Plasma Free Tryptophan Research Articles

Free tryptophan/large neutral amino acids ratios in blood plasma do not predict cerebral spinal fluid tryptophan concentrations in interleukin-1-induced anorexia

Peripheral administration of interleukin-1 (IL-1) reduces food intake and affects brain serotonergic activity, suggesting a causal relationship. Furthermore, IL-1 increases the brain concentrations of the serotonin precursor, tryptophan (TRP), by unclear mechanism(s). We aimed at confirming the link between IL-1 administration, raised brain TRP concentrations and the development of anorexia, and at investigating the mechanisms of TRP entry into the brain. Thirty adult, overnight fasted Sprague–Dawley rats were randomly assigned to i.p. injections of 1 μg/kg BW of IL-1α ( n = 10) or vehicle ( n = 10), or to pair-feeding with IL-1 animals ( n = 10). After 2 h, food intake, blood plasma concentrations of total TRP, free TRP, large neutral amino acids (LNAA; competing with TRP for brain entry) were measured. Cerebral spinal fluid (CSF) TRP concentrations were also measured. TRP brain availability was assessed by calculating the plasma ratio free TRP/LNAA. Following IL-1 injection, food intake significantly declined in IL-1 rats, which was paralleled by decreased plasma free TRP and increased plasma LNAA. Despite a decrease in the free TRP/LNAA ratios in plasma, IL-1 significantly increased concentrations of TRP in CSF. These data show that the acute peripheral administration of IL-1 induces anorexia and raises CSF TRP levels. Considering the possible role of the raised CSF TRP in influencing brain serotonin activity, it is postulated that increased serotonergic neurotransmission could be involved in IL-1 induced anorexia.

Effects of elevated plasma tryptophan on brain activation associated with the Stroop task

Central fatigue, such as that found in chronic fatigue syndrome, is a state in which cognition and action require increasing effort and performance is impaired without evidence for reduced peripheral motor responsiveness. Previous studies identified functional changes in subcortical regions in patients who experience central fatigue but did not address neural correlates of the subjective experience of fatigue. This study investigated responses to acute tryptophan feeding (after administration of 30 mg/kg body mass) using functional magnetic resonance imaging to investigate neural correlates of central fatigue during a cognitively demanding exercise, the counting Stroop task. In a double-blind, cross-over study, eight subjects ingested L: -tryptophan (Trp) or placebo (Plac) on two separate test days. Neutral (N) and interference (I) Stroop tasks were carried out. Plasma-free tryptophan (p[FT]) increased tenfold after L: -Trp administration (P < 0.01). Although reaction times were longer after Trp (mean+/-SD, Plac-Neut 669 +/- 163 ms, I 715 +/- 174 ms, P < 0.01; Trp-Neut 712 +/- 193 ms, I 761 +/- 198 ms, P < 0.05), the Stroop effect was not significantly different between Plac and Trp. L: -Trp administration was associated with relatively decreased activation in regions, including the left postcentral, angular, inferior frontal, and the lateral orbital gyri and the inferior frontal sulcus relative to Plac. Relatively increased activation was found after Trp in the left precuneus and in the posterior cingulate gyrus. Thus, Trp administration before the Stroop task caused distributed functional changes in primary sensory and in multimodal neocortex, including changes in a brain region, the activity of which has been shown previously to vary with conscious awareness (precuneus). Previous reports suggest that primary mechanisms of central fatigue may be predominantly subcortical. The present results demonstrate that neocortical activity changes are also found. Whether this activity contributes to the primary mechanisms underlying central fatigue or not, the neocortical activity changes may provide an index of the conscious experience.

Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized. The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT(1A) and 5-HT(2A) receptor binding in the rat. TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography. Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT(1A) binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT(1A) binding (frontal cortex, remaining cortex and hippocampus) or 5-HT(2A) binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT(2A) binding or postsynaptic 5-HT(1A) binding. Furthermore, 3-week CTD did not significantly alter 5-HT(1A) binding but significantly increased cortical 5-HT(2A) binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT(2A)-receptor binding. ATD-induced reduction in somatodendritic 5-HT(1A) autoreceptor binding may represent an intrinsic 'homeostatic response' reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT(2A) receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.

Acute Tryptophan Depletion Alters Gastrointestinal and Anxiety Symptoms in Irritable Bowel Syndrome

To assess the effect of acute changes in serotonin (5-HT) synthesis using the acute tryptophan depletion (ATD) paradigm on gastrointestinal (GI) and mood symptoms in irritable bowel syndrome (IBS). In a randomized double-blind crossover study, 29 subjects (18 patients with ROME II defined IBS and 11 age-matched controls) were studied under ATD and acute tryptophan increase (ATI) conditions. GI symptoms, mood and anxiety ratings, as well as plasma tryptophan concentrations were measured. Total (and free) plasma tryptophan concentrations decreased on the ATD day in patients (73%[82%]) and controls (73%[80%]), and increased on the ATI day in patients (59%[143%]) and controls (61%[381%]). Compared with the ATD day, IBS patients reported more GI symptoms on the ATI day at +210 (p < 0.001) and at +270 (p < 0.05) min post drink. IBS patients also reported less anxiety on the ATI day compared with the ATD day at +270 min (p < 0.001). ATD and ATI did not affect these ratings in control participants. IBS patients had a lower mood compared with controls (p < 0.05), but this did not differ between the ATI and ATD days in either group. IBS patients' GI and anxiety responses to changes in tryptophan load differ from controls. This suggests a difference in serotonergic functioning between these two groups and provides evidence to support the hypothesis that 5-HT dysfunction is involved in IBS.

The Effect of Supplementation with Branched-Chain Amino Acids on Cognitive Function in Active Dogs

A previous study has shown that human athletes given branched-chain amino acids (BCAA) in the form of a drink before and during exercise performed better on complex cognitive tests following exercise (1). The athletes were given a mixture of BCAA (40% valine, 35% leucine, and 25% isoleucine) in a 7% carbohydrate solution. The total amount of BCAA supplied to the subjects was 5.3 g. The athletes were taking part in a 30-km cross-country race and were asked to perform a variety of cognitive tasks and also to give blood samples before and after the race. The blood samples were necessary for measuring plasma free-tryptophan and plasma glucose concentrations. It is suggested that exercise increases the plasma concentration of tryptophan, which competes with BCAA for a common transport mechanism for entry to the brain. This increased concentration ratio would be expected to lead to an increased rate of transport of tryptophan into the brain, increased brain concentration, and hence increased serotonin (5-hydroxytrptamine, 5-HT). Studies with rats have shown that an increase in the concentration of 5-HT in the brain is associated with sleep as well as reduced levels of aggression (2). If BCAA can provide cognitive improvement in active dogs, then there could be numerous potential benefits for the dog and owner. The particular types of dogs that might benefit are: assistance, show, agility, working, and obedience dogs. Potentially, BCAA could be added in appropriate amounts to commercial diets, but more impact could be achieved if BCAA were provided in a snack or treat that the dog could eat just before an extra boost of energy and cognitive performance is required; similar to the way energy bars are used by humans.

The relation of free plasma tryptophan to anger, hostility, and aggression in a nonpatient sample of adult men and women

Dysregulation of central nervous system serotonergic (5-HT) activity is implicated in behavioral states and psychological traits associated with depression and aggression, with some studies suggesting possible gender-related differences. This study examined the relation of free plasma tryptophan (TRP) to aggression and depression in a sample of 138 nonsmoking adults recruited from the general community. It was hypothesized that TRP would be associated with anger, hostility, and aggression. To minimize effects of diurnal variation and menstrual cycle, fasting blood samples were collected in the morning, and, for women, during the follicular phase of the menstrual cycle. Participants were administered questionnaires following blood draw. Plasma TRP was determined by high performance liquid chromatography. In women, but not men, higher levels of TRP were associated with trait hostility, propensity for anger, a tendency to express anger outwardly, and an antagonistic interpersonal style. For men and women, greater severity of depressive symptoms, anger, and the verbal expression of anger were associated with higher TRP. These associations were independent of age, body mass index, fasting albumin, and race and ethnicity. These data suggest that in women, but not men, higher plasma levels of TRP, the precursor to 5-HT, are associated with anger-hostility-aggression and that these associations are independent of various potential confounds. Implications of these observations to studies employing acute TRP depletion studies are discussed.

Effects of experimental Neisseria meningitis W135 infection on serotoninergic parameters in mice

This study investigated the effects of Neisseria menigitidis W135 infection via intraperitoneal route on plasma free tryptophan concentration, brain serotonin and 5-hydroxyindole acetic acid (5-HIAA) levels in albino mice fed normal and tryptophan-enriched diets. The kinetics of appearance of viable bacteria in the blood, brain and liver following infection were also investigated. The serotoninergic parameters were determined by colorimetric and HPLC methods while colony counts were measured by plate count technique. Compared to normal diet, the tryptophan-enriched diet resulted in significantly (P increase in death score (8.3–66.7%) in the infected mice. Despite dietary tryptophan enrichment, the infected mice were also observed to elicit a time-dependent significant (P serotonin (253.9–131.4 vs. 262.4–283.7 ng/g tissue) but increase in 5-HIAA (71.8–174.5 ng/g vs. 70.4– 79.6 ng/g tissue) compared to uninfected animals. Establishment of N. meningitidis W135 meningitis in mice and subsequent brain serotonin depletion was further found to display a dose-dependent effect at 6–12 h post infection when inoculation with 104 and 106–107 cfu/ml were compared. Viable bacteria also appeared at different time-points in the blood, brain and liver of the infected mice with growths in blood and brain exhibiting similar kinetics but a disparity of 0.2–1.2 logarithmic cfu/ml. The results of this study strongly support the involvement of altered serotoninergic activity in meningococcal infection due to N. meningitidis

Chronic buspirone treatment normalizes regional serotonin synthesis in the olfactory bulbectomized rat brain: An autoradiographic study

The effects of chronic buspirone treatments, administered by minipump at doses of 10 and 20 mg/(kg day) for 14 days, on brain 5-HT synthesis in olfactory bulbectomized (OBX) rats were evaluated. The α-[ 14C]methyl- l-tryptophan autoradiographic method was used. We compared the synthesis in the buspirone treated OBX rats (administered either 10 mg/(kg day) (OBX-10) or 20 mg/(kg day) (OBX-20)) to that of the saline treated OBX rats (OBX-SAL), and the sham operated rats (SHX) treated with saline. In addition, OBX-10 rats were compared to SHX rats treated with 10 mg/(kg day) (SHX-10) of buspirone. All treatments were carried out for 14 days. Adult Sprague–Dawley rats were used. Two weeks following the OBX or SHX procedures, the rats were assigned to the OBX-10, OBX-20, OBX-SAL, SHX-10, or SHX-SAL groups, respectively. The 5-HT synthesis rates R (pmol/(g/min)) were calculated from the trapping constant of α-[ 14C]MTrp ( K*; ml/(g min)) and the plasma concentration of the plasma non-protein-bound tryptophan (Cp; pmol/ml) using the lumped constant (LC) measured previously in the rat brain. There was no significant difference in the plasma free or total tryptophan among these groups. The overall synthesis in the OBX-10 group was not statistically different from the OBX-SAL group, but it was different from the OBX-20 and SHX-SAL groups. The OBX-20 rats had an overall significant reduction in 5-HT synthesis, when compared to the OBX-SAL group, but did not differ from the SHX-SAL group, which did not differ from the SHX-10 group. These results suggest that 10 mg/(kg day) of buspirone for 14 days in the OBX rats did not produce a significant alteration in 5-HT synthesis, but 20 mg/(kg day) for 14 days resulted in an overall significant reduction in brain 5-HT synthesis. The latter treatment brought the synthesis to the level found in the sham operated rats, i.e., a normal level. These results suggest that normalization (reduction to the level found in the SHX-SAL rats) of 5-HT synthesis in the OBX requires a greater dose of buspirone (20 mg/(kg day)) than that needed to produce a desensitization of the 5-HT 1A receptors in the sham operated rats (10 mg/(kg day)). This probably indicates that 5-HT 1A receptors have different functionality in the OBX rats than that found in the intact or sham operated rats. Furthermore, our results support the hypothesis that 5-HT 1A receptors mediate the antidepressant-like effect of 5-HT 1A agonists, as the chronic 5-HT 1A agonist treatment in the depression model known to be sensitive to antidepressants resulted in the normalization of 5-HT synthesis.

Lack of Effects on Core Obsessive-Compulsive Symptoms of Tryptophan Depletion During Symptom Provocation in Remitted Obsessive-Compulsive Disorder Patients

Pharmacological evidence support that enhancement of serotonin (5-HT) neurotransmission is critical for treatment efficacy in obsessive-compulsive disorder (OCD). Surprisingly, acute tryptophan depletion (ATD), a procedure known to reduce 5-HT neurotransmission, carried out in remitted OCD patients on selective serotonin reuptake inhibitors (SSRIs) failed to worsen obsessive-compulsive (OC) symptoms. We hypothesized that the putative symptom exacerbation resulting from ATD would only be observed during symptom provocation but not at rest. Double-blind placebo-controlled ATD study conducted in 16 OCD patients with stable improvement under either SSRI (n = 8) or specialized cognitive behavior therapy alone (n = 8), coupled with gradual symptom provocation, performed 5 hours after drink ingestion. Acute tryptophan depletion markedly reduced total and free plasma tryptophan levels but did not significantly increase obsessions or compulsions at rest or following symptom provocation. However, subjective distress in response to triggering situations was significantly higher during ATD; significant mood lowering was also present during ATD. These results are consistent with the view that relapses in OC core symptoms in remitted OCD patients may not depend solely on short-term changes in presynaptic 5-HT availability. In contrast to its apparent lack of effect on core OC symptoms, ATD affected the patient's mood and distress level resulting from provocation.

Effects of Acute Tryptophan Depletion on Mood and Cognitive Functioning in Older Recovered Depressed Subjects

<h3>Objective</h3> Previous studies show that acute tryptophan depletion (ATD), by administration of an amino acid drink lacking tryptophan, can produce clinically significant depressive symptoms in subjects who have recovered from major depression. This is more likely in female patients who have had suicidal ideation, recurrent depression, and treatment with specific serotonin reuptake inhibitors. These risk factors are frequent in older recovered depressed people. The authors investigated the effects of ATD on mood and cognitive functioning in this group. <h3>Methods</h3> Sixteen recovered depressed (RD) subjects and 17 healthy-comparison subjects, over 60 years old, participated in a double-blind, placebo-controlled, crossover study involving administration of a tryptophan-depleting and a placebo drink. Mood ratings scales were administered at baseline and at 4 and 7 hours post-drink on each test day. A battery of neuropsychological tests, including the modified Mini-Mental State Examination (MMSE) was administered between 4 and 6 hours post-drink. <h3>Results</h3> Depletion of plasma free tryptophan was 71% at 4 and 7 hours after the active drink. There was no evidence of mood change at any time in either group. On the MMSE, however, the ATD/RD group showed a significant decrease compared with placebo. <h3>Conclusions</h3> There was no evidence of mood disturbance during ATD in any subject. This may imply less sensitivity to acute disturbance of the 5HT system than in younger recovered patients.

Effects of Acute Tryptophan Depletion on Mood and Cognitive Functioning in Older Recovered Depressed Subjects

Previous studies show that acute tryptophan depletion (ATD), by administration of an amino acid drink lacking tryptophan, can produce clinically significant depressive symptoms in subjects who have recovered from major depression. This is more likely in female patients who have had suicidal ideation, recurrent depression, and treatment with specific serotonin reuptake inhibitors. These risk factors are frequent in older recovered depressed people. The authors investigated the effects of ATD on mood and cognitive functioning in this group. Sixteen recovered depressed (RD) subjects and 17 healthy-comparison subjects, over 60 years old, participated in a double-blind, placebo-controlled, crossover study involving administration of a tryptophan-depleting and a placebo drink. Mood ratings scales were administered at baseline and at 4 and 7 hours post-drink on each test day. A battery of neuropsychological tests, including the modified Mini-Mental State Examination (MMSE) was administered between 4 and 6 hours post-drink. Depletion of plasma free tryptophan was 71% at 4 and 7 hours after the active drink. There was no evidence of mood change at any time in either group. On the MMSE, however, the ATD/RD group showed a significant decrease compared with placebo. There was no evidence of mood disturbance during ATD in any subject. This may imply less sensitivity to acute disturbance of the 5HT system than in younger recovered patients.

Potential role for nonesterified fatty acids in β-adrenoceptor-induced increases in brain tryptophan

We tested the hypothesis that β 2- and β 3-adrenergic receptor-mediated increases in brain tryptophan are due to the liberation of fatty acids, which in turn displace tryptophan from its albumin-binding site and thus facilitate its entry into the brain. Male CD-1 mice were injected with subtype-selective β-adrenergic agonists 1 h before brain samples were collected for analysis of tryptophan content by HPLC with electrochemical detection, and blood samples were collected for analysis of total and free tryptophan and nonesterified fatty acid (NEFA) concentrations. The β 2-selective agonist, clenbuterol (0.1 mg/kg), increased concentrations of tryptophan in all brain regions studied and decreased plasma total tryptophan, but had no effect on plasma free tryptophan or NEFAs. The β 3-selective agonists, BRL 37344 (0.2 mg/kg) or CL 316243 (0.01 mg/kg), increased brain tryptophan, plasma NEFAs and free tryptophan. Pretreatment with nicotinic acid (500 mg/kg), an inhibitor of lipolysis, almost completely prevented the increase in plasma free tryptophan and NEFAs, and attenuated the increase in brain tryptophan induced by CL 316243. These results suggest that β 2- and β 3-adrenergic agonists increase brain tryptophan by a mechanism other than the liberation of NEFAs. Nonetheless, β 3-adrenergic agonists appear to increase brain tryptophan by a mechanism that may depend partially on elevations of plasma NEFAs.

Increased insulin is not required for β 2-adrenoceptor-induced increases in mouse brain tryptophan

The current study tested the hypothesis that β 2-adrenoceptor-mediated increases in brain tryptophan are caused by increased insulin secretion. Male mice were treated with streptozotocin (40 mg/kg) for 5 days to induce experimental diabetes. Control and diabetic mice were treated with the β 2-adrenoceptor agonist, clenbuterol (0.1 mg/kg), 1 h before selected brain regions were dissected for analysis by high performance liquid chromatography (HPLC) with electrochemical detection for tryptophan content, and plasma was collected for analysis of total and free tryptophan and glucose concentrations. Clenbuterol increased brain tryptophan and plasma glucose and decreased plasma total tryptophan but did not alter plasma free tryptophan. There were no significant differences in brain or plasma tryptophan between control and streptozotocin-treated mice. In a separate experiment, pretreatment of the mice with an insulin antibody did not prevent the clenbuterol-induced increases in brain tryptophan. These results suggest that β 2-adrenoceptor agonists increase brain tryptophan by a mechanism that does not involve changes in insulin.

Involvement of plasma leptin, insulin and free tryptophan in cytokine-induced anorexia

Background: Hypothalamic serotonin, the synthesis of which parallels plasma free tryptophan, contributes to satiety. Plasma free tryptophan, insulin and leptin, all of which can also decrease food intake partly via the hypothalamic serotonergic system, are modulated by cytokines, which decrease food intake. The mechanisms of anorexia induced by cytokines, as related to plasma tryptophan, leptin and insulin, have not been fully determined. Objective: We determined the plasma concentrations of free as well as total tryptophan, leptin and insulin, and correlations to those of food intake and body weight change after cytokines or tryptophan injection. Design: Interleukin-1α and/or tumor necrosis factor-α, or tryptophan was injected subcutaneously into male rats for 2 days. Daily food intake, body weight, carcass adiposity, plasma total as well as free tryptophan, plasma leptin and insulin were measured. Results:Interleukin-1α injection decreased food intake, body weight, carcass adiposity and plasma leptin, but increased plasma free tryptophan and insulin. Tryptophan injection increased both free and total tryptophan, but did not change food intake, body weight, carcass adiposity or leptin. Plasma free tryptophan, but not total tryptophan, was significantly negatively correlated with food intake. There was a negative correlation between plasma insulin and food intake. Conclusions: Increased plasma free tryptophan may contribute to synthesis of brain serotonin but anorexia may be due to stimulation of its release induced by interleukin-1α. Plasma insulin, but not leptin, may partly contribute to anorexia of cytokines.

Biochemical markers for post-operative fatigue after major surgery

Objective: To establish a link between tryptophan (a precursor for 5-hydroxytryptamine (5-HT) or serotonin, involved in sleep and fatigue) and post-operative fatigue after major surgery. Background: There is a link between tryptophan (the precursor for the neurotransmitter 5-hydroxytryptamine), and its competitive binding with non-esterified fatty acids (NEFA) to albumin in the blood. An increase in the plasma concentration of free tryptophan can lead to an increased rate of synthesis of 5-HT in the brain. Free tryptophan competes with the branched chain amino acids (BCAA) for the same port of entry across the blood–brain barrier. It is suggested that the plasma concentration of these amino acids could be a marker of post-operative fatigue. In a previous study undertaken in this laboratory on patients undergoing two different types of major surgery, similar post-operative increases were observed in the plasma concentration of free tryptophan and the plasma concentration ratio of free tryptophan to branched chain amino acids. However, the study was retrospective and no measure of fatigue had been made. Methods: In the present study, this deficiency has been addressed by administering a modified Profile of Mood States questionnaire to patients undergoing reconstructive or colorectal surgery. In addition, blood samples were measured for plasma free tryptophan, albumin, NEFA and branched chain amino acids before and on 2 days after surgery. Results: There was a significant correlation between fatigue scores and plasma free tryptophan ( P<0.000), and the plasma concentration ratio of free tryptophan/BCAA ( P<0.016) after surgery in all the patients studied ( n=34). This correlation was more marked in the colorectal-surgery patients, in whom surgery was more severe. In the three categories of patients receiving elective reconstructive surgery ( n=24), those having breast reductions ( n=6) had a lower plasma concentration of NEFA and appeared to recover from fatigue more quickly than those with pre-tibial lacerations or malignant melanoma. Conclusions: These data provide further evidence of a possible biochemical mechanism for central fatigue which involves a precursor of 5-HT. The provision of branched chain amino acids may help to combat the surge in free tryptophan that occurs during stress such as major surgery.

Plasma leptin, insulin and free tryptophan contribute to cytokine-induced anorexia.

Cytokines contribute to anorexia of diseases. Tumor Necrosis Factor (TNF) and/or interleukin-1 (IL-1) stimulate leptin release, but not insulin. Both affect hypothalamus to decrease food intake (FI). Hypothalamic serotonin (5HT) decreases FI. Its synthesis depends on brain availability of precursor, tryptophan (TRP), which depends on plasma free TRP. Purpose is to test involvement of plasma leptin, insulin, TRP, and thus hypothalamic 5HT in cytokine-induced anorexia in rats. In male rats, IL-1alpha (10 mg/kg/d; n=9), TNFalpha (30 mg/kg/d; n=9), Il-1alpha+TNFalpha (10:30 mg/kg/d; n=9), TRP (100 mg/kg/d, n=8) and saline (n=8; Control) were injected sc for 2 days. FI, BW, plasma free and total TRP, leptin and insulin, and body fat were measured. Data analyzed via ANOVA. IL-1alpha and IL-1alpha+TNFalpha vs others decreased FI and BW. TNFalpha and TRP did not change FI and BW. Plasma total TRP was higher in TRP vs IL-1alpha, TNFalpha, and IL-1alpha+TNFalpha. Plasma free TRP was higher in IL-1alpha and IL-1alpha+TNFalpha vs Control. IL-1alpha and IL-1alpha+TNFalpha decreased leptin and body fat. Insulin in Control was lower than others. Data suggest: i) IL-1alpha increases plasma free TRP, but not total TRP, thus increases hypothalamic 5HT synthesis, resulting in anorexia; ii) leptin does not mediate anorexia, but; iii) insulin may contribute to anorexia induced by cytokines.

Tumor-induced changes in host metabolism: a possible role for free tryptophan as a marker of neoplastic disease.

Tumor growth is associated with a number of metabolic abnormalities. Glucose metabolism is deranged as frequently revealed by an impaired oral glucose tolerance test. Lipoprotein lipase activity is depressed, resulting in hypertrigliceridemia after an exogenous lipid load. Also protein metabolism is deranged in cancer patients, as revealed by changes of plasma amino acid profile. Our previous studies on plasma amino acids have shown that increased plasma free tryptophan levels are a frequent finding in cancer patients. To sustain a possible role for free tryptophan as a marker of neoplastic disease, we measured its plasma concentrations in 241 patients with cancer. Plasma free tryptophan concentrations were found to be significantly elevated with respect to healthy controls in patients with breast, lung, colon, stomach, and cancer from various origin. The sensitivity of this marker in predicting the presence of the tumor was highest for stomach and lung cancer patients. High plasma free tryptophan concentrations seem to be directly related to the presence of the tumor, since in breast cancer patients they returned to within normal range after eradicative surgery.

Effects of tryptophan depletion and catecholamine depletion on immune parameters in patients with seasonal affective disorder in remission with light therapy

Background Altered immunologic parameters are found in symptomatic depressed patients relative to remitted depressed patients and healthy controls. We investigated whether tryptophan depletion and catecholamine depletion induce alterations in immunologic parameters in patients with seasonal affective disorder remitted on light therapy, and whether these changes are associated with changes in mood. Methods Remitted patients with seasonal affective disorder underwent tryptophan depletion, catecholamine depletion, and sham depletion in a prospective randomized, double-blind crossover design. Measures of depression, plasma levels of tryptophan and catecholamine metabolites, and plasma levels of cytokines (sIL-4, IL-6, neopterin, sTNF-R1 and sTNF-R2) were obtained at baseline, and 7, 24, and 30 hours after monoamine depletion. Results Tryptophan depletion decreased plasma total and free tryptophan levels; catecholamine depletion decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Tryptophan depletion and catecholamine depletion, but not sham depletion, induced a transient exacerbation of depressive symptoms ( p < .001); plasma neopterin levels increased during tryptophan depletion and catecholamine depletion ( p < .05). Tryptophan depletion and catecholamine depletion induced a transient reduction of plasma sIL-4 levels ( p < .05). A significant correlation was found between sIL-4R levels and depression ratings after tryptophan depletion ( r = −.61, p < .05). Conclusions The monoamine depletion-induced alterations of humoral and cellular immunity suggest a potential role of immunologic parameters in the pathophysiology of seasonal affective disorder; however, the results must be considered preliminary and require further study.

Anorexia in space and possible etiologies: An overview

Objective Space travelers experience a flight duration-dependent loss in weight and body mass while in a microgravity environment, despite the absence of increased energy expenditure. Anorexia in space can lead to in-flight caloric deficits of 1330 kcal per 70 kg astronaut per day in the presence of abundant food and has a critical effect on endurance and performance. Microgravity, alterations in the light-and-dark cycle, and exposure to radiation energy are the environmental stresses believed to influence appetite, food intake, and gastrointestinal function during space flight. Methods and results Review of data and recent studies in rodents during microgravity showed a release of stress hormones and complex neuroendocrine and physiologic changes involving the modulation of hypothalamic activity, food intake–related hormones, and cytokines. The shift of dietary preference to carbohydrates, which occurs in astronauts, denotes a stress physiologic response and augments free-plasma tryptophan concentration in the brain, the precursor of the potent anorexic agent, serotonin (5-HT). Alterations of other neuroendocrine mediators, including corticotropin-releasing factor (CRF), coordinate the stress response, leading to a decrease in appetite and gastrointestinal function. Our laboratories used the antiorthostatic tail-suspension technique to successfully mimic some of these anorexia-related stress responses and to directly demonstrate the role of 5-HT in microgravity-related decreased food intake and delayed gastric emptying. Further rodent studies from our laboratories demonstrated the adverse effect of altered dark-and-light cycles on food intake and body weight. Radiation energy, through its documented effects on appetite, probably contributes to the decreased caloric intake by astronauts. Conclusion Modulation of hypothalamic activity, 5-HT, and CRF play a critical role in anorexia related to microgravity and circadian rhythm alterations. Specific gene knockout mice (e.g., 5-HT or CRF and their respective receptors) may prove fruitful in defining the pathways by which anorexia in space occurs. An understanding of these pathophysiologic problems as they relate to appetite, food intake, gastric emptying and gastrointestinal function, sufficiently to derive successful practical solutions, may lead to a quantitative enhancement of physiologic well-being and performance status, serving as a productive countermeasure in space.

The Effect of Tryptophan Depletion on Alcohol Self‐Administration in Non‐Treatment‐Seeking Alcoholic Individuals

Background Alcohol self‐administration in the laboratory has been used to evaluate pharmacological treatments and neurobiological mechanisms that underlie alcohol use in alcohol‐dependent individuals. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the amount of alcohol consumed in a self‐administration paradigm in non‐treatment‐seeking individuals with alcohol use disorders.Methods Individuals with alcohol dependence (n= 8) and alcohol abuse (n= 4) who were not seeking treatment were recruited by advertisement and participated in two test days, 1 week apart. Each test session was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double‐blind fashion. The test session began with a cue exposure session where subjects were exposed to their favorite alcoholic beverage and asked to rate their craving for alcohol. After this, subjects were administered a priming drink designed to raise blood alcohol levels to 0.02 g%. Subjects then had the opportunity to drink up to eight additional drinks, each designed to raise blood alcohol levels by 0.02 g%, or to receive $3 for each drink not consumed over a 2‐hr period.Results There were no significant differences in alcohol consumed or subjective intoxication with active tryptophan depletion compared with placebo. Self‐reported craving correlated with the amount of alcohol consumed in the session.Conclusions These data question the dependence of alcohol self‐administration on the ongoing synthesis of serotonin.