presumably mirrors an increased synthesis of serotonin in this area and might represent a local compensatory increase in a situation of a general serotonergic hypometabolism. Analyses of interactions of both ligands between striatal and prefrontal areas suggest significantly stronger positive correlations in depression than in health, that could be interpreted as a less pronounced autonomy between brain regions in depression.

Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects

The neuroendocrine and behavioral effects of gradual dietary tryptophan (TRP) depletion, utilizing two magnitudes of a 10-day TRP-restriction diet (700 mg/day and 200 mg/day), were studied in 22 healthy subjects. The prolactin response to a 7 gm L-TRP infusion was measured prior to and on day 10 of the diet. Both diets significantly reduced fasting total plasma TRP by 15 to 20%, but only the 200 mg/day TRP diet led to an enhancement of the prolactin response to intravenous L-TRP. Female subjects demonstrated a more robust increase in plasma prolactin following L-TRP infusion pre-diet and exhibited a larger decrease in plasma TRP following dietary TRP restriction compared to males. There were no significant behavioral effects of either diet. Gradual dietary TRP depletion leads to an enhancement of the prolactin response to L-TRP infusion, suggestive of postsynaptic serotonin receptor supersensitivity.