Brain Tryptophan Concentrations Research Articles

Increases in brain tryptophan concentration in stressed rats following ethanol administration.

To determine the effect of acute ethanol administration on tryptophan metabolism in stressed and unstressed rats. Phase I clinical trial. Department of Biochemistry, University of Karachi. The investigation was carried out in the year 2004. Male Albino Wistar rats (150-200 gm body wt) were selected and divided into four groups (n=5, in each group). Rats were injected either saline or 5% (v/v) ethanol (i.p) and were immediately subjected to 2 hours immobilization stress while respective control (non immobilized) groups remained in their home cages. There was no effect of 2 hours immobilization stress in male rats on peripheral liver tryptophan (Tp) metabolism, but brain Tp, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations were increased by 71.6% (P<0.01), 80.4% (P<0.01) and 179% (P<0.01) respectively. Two hours immobilization stress immediately after ethanol (5% v/v, 2 ml/kg) administration in rats increases holo and total tryptophan pyrrolase enzyme activities by 276% (P<0.01) and 129% (P<0.01) in ethanol injected stressed rats when compared with ethanol injected unstressed rats. Holo enzyme was increased by 60.7% but apoenzyme was decreased by 41% in ethanol injected stressed rats when compared with similarly treated saline injected stressed rats. Liver and serum total tryptophan concentrations were decreased by 25.7% (P<0.05) and 45.6% (P<0.01) respectively. Brain Tp and 5-HIAA concentrations were increased by 176% (P<0.01) and 168% (P<0.01) respectively. In ethanol injected unstressed group of rats holo and total enzyme activities were inhibited by 65% (P<0.01) and 53.1% (P<0.01) respectively leading to increase in liver Tp concentrations by 75.4% (P<0.01). Serum total Tp concentration was decreased by 64.4% (P<0.01). Brain Tp and 5-HIAA concentrations were not effected by ethanol injected unstress rats but 5-HT concentrations were increased by 75.8% (P<0.01) when compared with saline injected unstressed rats. It was found that increases in brain Tp concentrations were greater in ethanol injected stressed rats than in saline injected stressed group of rats when compared with their respective controls. Conditioned stress and ethanol both increase brain 5-HT concentrations when compared to saline treated unstressed controls.

Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter

To evaluate the consequences of inactivation of the serotonin transporter (SERT) gene on 5-HT homeostasis and function, 5-HT synthesis and turnover rates were measured using the decarboxylase inhibition method in multiple brain regions (frontal cortex, striatum, brainstem, hippocampus and hypothalamus) from mice with a genetic disruption of SERT. 5-HT synthesis rates were increased 30–60% in the different brain regions of SERT −/− mice compared to littermate +/+ control mice despite 55–70% reductions in tissue 5-HT concentrations. Brain regions that possessed a greater capacity to increase synthesis and turnover (frontal cortex, striatum) demonstrated lesser reductions in tissue 5-HT. Female SERT −/− mice had greater increases (79%) in brain 5-HT synthesis than male −/− mice did (25%), a finding associated with higher brain tryptophan concentrations in females. Despite increased 5-HT synthesis, there was no change in either TPH2 or TPH1 mRNA levels or in maximal in vitro TPH activity in the brainstem of SERT −/− mice. Catecholamine homeostasis as reflected in brain tissue concentrations and in synthesis and turnover of dopamine and norepinephrine was unchanged in SERT −/− mice. Taken together, the results demonstrate a markedly altered homeostatic situation in SERT −/− mice that lack 5-HT reuptake, resulting in markedly depleted tissue stores that are inadequately compensated for by increased 5-HT synthesis, with brain region and gender specificity observed.

Bacille Calmette‐Guérin Inoculation Induces Chronic Activation of Peripheral and Brain Indoleamine 2,3‐Dioxygenase in Mice

Activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and the resulting decrease in plasma tryptophan (TRP) levels appears to be a crucial link in the relationship between cytokines and depression. We aimed to develop an experimental model of chronic IDO activation based on bacille Calmette-Guérin (BCG) infection that elicits a robust increase in levels of interferon (IFN)- gamma, a key cytokine in the activation of IDO. Mice were inoculated intraperitoneally with BCG (10(7) cfu/mouse). Lung and brain IDO activity was measured over time, together with plasma levels of TRP and IFN- gamma. BCG induced, over the course of several weeks, a chronic increase in serum IFN- gamma levels that was associated with a sustained enhancement of lung and brain IDO activity and with decreases in peripheral (serum and lungs) and brain concentrations of TRP, with different time courses between tissues. The model of BCG-induced IDO activation will be useful for the study of the consequences of peripheral immune activation in the brain and the role of TRP metabolism in cytokine-induced mood alteration.

Activation of beta2- and beta3-adrenergic receptors increases brain tryptophan.

Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by beta-adrenoceptor antagonists. This study aimed to determine the beta-adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective beta-adrenergic antagonists 20 min before subtype-selective beta-agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The beta(2)-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak ( approximately 60%) 1 h following injection and small but statistically significant increases ( approximately 20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The beta(1)-selective agonist dobutamine (10 mg/kg) produced less robust increases ( approximately 40%) in brain tryptophan, whereas the beta(3)-selective agonists BRL 37344 (0.2 mg/kg (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl] phenoxy]acetic acid sodium)) and CL 316243 [0.1 mg/kg disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate)] resulted in larger increases (80 to 100%). Pretreatment with the beta(2)-selective antagonist ICI 118551 (0.5 mg/kg (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)amino]-2-butanol) attenuated the increases in tryptophan induced by both clenbuterol (0.1 mg/kg) and dobutamine (10 mg/kg). Pretreatment with the beta(1/2)-selective antagonist propranolol (2.5 mg/kg), the beta(3)-selective antagonist SR 59230A [1.5, 2.5, 5, or 20 mg/kg (3-(2-ethylphenoxy)-1[1S)-1,2,3,4-tertahydronaphth-1-yl-amino]-(2S)-2-propanol oxalate)], or ICI 118551 (0.5 mg/kg) did not prevent the BRL 37344-induced increase in brain tryptophan, whereas the beta(1/2/3)-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in beta(3)-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that beta-adrenergic modulation of brain tryptophan occurs in the absence of beta(3)-receptors. We conclude that activation of either beta(2)- or beta(3)-adrenergic receptors, but not beta(1)-adrenergic receptors, increases mouse brain tryptophan content.

Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios

The delivery of circulating tryptophan to the brain and its conversion to serotonin vary directly with plasma concentrations of tryptophan and inversely with those of other large neutral amino acids (LNAAs). Although carbohydrate-rich, protein-free formula diets have been shown to elevate, and high-protein diets to depress, the tryptophan-LNAA ratio, few data are available about this ratio's responses to actual meals. We determined whether carbohydrate-rich or protein-rich breakfasts, such as those Americans normally eat, produce substantial differences in the plasma tryptophan-LNAA ratio and in the corresponding ratio for tyrosine, the precursor of brain dopamine and norepinephrine. Nine overnight-fasted subjects consumed, 3-7 d apart, a carbohydrate-rich (69.9 g carbohydrate and 5.2 g protein) and a protein-rich (15.4 g carbohydrate and 46.8 g protein) breakfast. Blood samples collected at baseline and after 40, 80, 120, and 240 min were assayed for tryptophan, tyrosine, the 5 other LNAAs, and insulin. The carbohydrate-rich and protein-rich breakfasts had significantly different effects on both the plasma tryptophan-LNAA and tyrosine-LNAA ratios (each P < 0.01). Among the 8 subjects who consumed both breakfasts, the median difference for tryptophan:LNAA was 54% (range: 36-88%) and for tyrosine:LNAA was 28% (range: 10-64%). Insulin concentrations rose significantly after the carbohydrate but not after the protein meal. High-carbohydrate and high-protein breakfasts similar to those Americans normally eat can cause substantial differences in the plasma tryptophan ratio and thus, probably, in brain tryptophan concentrations and serotonin synthesis. Such meals also change the plasma tyrosine ratio and may thereby modify catecholamine synthesis.

Inhibition of tryptophan - pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats.

To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine (SSRI) on tryptophan metabolism in rats. A pre-clinical study. Clinical Biochemistry Research Laboratory, Department of Biochemistry, University of Karachi. The investigation was carried out during 2000 to 2001. Male Wistar rats (150-200 g body wt) were selected and divided into control and test groups (n = 5) for comparison. In in-vitro (10 - 1000mM) as well in-vivo (0.5-30 mg/kg body wt.) studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase (tryptophan-2,3-dioxygenase; EC 1.13.11.11) activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum (total and free) and liver L-tryptophan concentrations. Similarly, serum non-estrified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.

Bacterial translocation can increase plasma corticosterone and brain catecholamine and indoleamine metabolism

The potential contribution of stress-induced bacterial translocation to the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and brain biogenic amines was assessed. Mice were restrained for various periods, and brain concentrations of tryptophan, catecholamines, serotonin, and their metabolites, plasma corticosterone, and the translocation of viable bacteria from the gastrointestinal tract to the mesenteric lymph nodes, spleen, and liver were measured. Restraint induced the translocation of indigenous gram-positive bacteria in only a small proportion of animals, but translocation of gram-negative bacteria did not occur. Restraint induced short-lived increases in plasma corticosterone and brain amine metabolism, whereas bacterial translocation was slower and persisted long after the HPA axis and neurochemical responses had dissipated. When mice were infected with Salmonella typhimurium, spontaneous translocation occurred and plasma corticosterone, interleukin-6 concentrations, and brain catecholamine and indoleamine metabolism were elevated. These findings indicate that the translocation of indigenous gastrointestinal bacteria did not contribute to the HPA axis and neurochemical changes induced by restraint. However, translocation of nonindigenous S. typhimurium with or without restraint did induce HPA and neurochemical responses.

Cerebrospinal fluid concentrations of tryptophan and 5-hydroxyindoleacetic acid in Macaca mulatta: diurnal variations and response to chronic changes in dietary protein intake.

In rats, dietary protein is known to influence brain tryptophan (TRP) concentrations and serotonin (5HT) synthesis. However, few studies have examined this relationship in primates (including humans). We therefore studied the effect in monkeys of changes in chronic protein intake on plasma and cerebrospinal fluid (CSF) concentrations of TRP and 5-hydroxyindoleacetic acid (5HIAA), the principal 5HT metabolite. Juvenile male monkeys (Macacca mulatta) consumed for sequential 4-week periods diets differing in protein content (approximately 23%-->approximately 16%--> approximately 10%-->approximately 6% protein [%-energy/day]). Each day, food was presented as a morning meal of fruit, and an afternoon meal consisting of a pelleted, commercial diet and fruit. During week 4 on each diet, blood and CSF were sampled diurnally via indwelling catheters. Plasma and CSF TRP varied diurnally and with dietary protein content. On all diets, CSF TRP declined modestly in the morning, and increased in the afternoon; the magnitude of the increments varied directly with dietary protein content. Diurnal variations were absent for CSF 5HIAA; however, CSF 5HIAA varied directly with chronic dietary protein content. We conclude that dietary protein content can chronically influence CSF TRP concentrations in monkeys. The variation in CSF 5HIAA suggests chronic protein intake may influence serotonin synthesis and turnover, perhaps via changes in TRP concentrations.

Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female offspring.

The present study was designed to evaluate the long-term consequences of tryptophan treatment on the central serotonergic activity in the female offspring of rats, and particularly on serotonin-controlled hormone release. During the second half of gestation, tryptophan (200 mg/kg/day) was given daily by stomach intubation to pregnant rats and the brain concentrations of serotonin and 5-hydroxyindole acetic acid and the plasma concentrations of prolactin, progesterone, oestradiol and luteinizing hormone were quantified in the adult female offspring. The offspring showed an increase in hypothalamic serotonin and serum progesterone and prolactin. In addition, maternal ingestion of tryptophan induced a marked rise in 665-day-old offspring in the incidence of both pituitary prolactinomas (62%) and mammary adenomas (49%). Present data suggest that tryptophan regulates serotonergic differentiation during early development. A transitory modification of the tryptophan concentration in the fetal brain induces a permanent increase in hypothalamic serotonin level and, in addition to modifying the release of prolactin, increases the incidence of tumours in the hypophysis and mammary gland.

Peripherally injected IL-1 induces anorexia and increases brain tryptophan concentrations.

Interleukin-1 is an anorexigenic cytokine, and is involved in the pathogenesis of cancer anorexia. Interleukin-1 induced anorexia is mediated by direct action within the hypothalamus, and by peripheral mechanism(s) yet to be determined. Here we present evidence showing that in an animal model the peripheral injection of interleukin-1 is followed by a significant rise in brain tryptophan concentrations. Tryptophan is the precursor of the neurotransmitter serotonin, known to mediate the onset of satiety under normal and pathological conditions. By inference, we conclude that interleukin-1 induced anorexia is mediated by at least two different mechanism: i) interleukin-1 direct action within the hypothalamus; ii) increased brain serotonergic activity, secondary to interleukin-1 induced increased brain availability of the serotonin precursor, tryptophan.

Body weight loss and changes in tryptophan homeostasis by chlorinated dibenzo-p-dioxin congeners in the most TCDD-susceptible and the most TCDD-resistant rat strain.

We compared the effects of 2,3,7,8-tetra (TCDD), 1,2,3,7,8-penta (PeCDD), 1,2,3,4,7,8-hexa (HxCDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) on brain serotonin metabolism, plasma tryptophan and liver tryptophan pyrrolase activity in two rat strains, TCDD-sensitive Long-Evans (Turku AB; L-E) and TCDD-resistant Han/Wistar (Kuopio; H/W). Previously it was shown that L-E rats exhibit the expected rank order of potency for CDDs in terms of acute toxicity with TCDD being the most potent, followed by PeCDD, HxCDD and HpCDD. In contrast, to H/W rats HxCDD was the most toxic and TCDD the least toxic of these congeners. In the present study, the CDDs decreased body weight in L-E rats in the following order of potency: TCDD > PeCDD > HxCDD > HpCDD. The same rank order was recorded for elevations in brain tryptophan and plasma free tryptophan concentrations as well as for inhibition of the main hepatic tryptophan metabolizing enzyme, tryptophan pyrrolase. By contrast, in H/W rats HxCDD was the most effective congener in producing loss of body weight, followed by HpCDD, PeCDD and TCDD. This was also true of changes in tryptophan homeostasis. These findings imply that in TCDD-susceptible L-E and TCDD-resistant H/W rats the potency of dioxin congeners in inducing acute toxicity highly correlates with their ability to disrupt tryptophan homeostasis. However, there may not be a direct causal relationship between body weight loss and altered tryptophan homeostasis, because the magnitudes of these two phenomena were not consistently parallel across the dioxin congeners tested.

Brain catecholaminergic and tryptophan responses to restraint are attenuated by nitric oxide synthase inhibition

Increases in the brain concentrations of tryptophan and in serotonin (5-HT) metabolism are commonly observed in animals under stress. Previous experiments indicated that the increase in brain tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) observed in response to administration of endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) were largely prevented by pretreatment with N-nitro-L-arginine methylester (L-NAME), an inhibitor of NO synthase (NOS). Therefore we tested whether the increases in tryptophan and 5-HT metabolism observed following restraint and footsthock were similarly affected. Mice were injected with L-NAME (30 mg/kg) or saline and restrained for 40 min. Restraint caused increases in concentrations of tryptophan and the catabolites of dopamine (DA), norepinephrine (NE) and 5-HT in the medial prefrontal cortex, hypothalamus, and brain stem. The L-NAME pretreatment significantly attenuated, but did not prevent, the changes in tryptophan and catecholamine metabolism, with a very small effect on the increase in plasma corticosterone. When mice pretreated with L-NAME were subjected to 30 min footshock, the NOS inhibitor had no statistically significant effects on the increases in DA, NE and 5-HT metabolism, but tended to attenuate the increases in tryptophan. We interpret these results to indicate that NOS plays a relatively small role in the cerebral neurochemical responses to restraint and footshock, but the role in the restraint-induced changes was greater than that in the footshock-induced ones. The attenuation of the restraint-related effects on the catecholamines most probably reflects a contribution to the CNS responses from peripheral vascular changes which are likely to be limited by the inhibition of NOS.

P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia

P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia

Theanine-induced reduction of brain serotonin concentration in rats.

Following the administration of theanine, the brain tryptophan content significantly increased or tended to increase, but the contents of serotonin and 5-hydroxyindole acetic acid (5HIAA) decreased. The use of inhibitors of serotonin metabolism enable us to speculate that theanine reduced serotonin synthesis and also increased serotonin degradation in the brain.

Brain serotonin content: physiological regulation by plasma neutral amino acids. 1971.

AbstractWhen plasma tryptophan is elevated by the injection of tryptophan or insulin, or by the consumption of carbohydrates, brain tryptophan and serotonin also rise; however, when even larger elevations of plasma tryptophan are produced by the ingestion of protein‐containing diets, brain tryptophan and serotonin do not change. The main determinant of brain tryptophan and serotonin concentrations does not appear to be plasma tryptophan alone, but the ratio of this amino acid to other plasma neutral amino acids (that is, tyrosine, phenylalanine, leucine, isoleucine, and valine) that compete with it for uptake into the brain.

Studies on the pharmacological properties of oxindole (2-hydroxyindole) and 5-hydroxyindole: are they involved in hepatic encephalopathy?

It has been repeatedly described that plasma or CSF tryptophan concentrations increase in experimental animal models of liver impairment and in patients suffering from hepatic encephalopathy or hepatic coma (Hirayama, 1971; Curzon et al. 1973; Sourkes, 1978; ONO et al. 1996). It has also been demonstrated that the administration of large doses of tryptophan to patients affected by hepatic disorders or to dogs with a portocaval shunt may lead to coma (Sherlock, 1975; Rossi-Fanelli et al. 1982). On the basis of the widely agreed assumption that increased brain tryptophan concentrations signify increased 50Htryptamine turnover, several years ago, a number of investigators proposed that an increased stimulation of 50H-tryptamine receptors plays a key role in the neurological and psychiatric symptoms associated with liver diseases (Cummings et al. 1976). Tryptophan may be metabolized not only into 50H-tryptamine, but also into quinolinic or kynurenic acids, neuroactive compounds which are able to interact with glutamate receptors of the NMDA type (see: Stone, 1993 for a review). Approximately ten years ago, we observed that quinolinic acid was indeed increased in the rat brain with portocaval anastomosis or in patients who had died in hepatic coma (Moroni et al. 1986; Moroni et al. 1986a). We therefore proposed that “..quinolinic acid should be added to the list of compounds possibly involved in the pathogenesis and symptomatology of brain disorders associated to liver failure.” Other groups have recently confirmed that quinolinic acid is indeed increased in the blood and brain of rat models suffering from either acute or chronic liver failure. The concentration of quinolinic acid in the brain, however, does not seem to correlate with the neurological symptoms observed in these liver disorders. Furthermore, it is possible that quinolinic acid synthesis occurs mostly in macrophages or other periphalopathy may be “minor” (Bergquist et al. 1995; Basile et al. 1995).

Cracking the riddle of cancer anorexia

During tumor growth, anorexia and reduced food intake are among the major causes leading to malnutrition and eventually cachexia, which negatively affect patients' outcome. Consistent evidence from our laboratories in rats and humans indicates a key role for ventromedial hypothalamic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan levels (the precursor of serotonin) lead to increased cerebrospinal fluid tryptophan concentrations and increased VMH serotonin synthesis, which then mediates the occurrence of anorexia. However, recent data strongly suggest that factors other than tryptophan supplied to the central nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 infusion in normal rats causes changes in food intake and its determinants, meal number and meal size, similar to those characterizing cancer anorexia, thus supporting the involvement of this cytokine in the development of anorexia. Interestingly, IL-1 and the VMH serotonergic system appear to be closely linked: peripherally infused IL-1 increases brain tryptophan and serotonin concentrations, while intracerebrally infused IL-1 increases neuronal firing rate and serotonin release. We therefore hypothesize that during tumor growth, increased production/secretion of IL-1 occurs, which facilitates the tryptophan supply to the brain. IL-1 can then also act on the VHM itself, where IL-1 receptors exist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic neuronal firing rate and serotonin release, while peripherally acting IL-1 is critical in supplying the hypothalamus with the precursor, tryptophan, in order to maintain the high rate of serotonin synthesis. Also, additional factors recently proposed as mediators of anorexia (including neuropeptide Y and nitric oxide) appear to be part of the hypothesized pathogenic mechanism.

Cancer anorexia: new pathogenic and therapeutic insights.

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thus worsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Cancer anorexia: new pathogenic andtherapeutic insights

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thusworsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Brain tryptophan concentrations and serotonin synthesis remain responsive to food consumption after the ingestion of sequential meals

The response of brain tryptophan concentration and serotonin synthesis to the ingestion of two sequential meals was examined in rats. Fasted rats ingested a carbohydrate meal followed 2 h later by a protein-containing meal and were examined 2 or 4 h after the first meal. Other rats ingested a protein meal first, followed by a carbohydrate meal. When the carbohydrate meal was fed first, brain tryptophan concentrations and serotonin synthesis increased at 2 h; these changes were reversed at 4 h if the second meal contained protein. When the protein meal was fed first, there were no changes in brain tryptophan or serotonin at 2 h, and a second carbohydrate meal at 2 h did not raise brain tryptophan or serotonin 2 h later. Carbohydrate ingestion 3 h after a protein meal, however, did raise brain tryptophan and serotonin 2 h later. Brain tryptophan concentrations and serotonin synthesis are thus responsive to the sequential ingestion of protein and carbohydrate meals if there is a sufficient interval between meals.