Increased Brain Tryptophan Research Articles

Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Mecp2 Heterozygous Mouse Model of Rett Syndrome.

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2-3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice.

Citalopram and Tianeptine: Pharmacological Interventions in alcohol withdrawal-induced negative mood states and serotonin insufficiency in Albino Wistar male rats

ABSTRACT The present study aims to investigate the neurochemical and behavioural effects of tianeptine and citalopram to block alcohol withdrawal-induced audiogenic seizures in alcohol withdrawal (AW) rats. Citalopram and tianeptine were administered sub-chronically to block AW-induced audiogenic seizures. Brain regional tryptophan (TRP), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined using high-performance liquid chromatography connected to the fluorimetric detector. Citalopram increased brain TRP concentration in all the regions, however, tianeptine increased brain TRP concentration only in amygdala and hippocampus. Increased brain serotonin concentration was seen by citalopram but not by tianeptine in all the regions. Further, tianeptine was shown to increase 5-HT turnover in all the regions, however, citalopram appeared to increase 5-HT turnover only in the hippocampus. It is concluded that the citalopram and tianeptine behave differently on the intrinsic pathway of serotonin metabolism that appeared to be compensated by the release pattern of serotonin. Further, chronic exposure of serotonergic agents causes restoration and structural reforming of serotonin reuptake mechanism that is desensitized following chronic alcohol exposure. Thus the inclusive approach of the serotonergic system plays an undoubted role in the pharmacological management of AW syndrome.

A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates

Over the past 50 y, tryptophan has been ingested in amounts well in excess of its dietary requirement. This use is based on extensive findings that ingesting tryptophan increases brain tryptophan concentrations, which stimulates the synthesis and release of the neurotransmitter serotonin, from which it is derived. Such increases in serotonin function may improve mood and sleep. However, tryptophan ingestion has other effects, such as increasing serotonin production in the gut, increasing serotonin concentrations in blood, stimulating the production of the hormone melatonin (a tryptophan metabolite), stimulating tryptophan metabolism via the kynurenine pathway, and possibly stimulating the production of tryptophan metabolites in the gut microbiome. Several of the kynurenine metabolites have actions on excitatory glutamate receptors in the gut and brain and on cells of the immune system. In addition, metabolites of tryptophan produced by colonic bacteria are reported to cause adverse effects in some species. This review examines each of these tryptophan pathways to determine if any of the metabolites increase after tryptophan ingestion, and if so, whether effects are seen on target body functions. In this regard, recent research suggests that it may be useful to examine kynurenine pathway metabolites and some microbial tryptophan metabolites to determine whether supplemental tryptophan consumption increases their concentrations in the body and amplifies their actions.

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial

To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. ClinicalTrials.gov: NCT00873509.

Improved Serotonergic Tone Contributes to the Mechanism of Action of St John’s Wort in Nicotine Withdrawn Mice

Present study aims to investigate the acute effects of St John’s Wort (SJW) on nicotine withdrawal syndrome and serotonergic hypo activity in mice. Adult male Albino mice weighing 20-25g were housed 6 per cage under light and dark conditions at 22±3oC and maintained on lab chow and water ad libitum under standard housing conditions. Nicotine was administered at the concentrations of 3.08mg (1mg of free base) in 100 ml of drinking water for 4 weeks. Nicotine withdrawal was achieved by substituting nicotine containing water with drinking water. Nicotine withdrawn (NW) mice were evaluated for locomotor activity and abstinence signs at 72 h. Whole brain tryptophan (TRP). 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high performance liquid chromatography connected to fluorescence detector. St John’s Wort (SJW) (500mg/kg) was given intraperitonially 3 h prior to completion of 72 h of nicotine withdrawal period. Behavioral analysis in SJW administered NW mice showed attenuation in nicotine abstinence signs (shaking, scratching, chewing and facial tremors) and locomotor activity when compared with respective controls. NW mice showed decrease in plasma TRP, brain TRP and 5-HT concentrations while increase in 5-HT turnover and corticosterone concentrations as compared to respective controls. SJW administrated NW mice showed decrease in corticosterone levels and 5-HT turnover while plasma TRP, brain TRP and 5-HT synthesis were increased when compared with similarly treated saline injected group. Our findings warrant SJW’s therapeutic efficacy to alleviate nicotine withdrawal associated depression by virtue of its ability to improve serotonergic activity by increasing brain TRP, 5-HT concentrations and decreased turnover.

Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers

Reduced brain serotonin function is acknowledged as a vulnerability factor for affective disturbances. Since the production of serotonin is limited by the availability of its plasma dietary amino acid precursor tryptophan (TRP), the beneficial effects of tryptophan-rich alpha-lactalbumin whey protein (ALAC) have recently been studied. The effects of ALAC remain rather modest, and alternative protein sources of tryptophan may be more effective. We tested whether hydrolyzed protein (HPROT) has greater effects on the plasma TRP/large neutral amino acids (LNAA) ratio and mood than intact ALAC protein in healthy volunteers. In a double-blind, randomized cross-over study, plasma amino acids and mood were repeatedly measured in 18 healthy subjects before and after intake of ALAC and HPROT as well as after placebo protein, pure tryptophan, and a tryptophan-containing synthetic peptide. Except for the placebo protein, all interventions contained 0.8 g TRP. Significantly faster and greater increases in plasma TRP/LNAA were found after HPROT than after ALAC. In addition, the effects of HPROT on plasma TRP/LNAA were comparable with the effects of the tryptophan-containing synthetic peptide and even exceeded the effect of pure tryptophan. Sixty minutes after intake, mood was improved only following intake of HPROT and pure tryptophan, whereas longer-lasting mood effects were only found after intake of HPROT. The use of a tryptophan-rich hydrolyzed protein source may be more adequate to increase brain tryptophan and 5-HT function compared with intact alpha-lactalbumin protein or pure tryptophan.

Behavioral effects of the β3 adrenoceptor agonist SR58611A: Is it the putative prototype of a new class of antidepressant/anxiolytic drugs?

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.

Exercise, Serum Free Tryptophan, and Central Fatigue

Brain tryptophan (TRP) concentrations and serotonin (5HT) synthesis and release increase during running. This increase in 5HT function may promote central fatigue and contribute to suboptimal physical performance. The rise in brain TRP is reputed to result from exercise-induced elevations in serum nonesterified fatty acid (NEFA) concentrations, which dissociate TRP from albumin in blood and increase the serum free TRP pool. But, as discussed in this article, ample evidence exists that the serum free TRP pool does not control brain TRP uptake. The clearest data are dietary, but pharmacologic data in exercising rats also support this conclusion. Changes in the serum levels of amino acids that compete with TRP for brain uptake appear also not to explain the rise in brain TRP. The mechanism is therefore not presently known. The link between the rise in brain TRP and 5HT synthesis/release is not simple: a rise in brain TRP stimulates 5HT synthesis/release in actively firing neurons. Hence, during exercise, only 5HT neurons that are firing should increase 5HT production/release when brain TRP rises. It is not known which 5HT neurons fire during exercise; the 5HT neurons that respond to exercise-induced increases in brain TRP are therefore not known. Hence, it is not possible to conclude which 5HT neurons contribute to the generation of central fatigue. Because some 5HT neurons control specific functions important to physical performance (e.g., respiration), the current understanding of 5HT neuronal function in central fatigue might benefit from the study of specific 5HT pathways during exercise.

Physiological and behavioral responses to interleukin-1β and LPS in vagotomized mice

It is well established that peripheral administration of interleukin-1 (IL-1) and lipopolysaccharide (LPS) can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, alter brain catecholamine and indoleamine metabolism, and affect behavior. However, the mechanisms of these effects are not fully understood. Stimulation of afferents of the vagus nerve has been implicated in the induction of Fos in the brain, changes in body temperature, brain norepinephrine, and some behavioral responses. In the present study, the IL-1β- and LPS-induced changes in certain behaviors, HPA axis activation, and catecholamine and indoleamine metabolism were studied in mice following subdiaphragmatic vagotomy. IL-1β and LPS induced the expected decreases in sweetened milk, food intake, and locomotor activity, and the responses to IL-1β, but not LPS, were slightly attenuated in vagotomized mice. Subdiaphragmatic vagotomy also attenuated the IL-1β- and LPS-induced increases in plasma ACTH and corticosterone, but the attenuations of the responses to IL-1β were only marginally significant. There were also slight reductions in the responses in catecholamine and serotonin metabolism, and the increases in brain tryptophan in several brain regions. These results indicate that the vagus nerve is not the major pathway by which abdominal IL-1β and LPS effect behavioral, HPA and brain catecholamine and indoleamine responses in the mouse. These results resemble those we observed in subdiaphragmatically vagotomized rats, but in that species the subdiaphragmatic vagotomy markedly attenuated the ACTH and corticosterone responses, and prevented the hypothalamic noradrenergic activation, as well as the fever. Overall the results indicate that the various responses to peripheral IL-1 and LPS involve multiple mechanisms including vagal afferents, and that there are species differences in the relative importance of the various mechanisms.

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.

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.

Evidence that tryptophan reduces mechanical efficiency and running performance in rats

It has been reported that exercise increases brain tryptophan (TRP), which is related to exhaustive fatigue. To study this further, the effect of increased TRP availability on the central nervous system (CNS) with regard to mechanical efficiency, oxygen consumption (VO 2) and run-time to exhaustion was studied in normal untrained rats. Each rat was anesthetized with thiopental (30 mg/kg ip b. wt.) and fitted with a chronic guiding cannula attached to the right lateral cerebral ventricle 1 week prior to the experiments. Immediately before exercise, the rats were randomly injected through these cannulae with 2.0 μl of 0.15 M NaCl ( n=6) or 20.3 μM l-TRP solution ( n=6). Exercise consisted of running on a treadmill at 18 m min −1 and 5% inclination until exhaustion. TRP-treated rats presented a decrease in their mechanical efficiency (21.25±0.84%, TRP group vs. 24.31±0.98%, saline-treated group; P≤.05), and increased VO 2 at exhaustion (40.3±1.6 ml kg −1 min −1, TRP group vs. 36.0±0.8 ml kg −1 min −1, saline group; P≤.05), indicating that the metabolic cost of exercise was higher in the former group. In addition, a highly significant reduction was also observed in run-time to exhaustion of TRP animals compared to those of the saline-treated group (15.2±1.52 min, TRP group vs. 50.6±5.4 min, saline group; P≤.0001). It can be deduced from the data that intracerebroventricular TRP injection in rats increases O 2 consumption and reduces mechanical efficiency during exercise, diminishing running performance.

Whey protein rich in α-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects

Cognitive performance often declines under chronic stress exposure. The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). In addition, a diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects. We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects. Twenty-three high stress-vulnerable subjects and 29 low stress-vulnerable subjects participated in a double-blind, placebo-controlled, crossover study. All subjects conducted a memory-scanning task after the intake of a diet enriched with either alpha-lactalbumin (alpha-lactalbumin diet) or sodium caseinate (control diet). Blood samples were taken to measure the effect of dietary manipulation on the plasma Trp-LNAA ratio. A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet (P = 0.0001) was observed; memory scanning improved significantly only in the high stress-vulnerable subjects (P = 0.019). Because an increase in the plasma Trp-LNAA ratio is considered to be an indirect indication of increased brain serotonin function, the results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.

Cancer anorexia and cachexia

Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP–dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin–proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia.

Cytokine activation of the HPA axis.

The observation that administration of interleukin-1 (IL-1) to animals activates the hypothalamo-pituitary-adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) share HPA-activating activity, although they are less potent and effective than IL-1, whereas IL-2 and interferon alpha(IFN alpha) lack activity. Small increases in body temperature occur in response to IL-1, IL-6 and TNF alpha, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA-activation. The rapid HPA-activating effects of IL-1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL-1-induced HPA activation. The HPA response to IL-6 is not sensitive to COX inhibitors, but that to TNF alpha appears to be. The HPA-activating activity of IL-1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5-HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not these in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL-6 has effects on serotonin and tryptophan like those of IL-1, but no detected effect on NA. TNF alpha has some effect on NA and tryptophan, but only at relatively high doses. IFN alpha lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL-1-induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.

The Effects of Paradoxical Sleep Deprivation and Valine on Spatial Learning and Brain 5-HT Metabolism

We have previously reported that rapid eye movement sleep deprivation (REMSD), induced by the flower pot technique, causes a deficit in reference spatial memory and increases rates of serotonin (5-HT) metabolism in the brain. In this study we used increased concentrations of dietary valine to inhibit tryptophan (TRP) transport across the blood–brain barrier in an attempt to modify the REMSD-induced increase of 5-HT metabolism. Rats were fed either a control diet or the same diet supplemented to 2% by weight valine, and were allocated to one of three experimental groups: cage control (CC), stress tank control (TC), or REMSD. Reference and working spatial memory of all rats was tested in a Morris water maze on Days 2, 3, and 4. REMSD produced a significant decrement in reference memory on Days 2 and 4, independent of dietary condition. The valine diet had a detrimental effect on the reference memory of TC rats on Day 2 but not Day 4. Measurements made on Day 4 indicated that the valine diet decreased brain TRP only in the CC rats. In contrast, the valine diet did not prevent increases in brain TRP or 5-HT metabolism in REMSD rats, and increased hypothalamic and brain stem TRP concentrations and the hippocampal 5-HIAA/5-HT ratio in TC rats. These results indicate that dietary valine does not prevent REMSD-induced changes in spatial memory or serotonin metabolism, although it does reduce brain TRP in nonstressed rats.

Liquid Concentrates Are Lower in Bioavailable Tryptophan than Powdered Infant Formulas, and Tryptophan Supplementation of Formulas Increases Brain Tryptophan and Serotonin in Rats

The bioavailability of tryptophan in powdered and/or liquid concentrate forms of milk-based infant formulas was determined by studying rat growth response by using a slope ratio method (food conversion efficiency: weight gain/food consumed vs. tryptophan consumed). A gelatin basal diet formulated to be adequate in all nutrients, except tryptophan (0.03%), for rat growth was supplemented with graded levels of crystalline L-tryptophan (0.02, 0.04, 0.06, 0.08, 0.10, 0.12 and 0.14%, standard diets) or infant formulas providing 0.04 and 0.08% supplemental tryptophan (test diets). These diets were fed to weanling rats for 2 wk. Tryptophan bioavailabilities of various formulas varied from 83 to 95%, with some of the liquid concentrates having the lowest values. The levels of bioavailable tryptophan in the liquid concentrate forms (9.7–12.6 mg/g protein) and the powdered forms (11.1–13.1 mg/g protein) were considerably lower than those of human milk (17–19 mg/g protein). Supplementation of the liquid concentrates with graded levels of L-tryptophan (0.1, 0.5 and 1.0%) had no effect on protein quality indices, based on rat growth, but resulted in a dose-related increase in the concentrations of tryptophan in the plasma and brain and of serotonin and 5-hydroxyindole-3-acetic acid in the brains of rats. This study supports further research to investigate the influence of tryptophan supplementation of infant formulas, to more closely simulate tryptophan composition of human milk, on tryptophan metabolites and their potential related effects on sleep latency and neurobehavioral developments in infants.

Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin and the hypothalamo-pituitary-adrenocortical axis.

Biological activities of the multifunctional cytokine, interleukin-6 (IL-6) include stimulation of B cell proliferation, immunoglobulin production, and initiation of the acute-phase response. IL-6 affects the CNS in that it activates the hypothalamo-pituitary-adrenocortical (HPA) axis and increases brain tryptophan and serotonin metabolism. IL-6 has been proposed as an important mediator of interaction between the neuroendocrine and immune systems. The peripheral and central effects of IL-6 are presumably mediated through its membrane receptor (IL-6R). IL-6, IL-6R and their respective mRNAs have been detected in several brain regions. Although the functions of cytokines overlap considerably, each displays its own characteristic properties. Expression of IL-6 in the brain has been observed in several CNS disorders, some of which have been associated with disorders of serotonin metabolism. It is proposed that interactions between IL-6 and brain serotonin is a complex process which involves corticotropin-releasing factor (CRF) and opioid peptides. It is likely that the molecular mechanisms underlying the actions of IL-6 on the HPA axis and its other brain functions involve the integrated effects of glutamate, Ca2+, 3',5'-cyclic AMP, protein kinase C, and other metabolic pathways.

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.