Plasma Free Tryptophan Research Articles

Neurospecific Molecules Measured in Periphery in Humans: How Do They Correlate with the Brain Levels? A Systematic Review.

Human brain state is usually estimated by brain-specific substances in peripheral tissues, but, for most analytes, a concordance between their content in the brain and periphery is unclear. In this systematic review, we summarized the investigated correlations in humans. PubMed was searched up to June 2022. We included studies measuring the same endogenous neurospecific analytes in the central nervous system and periphery in the same subjects. Not eligible were studies of cerebrospinal fluid, with significant blood–brain barrier disruption, of molecules with well-established blood-periphery concordance or measured in brain tumors. Seventeen studies were eligible. Four studies did not report on correlation and four revealed no significant correlation. Four molecules were examined twice. For BDNF, there was no correlation in both studies. For phenylalanine, glutamine, and glutamate, results were contradictory. Strong correlations were found for free tryptophan (r = 0.97) and translocator protein (r = 0.90). Thus, only for three molecules was there some certainty. BDNF in plasma or serum does not reflect brain content, whereas free tryptophan (in plasma) and translocator protein (in blood cells) can serve as peripheral biomarkers. We expect a breakthrough in the field with advanced in vivo metabolomic analyses, neuroimaging techniques, and blood assays for exosomes of brain origin.

Tryptophan pathway catabolites (serotonin, 5-hydroxyindolacetic acid, kynurenine) and enzymes (monoamine oxidase and indole amine 2,3 dioxygenase) in patients with septic shock: A prospective observational study versus healthy controls.

Septic shock is associated with a strong inflammatory response that induces vasodilation and vascular hyporeactivity. We investigated the role for tryptophan-pathway catabolites of proinflammatory cytokines in septic shock.We prospectively included 30 patients with very recent-onset septic shock and 30 healthy volunteers. The following were assayed once in the controls and on days 1, 2, 3, 7, and 14 in each patient: plasma free and total tryptophan, platelet and plasma serotonin, total blood serotonin, urinary serotonin, plasma and urinary 5-hydroxyindolacetic acid, plasma kynurenine, monoamine oxidase activity, and total indole amine 2,3-dioxygenase activity. Organ-system failure and mortality were recorded.Compared with the healthy controls, the patients with septic shock had 2-fold to 3-fold lower total tryptophan levels throughout the 14-day study period. Platelet serotonin was substantially lower, while monoamine oxidase activity and 5-hydroxyindolacetic acid were markedly higher in the patients than in the controls, consistent with the known conversion of tryptophan to serotonin, which is then promptly and largely degraded to 5-hydroxyindolacetic acid. Plasma kynurenine was moderately increased and indole amine 2,3-dioxygenase activity markedly increased in the patients versus the volunteers, reflecting conversion of tryptophan to kynurenine. Changes over time in tryptophan metabolites were not associated with survival in the patients but were associated with the Sequential Organ Failure Assessment score and hemodynamic variables including hypotension and norepinephrine requirements.Our results demonstrate major tryptophan pathway alterations in septic shock. Marked alterations were found compared with healthy volunteers, and tryptophan metabolite levels were associated with organ failure and hemodynamic alterations. Tryptophan metabolite levels were not associated with surviving septic shock, although this result might be ascribable to the small sample size.Trial registration: ClinicalTrials.gov; No: NCT00684736; URL: www.clinicaltrials.gov.

PSIX-24 Effects of rice feeding on growth performance and protein (amino acids) metabolism in weaning piglets

Abstract This experiment was conducted to clarify the effects of feeding rice on growth performance and protein (amino acids) metabolism in weaning piglets. Sixteen weaning piglets with an average initial weight of 7.5 kg were divided into two groups. One group was fed a corn-soybean meal based diet, and the other was fed a rice-soybean meal diet. Each diet contained about 46% of corn or rice. A 2-week growth trial was conducted and growth performance, dry matter and crude protein digestibility, liver lysine-ketoglutarate reductase activity, plasma urea nitrogen, glucose, insulin, and free amino acids concentrations were measured. The average daily gain (g/d) and feed efficiency (gain/feed) in rice-fed piglets were significantly higher than those in corn-fed piglets. Average feed intake, however, was not significantly different between corn- and rice-fed piglets. Dry matter and and crude protein digestibility were not significantly different between two groups. Liver lysine-ketoglutarate reductase activity tended to be lower (P = 0.073) in rice-fed piglets than that in corn-fed piglets. Plasma urea nitrogen concentration in rice-fed piglets was significantly lower than that in corn-fed piglets. Plasma glucose and insulin concentrations were significantly higher in rice-fed piglets than those in corn-fed piglets. Plasma free valine, isoleucine, tryptophan, and glysine concentrations were significantly higher in rice-fed piglets than those in corn-fed piglets. On the other hand, plasma histidine concentration in rice-fed piglets was significantly lower than that in corn-fed piglets. In conclusion, these results clearly show that rice feeding affects the protein and amino acids metabolism and improves the growth performance in weaning piglets. Rice could be considered to be a good feedstuff for weaning piglets.

Simultaneous voltammetric determination of free tryptophan, uric acid, xanthine and hypoxanthine in plasma and urine

We have designed an improved electrochemical analysis of clinical samples in bodily fluids. The method allows reliable identification of several coexisting substances (tryptophan, uric acid, xanthine and hypoxanthine) present on different physiological levels. We prepared in situ electrogenerated graphite oxides (GrO) directly on the surface of a graphite pencil electrode. GrO presence enhances electrooxidation signals of small aromatic molecules and can shift their oxidation potentials. The oxidation potentials of tryptophan and tyrosine in their free and protein-bound forms, and free xanthine are very close to each other on common carbon-based materials. We found that free tryptophan’s oxidation signal is significantly more enhanced (about 11-times) than the free tyrosine signal (only negligibly in the given conditions). Distinguishing xanthine’s oxidation signal from that of the free tryptophan is allowed by their approximately 60 mV separation, sufficient for parallel determination by signal deconvolution. Additionally, we show that proteins containing tyrosine and/or tryptophan behave as electro-inactive and do not interfere with free amino acid determination on the GrO-modified graphite electrodes, while they strongly influence all species’ detection on other carbon-based materials. Determining all individual compounds was possible at corresponding physiological values after sole dilution of human plasma (urine) and direct measurement with no pre-separation steps.

Effects of tryptophan depletion on selective serotonin reuptake inhibitor-remitted patients with obsessive compulsive disorder.

Serotonergic antidepressants are first-line medication therapies for obsessive-compulsive disorder, however it is not known if synaptic serotonin availability is important for selective serotonin reuptake inhibitor efficacy. The present study tested the hypothesis that temporary reduction in central serotonin transmission, through acute tryptophan depletion, would result in an increase in anxiety in selective serotonin reuptake inhibitor-remitted obsessive-compulsive disorder patients. Eight patients (four males) with obsessive-compulsive disorder who showed sustained clinical improvement with selective serotonin reuptake inhibitor treatment underwent acute tryptophan depletion in a randomized, double-blind, placebo-controlled, within-subjects design, over two days one week apart. Five hours after consumption of the depleting/sham drink the participants performed a personalized obsessive-compulsive disorder symptom exposure task. Psychological responses were measured using the Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and Visual Analogue Scales. Free plasma tryptophan to large neutral amino acid ratio decreased by 93% on the depletion day and decreased by 1% on the sham day, as anticipated. Psychological rating scores as measured by Visual Analogue Scale showed a significant decrease in perceived control and increase in interfering thoughts at the time of provocation on the depletion day but not on the sham day. A measure of convergent validity, namely Visual Analogue Scale Similar to past, was significantly higher at the time of provocation on both the depletion and sham days. Both the depletion and time of provocation scores for Visual Analogue Scale Anxiety, Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and blood pressure were not significant. Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation. Acute tryptophan depletion had no effect on the Spielberger State Anxiety Inventory or Visual Analogue Scale Anxiety measures, which suggests that the mechanism of action of selective serotonin reuptake inhibitors may be different to that seen in panic, social anxiety and post-traumatic stress disorder. Successful selective serotonin reuptake inhibitor treatment of obsessive-compulsive disorder may involve the ability of serotonin to switch habitual responding to goal-directed behaviour.

The Association between Baseline Subjective Anxiety Rating and Changes in Cardiac Autonomic Nervous Activity in Response to Tryptophan Depletion in Healthy Volunteers.

The aim of this study was to investigate the influence of serotonin on anxiety and autonomic nervous system (ANS) function; the correlation between subjective anxiety rating and changes of ANS function following tryptophan depletion (TD) in healthy volunteers was examined. Twenty-eight healthy participants, consisting of 15 females and 13 males, with an average age of 33.3 years, were recruited.Baseline Chinese Symptom Checklist-90-Revised and ANS function measurements were taken. TD was carried out on the testing day, and participants provided blood samples right before and 5 hours after TD. ANS function, somatic symptoms, and Visual Analogue Scales (VASs) were determined after TD. Wilcoxon signed rank test and Spearman ρ correlation were adapted for analyses of the results.The TD procedure reduced total and free plasma tryptophan effectively. After TD, the sympathetic nervous activity increased and parasympathetic nervous activity decreased. Baseline anxiety ratings positively correlated with post-TD changes in sympathetic nervous activity, VAS ratings, and physical symptoms. However, a negative correlation with post-TD changes in parasympathetic nervous activity was found.The change in ANS function after TD was associated with the severity of anxiety in healthy volunteers. This supports the fact that the effect of anxiety on heart rate variability is related to serotonin vulnerability. Furthermore, it also shows that the subjective anxiety rating has a biological basis related to serotonin.

Abstract 1168: Impact of some common organics on cellular glycolysis and the differential survival of lung fibroblast and lung carcinoma cell lines

Abstract Tumor growth and abnormal cell survival were shown to be associated with a number of cellular metabolic abnormalities revealed by impaired oral glucose tolerance, depressed lipoprotein lipase activity leading to hypertriglyceridemia, and changes in amino acid profile as evidenced by increased plasma free tryptophan levels in patients with breast, lung, colon, stomach, and other cancers from various origins. The above findings seem to relate to or indicate a shift to non-oxidative metabolic pathways in cancer. In contrast to normal cells, cancer cells may lose the ability to utilize aerobic respiration due to either defective mitochondria or hypoxia within the tumor microenvironments. Glucose was shown to be the major energy source in cancer cells where it utilizes aerobic /anaerobic glycolysis with the resultant lactic acid formation. The role of energetic modulations and use of glycolytic inhibitors on cancer/normal cell survival is not clearly established in the literature. Therefore, the purpose of this study was to evaluate six potential glycolytic inhibitors namely, sodium ascorbate, oxalic acid, oxaloacetic acid, sodium citrate, fructose diphosphate (FDP) and sodium bicarbonate at mM concentrations on growing A549 (lung cancer) and MRC-5 (normal; human lung fibroblast) cell lines with the objective of determining their influence on cell survival. Exposed and non-exposed cells were tested with phase-contrast micro-scanning, survival/death and metabolic activity trends through MTT-assays, as well as death end-point determinations by testing re-growth on complete media and T4 cellometer counts. Results showed that oxalic acid and oxaloacetic acid both influenced the pH of the medium and resulted in differential massive cell debris within the exposure period. Sodium ascorbate, sodium citrate, sodium bicarbonate and FDP did not cause pH changes; however, they caused detectable cell disfigurement and loss of metabolic activity and survival/ death end points with the resultant death of the A549 cell line. MRC-5 cells were differentially unaffected by exposure to sodium ascorbate, sodium citrate, sodium bicarbonate, FDP and oxaloacxetic acid, underwent complete recovery and remained both attached and healthy for 6 weeks upon subculture when transferred to a new complete medium. Oxalic acid did not show differential modulation with the consequent loss of survival and death of the MRC-5 cell line. Phase contrast findings as well as the cell counts confirmed the findings of other tests. These studies show the potential for exploiting cellular metabolic differences in cancer control. Citation Format: Ibrahim O. Farah, Veshell L. Lewis, Zikri Arslan. Impact of some common organics on cellular glycolysis and the differential survival of lung fibroblast and lung carcinoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1168. doi:10.1158/1538-7445.AM2015-1168

Effects of supplementation with branched chain amino acids and ornithine aspartate on plasma ammonia and central fatigue during exercise in healthy men.

Our previous studies showed only slight improvement in central fatigue, measured indirectly by psychomotor performance, after branched chain amino acids (BCAA) supplementation during various efforts in healthy men. It is hypothesised that hyperammonaemia resulting from amino acids metabolism may attenuate their beneficial effect on psychomotor performance; therefore, the L-ornithine L-aspartate (OA) as an ammonia decreasing agent was used. The aim of this study was to investigate the effectiveness of oral BCAA + OA supplementation to reduce plasma ammonia concentration and enhance psychomotor performance during exhaustive exercise in healthy men. Eleven endurance-trained men (mean age 32.6 ± 1.9 years) performed two sessions (separated by one week) of submaximal cycloergometer exercise for 90 minutes at 60% of maximal oxygen uptake followed by graded exercise until exhaustion with randomised, double-blind supplementation with a total of 16 g BCAA and 12 g OA (BCAA + OA trial) or flavoured water (placebo trial). Before exercise, during both efforts and after 20 minutes of recovery multiple choice reaction time (MCRT), perceived exertion, heart rate and oxygen uptake were measured and venous blood samples were taken for plasma leucine, valine, isoleucine, ornithine, aspartate, free tryptophan (fTRP), ammonia, lactate and glucose determination. After ingestion, during both efforts and after 20 minutes of recovery the plasma concentrations of all supplemented amino acids were significantly increased, while the fTRP/BCAA ratio decreased in the BCAA + OA trial more than in the placebo trial. At the end of graded exercise plasma fTRP was lower and MCRT shorter in BCAA + OA than in the placebo trial (p < 0.05). At the end of prolonged exercise the plasma ammonia concentration was higher in BCAA + OA than in placebo trial (p < 0.05). Decreases in plasma ammonia during recovery were significantly higher in BCAA + OA than in the placebo trial. Plasma ammonia positively correlated with the total plasma BCAA and MCRT only in the BCAA + OA trial. The fTRP/BCAA ratio positively correlated with MCRT only in the placebo trial. Supplementation with BCAA and OA is a useful way to improve MCRT during high-intensity exercise and accelerate the elimination of ammonia at the recovery stage after exercise in healthy young men.

Mechanisms of the pellagragenic effect of leucine: stimulation of hepatic tryptophan oxidation by administration of branched-chain amino acids to healthy human volunteers and the role of plasma free tryptophan and total kynurenines.

The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05–6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynure-nines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed.

Acute tryptophan depletion does not improve endurance cycling capacity in a warm environment

Newsholme's theory of central fatigue suggests that acute tryptophan depletion should improve endurance exercise capacity in a warm environment by reducing serotonergic activity in the brain. Eight males cycled to volitional exhaustion at 55 % VO(2) peak in 30.1 ± 0.5 °C and 30 ± 7 % relative humidity on two separate occasions, after consuming either an amino acid load to deplete their circulating tryptophan concentration (TD), or a control amino acid load (CON). Blood samples were taken before ingesting the amino acids, before the start of exercise, every 15 min during exercise and at the point of exhaustion. Heart rate (HR), core (Tc) and skin (Tsk) temperatures and ratings of perceived exertion (RPE) and thermal comfort (TC) were also monitored every 10 min during exercise. Plasma tryptophan (P = 0.003) and free tryptophan (P < 0.001) concentrations, and the free tryptophan to branched-chain amino acid ratio (P = 0.004) were all lower on the TD trial than on the CON trial. There was no difference in endurance exercise capacity (TD 99.2 ± 24.4 min as compared to CON 108.4 ± 21.6 min; P = 0.088). There was a tendency for HR (P = 0.053) and Tc (P = 0.069) to be higher on the TD trials. There were no differences for any of the other parameters. Endurance cycling capacity in a warm environment is not improved by acute tryptophan depletion, suggesting tryptophan availability is not a significant factor in the development of fatigue in such situations.

Acute treatment with fluvoxamine elevates rat brain serotonin synthesis in some terminal regions: An autoradiographic study

A considerable body of evidence indicates the involvement of the neurotransmitter serotonin (5-HT) in the pathogenesis and treatment of depression. The acute effect of fluvoxamine, on 5-HT synthesis rates was investigated in rat brain regions, using α-(14)C-methyl-L-tryptophan as a tracer. Fluvoxamine (25 mg/kg) and saline (control) were injected intraperitoneally, one hour before the injection of the tracer (30 μCi). There was no significant effect of fluvoxamine on plasma free tryptophan. After Benjamini-Hochberg False Discovery Rate correction, a significant decrease in the 5-HT synthesis rate in the fluvoxamine treated rats, was found in the raphe magnus (-32%), but not in the median (-14%) and dorsal (-3%) raphe nuclei. In the regions with serotonergic axon terminals, significant increases in synthesis rates were observed in the dorsal (+41%) and ventral (+43%) hippocampus, visual (+38%), auditory (+65%) and parietal (+37%) cortex, and the substantia nigra pars compacta (+56%). There were no significant changes in the 5-HT synthesis rates in the median (+11%) and lateral (+24%) part of the caudate-putamen, nucleus accumbens (+5%), VTA (+16%) or frontal cortex (+ 6%). The data show that the acute administration of fluvoxamine affects 5-HT synthesis rates in a regionally specific pattern, with a general elevation of the synthesis in the terminal regions and a reduction in some cell body structures. The reasons for the regional specific effect of fluvoxamine on 5-HT synthesis are unclear, but may be mediated by the presynaptic serotonergic autoreceptors.

Effect of low-dose acute tryptophan depletion on the specificity of autobiographical memory in healthy subjects with a family history of depression

Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to reduce specificity of autobiographical memory in patients who have recovered from a depressive episode. This study aimed to explore if reduced specificity of autobiographical memory with LD-ATD is common to other groups of individuals at risk of depression, specifically a healthy population with a family history of depression. Nineteen healthy young adults with at least one first-degree relative with a history of major depression were recruited. LD-ATD drinks containing 1.15 g of tryptophan (T+) or no tryptophan (T−) were administered on two separate occasions, in a double blind random order crossover design. The Autobiographical Memory Test (AMT) was administered 5 h after drink administration. Analysis of variance revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. There was no within-subject main effect of LD-ATD on the memory task. However, there was a main effect of order of drink. Exploratory analysis of visit 1 data indicated a large between-subject effect (d=1.4) of LD-ATD on AMT with T− associated with less specificity in response to negative cue words (F(1, 17)08.71, p=0.009). Similar to findings following recovery from depression, LD-ATD can reduce specificity of AMT in the absence of lowered mood in healthy individuals with a strong family history of depression. These findings may reflect a 5-HT-dependent cognitive vulnerability to depression in different populations and warrant further research.

Total and free-plasma tryptophan concentrations in rheumatoid disease.

Abstract It has been proposed (McArthur, Dawkins &amp; others, 1971) that human connective tissue diseases may arise from modifications in the binding characteristics of the plasma proteins. McArthur, Smith &amp; Freeman (1972) presented evidence that human serum contains a substance that possesses anti-inflammatory activity and is bound to circulating proteins. Furthermore, it has been suggested that, in patients with active rheumatoid arthritis, the anti-inflammatory substance is bound to an abnormal extent to the plasma proteins and that the clinically useful antirheumatic drugs act by re-establishing the bound: free ratio to that in the normal subject (Smith &amp; Dawkins, 1971). There is evidence that the behaviour of L-tryptophan mimics that of the hypothetical substance which protects susceptible tissues against chronic inflammatory insults. All the clinically useful antirheumatic agents were found to displace L-tryptophan from human plasma in vitro (McArthur, Dawkins &amp; Smith, 1971) but not so other drugs which bind to plasma proteins to an equivalent extent but have no demonstrable antirheumatic effects (Smith, Dawkins &amp; McArthur, 1971). In patients with rheumatoid arthritis receiving drug therapy the percentage of L-tryptophan bound to plasma proteins is significantly reduced but increases when drug administration is stopped (McArthur, Dawkins &amp; others, 1971).

Biochemical Markers of Possible Immunodepression in Military Training in Harsh Environments

Prolonged, exhaustive exercise frequently leads to an increased incidence of upper respiratory tract illness (URTI) which is linked to transient immunodepression. We investigated potential biochemical markers of stress and fatigue, and URTI symptoms as a surrogate of immunodepression, in US Marines undergoing intensive winter training at altitude. Selected plasma amino acids and leptin (p[Lep]) were measured as possible markers of fatigue and immunodepression, together with nonesterified fatty acids (p[NEFA]) and total antioxidant capacity (p[TAC]). Changes were observed in plasma free tryptophan (p[FT]), p[Gln], p[Lep], p[NEFA], p[TAC] but not branched chain amino acids (p[BCAA]). p[FT] decreased markedly. Resting p[Gln] decreased overall after one month at altitude. p[Gln] routinely decreases 1-2 hrs after prolonged exercise. Importantly, we observed early morning decreases in p[Gln], suggesting a cumulative effect of prolonged activity, stress, and fatigue. Concomitantly, individuals with highest illness scores had the greatest p[Gln] decrease: low p[Gln] may therefore be associated with a diminished stress tolerance.

Brain serotonergic and dopaminergic modulators, perceptual responses and endurance exercise performance following caffeine co-ingested with a high fat meal in trained humans

BackgroundThe present study examined putative modulators and indices of brain serotonergic and dopaminergic function, perceptual responses, and endurance exercise performance following caffeine co-ingested with a high fat meal.MethodsTrained humans (n = 10) performed three constant-load cycling tests at 73% of maximal oxygen uptake (VO2max) until exhaustion at 10°C remove space throughout. Prior to the first test, subjects consumed a 90% carbohydrate meal (Control trial) and for the remaining two tests, a 90% fat meal with (FC trial) and without (F trial) caffeine.ResultsTime to exhaustion was not different between the F and FC trials (P > 0.05); [Control trial: 116(88-145) min; F trial: 122(96-144) min; FC trial: 127(107-176) min]. However, leg muscular discomfort during exercise was significantly lower on the FC relative to F trial (P < 0.01). There were no significant differences between F and FC trials in key modulators and indices of brain serotonergic (5-HT) and dopaminergic (DA) function [(i.e. plasma free and total tryptophan (Trp), tyrosine (Tyr), large neutral amino acids (LNAA), Trp:LNAA ratio, free-Trp:Tyr ratio, total Trp:Tyr ratio, and plasma prolactin] (P > 0.05) with the exception of plasma free-Trp:LNAA ratio which was higher at 90 min and at exhaustion during the FC trial (P < 0.05).ConclusionsNeither brain 5-HT nor DA systems would appear to be implicated in the fatigue process when exercise is performed without significant thermoregulatory stress, thus indicating fatigue development during exercise in relatively cold temperatures to occur predominantly due to glycogen depletion.

Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder

Serotonergic antidepressants [selective serotonin reuptake inhibitor (SSRI)] are first-line treatments for generalised anxiety disorder (GAD); however, it is not known if synaptic serotonin (5-HT) availability is important for SSRI efficacy. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion (ATD), would reverse the therapeutic effect of the SSRIs in GAD patients. Twelve patients (six males) with GAD, who showed sustained clinical improvement with SSRI treatment, underwent ATD in a double-blind, placebo-controlled, within-subjects design over 2 days, 1 week apart. At the peak time of depletion, the participants inhaled 7.5% CO2 and air in random order for at least 12 min each. Psychological responses were measured using the Spielberger State Anxiety Inventory (STAI-S) and GAD-symptom visual analogue scales (VASs; e.g., worry and tense) and Profile of Mood States. Free plasma tryptophan to large neutral amino acid (LNAA) ratio decreased by 92% on the depletion day and decreased by 2% on the control day. Irrespective of depletion condition, 7.5% CO(2) inhalation significantly increased STAI-S and GAD-related VAS scores (all p < 0.05) compared with air inhalation. ATD had no effect on any of these measures despite the substantial reduction in free tryptophan/LNAA ratio. Although SSRIs treat GAD effectively, the present results suggest that the mechanism of action is different to that seen in panic, social anxiety, and post-traumatic stress disorders. Successful SSRI treatment of GAD may involve long-term receptor changes or alterations in other neurotransmitter systems downstream of serotonin.

Plasma free tryptophan revisited: what you need to know and do before measuring it

Plasma free tryptophan (Trp) is an important peripheral parameter widely used by psychopharmacologists to assess Trp entry into the brain for cerebral serotonin synthesis, although, along with total Trp, it can give much more information on Trp metabolism and disposition. Plasma free Trp is, however, a labile parameter easily influenced by a great many modulators, including fasting, food intake, many prescribed and over the counter medications, consumption of alcoholic and of common hot beverages, illicit drug use, some hormones, exercise and mild stressors. Interpretation of changes in plasma free Trp requires appropriate preparation of ultrafiltrates from freshly isolated plasma or serum, accurate analytical methodology and awareness of the multitude of physiological and pharmacological modulators of its concentration. This article highlights these points and makes recommendations aimed at avoiding pitfalls in studies involving this parameter.

Repeated Administration of Fresh Garlic Increases Memory Retention in Rats

Garlic (Allium sativum) is regarded as both a food and a medicinal herb. Increasing attention has focused on the biological functions and health benefits of garlic as a potentially major dietary component. Chronic garlic administration has been shown to enhance memory function. Evidence also shows that garlic administration in rats affects brain serotonin (5-hydroxytryptamine [5-HT]) levels. 5-HT, a neurotransmitter involved in a number of physiological functions, is also known to enhance cognitive performance. The present study was designed to investigate the probable neurochemical mechanism responsible for the enhancement of memory following garlic administration. Sixteen adult locally bred male albino Wistar rats were divided into control (n = 8) and test (n = 8) groups. The test group was orally administered 250 mg/kg fresh garlic homogenate (FGH), while control animals received an equal amount of water daily for 21 days. Estimation of plasma free and total tryptophan (TRP) and whole brain TRP, 5-HT, and 5-hydroxyindole acetic acid (5-HIAA) was determined by high-performance liquid chromatography with electrochemical detection. For assessment of memory, a step-through passive avoidance paradigm (electric shock avoidance) was used. The results showed that the levels of plasma free TRP significantly increased (P < .01) and plasma total TRP significantly decreased (P < .01) in garlic-treated rats. Brain TRP, 5-HT, and 5-HIAA levels were also significantly increased following garlic administration. A significant improvement in memory function was exhibited by garlic-treated rats in the passive avoidance test. Increased brain 5-HT levels were associated with improved cognitive performance. The present results, therefore, demonstrate that the memory-enhancing effect of garlic may be associated with increased brain 5-HT metabolism in rats. The results further support the use of garlic as a food supplement for the enhancement of memory.

Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain

In human subjects, the acute tryptophan (TRP) depletion (ATD) paradigm has been shown to have effects on mood and cognition. It is assumed that these effects are mediated through the serotonin system. In this study, we have examined the effects of ATD on the central concentrations of the monoamine transmitters, noradrenaline (NA) and dopamine (DA) as well as on serotonin (5-HT). Effects on NA and DA could also affect mood and cognition. Following oral administration of TRP-containing (TRP+) and TRP-free (TRP-) amino acid mixtures, neurotransmitter concentrations and free plasma TRP concentrations were determined by High Performance Liquid Chromatography (HPLC) with electrochemical detection. Free plasma TRP was significantly and substantially reduced (79%) in rats given a TRP- amino acid mixture when compared with those given a TRP+ mixture. ATD also significantly decreased 5-HT and 5-hydroxyindolacetic acid in the frontal cortex, remaining cortex and hippocampus, but did not significantly reduce these in the striatum. Furthermore, ATD did not significantly alter the concentration of NA and DA in any brain region examined. This study demonstrates that the administration of a TRP- amino acid mixture in rats can reduce free plasma TRP to levels comparable to those reported in human studies. These results indicate that behavioural and cognitive changes produced by ATD in preclinical or clinical studies are likely to be due to specific effects on the serotonergic system.

Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation

BackgroundThe present experiment examined the responses of peripheral modulators and indices of brain serotonin (5-HT) and dopamine (DA) function and their association with perception of effort during prolonged exercise in the heat after creatine (Cr) supplementation.MethodsTwenty one endurance-trained males performed, in a double-blind fashion, two constant-load exercise tests to exhaustion at 63 ± 5% O2 max in the heat (ambient temperature: 30.3 ± 0.5 °C, relative humidity: 70 ± 2%) before and after 7 days of Cr (20 g·d-1 Cr + 140 g·d-1 glucose polymer) or placebo (Plc) (160 g·d-1 glucose polymer) supplementation.Results3-way interaction has shown that Cr supplementation reduced rectal temperature, heart rate, ratings of perceived leg fatigue (P < 0.05), plasma free-tryptophan (Trp) (P < 0.01) and free-Trp:tyrosine ratio (P < 0.01) but did not influence the ratio of free-Trp:large neutral amino acids or contribute in improving endurance performance (Plc group, n = 10: 50.4 ± 8.4 min vs. 51.2 ± 8.0 min, P > 0.05; Cr group, n = 11: 47.0 ± 4.7 min vs. 49.7 ± 7.5 min, P > 0.05). However, after dividing the participants into "responders" and "non-responders" to Cr, based on their intramuscular Cr uptake, performance was higher in the "responders" relative to "non-responders" group (51.7 ± 7.4 min vs.47.3 ± 4.9 min, p < 0.05).Conclusionalthough Cr influenced key modulators of brain 5-HT and DA function and reduced various thermophysiological parameters which all may have contributed to the reduced effort perception during exercise in the heat, performance was improved only in the "responders" to Cr supplementation. The present results may also suggest the demanding of the pre-experimental identification of the participants into "responders" and "non-responders" to Cr supplementation before performing the main experimentation. Otherwise, the possibility of the type II error may be enhanced.