Availability Of Plasma Tryptophan Research Articles

STRIATAL GABAERGIC AND GLUTAMATERGIC DYSREGULATIONS AS POTENTIAL PREDICTORS OF CONVERSION TO PSYCHOSIS IN INDIVIDUALS AT ULTRA-HIGH RISK

Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders of unknown etiology that most commonly begin during adolescence in women. AN and BN have unique and puzzling symptoms, such as restricted eating or binge-purge behaviors, body image distortions, denial of emaciation, and resistance to treatment. These are often chronic and relapsing disorders, and AN has the highest death rate of any psychiatric disorder. The lack of understanding of the pathogenesis of this illness has hindered the development of effective interventions, particularly for AN. Individuals with AN and BN are consistently characterized by perfectionism, obsessive–compulsiveness, and dysphoric mood. Individuals with AN tend to have high constraint, constriction of affect and emotional expressiveness, ahendonia and asceticism, whereas individuals with BN tend to be more impulsive and sensation seeking. Such symptoms often begin in childhood, before the onset of an eating disorder, and persist after recovery, suggesting they are traits that create a vulnerability for developing an ED. There is growing acknowledgement that neurobiological vulnerabilities make a substantial contribution to the pathogenesis of AN and BN. Considerable evidence suggests that altered brain serotonin (5-HT) function contributes to dysregulation of appetite, mood, and impulse control in AN and BN. Brain imaging studies, using 5-HT specific ligands, show that disturbances of 5-HT function occur when people are ill, and persist after recovery from AN and BN. It is possible that a trait-related disturbance of 5-HT neuronal modulation predates the onset of AN and contributes to premorbid symptoms of anxiety, obsessionality, and inhibition. This dysphoric temperament may involve an inherent dysregulation of emotional and reward pathways which also mediate the hedonic aspects of feeding, thus making these individuals vulnerable to disturbed appetitive behaviors. Restricting food intake may become powerfully reinforcing because it provides a temporary respite from dysphoric mood. Several factors may act on these vulnerabilities to cause AN to start in adolescence. First, puberty-related female gonadal steroids or age-related changes may exacerbate 5-HT dysregulation. Second, stress and/or cultural and societal pressures may contribute by increasing anxious and obsessional temperament. Individuals with AN may discover that reduced dietary intake, by reducing plasma tryptophan availability, is a means by which they can modulate brain 5-HT functional activity and anxious mood. People with AN enter a vicious cycle which accounts for the chronicity of this disorder because caloric restriction results in a brief respite from dysphoric mood. However, malnutrition and weight loss, in turn, produce alterations in many neuropeptides and monoamine function, perhaps in the service of conserving energy, but which also exaggerates dysphoric mood. In summary, this article reviews findings in brain chemistry and neuroimaging that shed new light on understanding the psychopathology of these difficult and frustrating disorders.

Neurobiology of anorexia and bulimia nervosa

Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders of unknown etiology that most commonly begin during adolescence in women. AN and BN have unique and puzzling symptoms, such as restricted eating or binge-purge behaviors, body image distortions, denial of emaciation, and resistance to treatment. These are often chronic and relapsing disorders, and AN has the highest death rate of any psychiatric disorder. The lack of understanding of the pathogenesis of this illness has hindered the development of effective interventions, particularly for AN. Individuals with AN and BN are consistently characterized by perfectionism, obsessive–compulsiveness, and dysphoric mood. Individuals with AN tend to have high constraint, constriction of affect and emotional expressiveness, ahendonia and asceticism, whereas individuals with BN tend to be more impulsive and sensation seeking. Such symptoms often begin in childhood, before the onset of an eating disorder, and persist after recovery, suggesting they are traits that create a vulnerability for developing an ED. There is growing acknowledgement that neurobiological vulnerabilities make a substantial contribution to the pathogenesis of AN and BN. Considerable evidence suggests that altered brain serotonin (5-HT) function contributes to dysregulation of appetite, mood, and impulse control in AN and BN. Brain imaging studies, using 5-HT specific ligands, show that disturbances of 5-HT function occur when people are ill, and persist after recovery from AN and BN. It is possible that a trait-related disturbance of 5-HT neuronal modulation predates the onset of AN and contributes to premorbid symptoms of anxiety, obsessionality, and inhibition. This dysphoric temperament may involve an inherent dysregulation of emotional and reward pathways which also mediate the hedonic aspects of feeding, thus making these individuals vulnerable to disturbed appetitive behaviors. Restricting food intake may become powerfully reinforcing because it provides a temporary respite from dysphoric mood. Several factors may act on these vulnerabilities to cause AN to start in adolescence. First, puberty-related female gonadal steroids or age-related changes may exacerbate 5-HT dysregulation. Second, stress and/or cultural and societal pressures may contribute by increasing anxious and obsessional temperament. Individuals with AN may discover that reduced dietary intake, by reducing plasma tryptophan availability, is a means by which they can modulate brain 5-HT functional activity and anxious mood. People with AN enter a vicious cycle which accounts for the chronicity of this disorder because caloric restriction results in a brief respite from dysphoric mood. However, malnutrition and weight loss, in turn, produce alterations in many neuropeptides and monoamine function, perhaps in the service of conserving energy, but which also exaggerates dysphoric mood. In summary, this article reviews findings in brain chemistry and neuroimaging that shed new light on understanding the psychopathology of these difficult and frustrating disorders.

Evening intake of α-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention

Brain serotonin function is thought to promote sleep regulation and cognitive processes, whereas sleep abnormalities and subsequent behavioral decline are often attributed to deficient brain serotonin activity. Brain uptake of the serotonin precursor tryptophan is dependent on nutrients that influence the availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp:LNAA). We tested whether evening consumption of alpha-lactalbumin protein with an enriched tryptophan content of 4.8 g/100 g increases plasma Trp:LNAA and improves alertness and performance on the morning after sleep, particularly in subjects with sleep complaints. Healthy subjects with (n = 14) or without (n = 14) mild sleep complaints participated in a double-blind, placebo-controlled study. The subjects slept at the laboratory for 2 separate nights so that morning performance could be evaluated after an evening diet containing either tryptophan-rich alpha-lactalbumin or tryptophan-low placebo protein. Evening dietary changes in plasma Trp:LNAA were measured. Behavioral (reaction time and errors) and brain measures of attention were recorded during a continuous performance task. Evening alpha-lactalbumin intake caused a 130% increase in Trp:LNAA before bedtime (P = 0.0001) and modestly but significantly reduced sleepiness (P = 0.013) and improved brain-sustained attention processes (P = 0.002) the following morning. Only in poor sleepers was this accompanied by improved behavioral performance (P = 0.05). Evening dietary increases in plasma tryptophan availability for uptake into the brain enhance sustained alertness early in the morning after an overnight sleep, most likely because of improved sleep.

Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers

Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to alterations in the plasma Trp:LNAA ratio and brain 5-HT. In the present study, we tested whether whisky consumption as part of a meal may alter the plasma Trp:LNAA ratio and influence mood and performance in healthy volunteers. Twenty-four healthy male subjects participated in a within-subjects cross-over study. Subjects consumed whisky (125 ml; 40 g alcohol) or water (125 ml) as part of a standard evening meal. Effects of whisky consumption were tested on mood and choice reaction time and blood samples were taken to measure changes in plasma amino acids, glucose and insulin. The plasma Trp:LNAA ratio showed a significant decline 2 h after whisky consumption of alcohol (P<0.001). No effects were found on choice reaction time or mood as compared with the control condition. The present findings reveal that whisky consumption alters available plasma Trp for uptake into the brain, whereas there were no effects on mood and performance.

Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation

There is now some evidence that i) the availability of plasma tryptophan, the precursor of serotonin, is significantly lower in pregnant women at the end of term and the first few days after delivery than in nonpregnant women; and ii) both pregnancy and the early puerperium are accompanied by activation of the inflammatory response system. The aims of the present study were to examine the effects of pregnancy and delivery on plasma kynurenine, a major tryptophan catabolite synthesized after induction of indoleamine-2, 3 dioxygenase (IDO) by pro-inflammatory cytokines. We measured plasma kynurenine and tryptophan and immune markers, such as serum interleukin-6 (IL-6), IL-8 and the leukemia inhibitory factor–receptor (LIF-R) in healthy, nonpregnant and pregnant women at the end of term and one and three days after delivery. Plasma kynurenine was significantly lower in pregnant women at the end of term than in nonpregnant women, findings which may be attributed to lower plasma tryptophan at the end of term. The kynurenine/tryptophan (K/T) quotient was significantly higher in the pregnant women at the end of term and in the early puerperium than in nonpregnant women. In the early puerperium there was a significant increase in plasma kynurenine and the K/T quotient. The increases in plasma kynurenine and the K/T quotient were significantly more pronounced in women whose anxiety and depression scores significantly increased in the puerperium. The changes from the end of term to the early puerperium in plasma kynurenine and the K/T quotient were significantly related to those in the immune markers. It is concluded that 1) lower plasma kynurenine at the end of term is the consequence of lower plasma tryptophan; 2) the increased K/T quotient at the end of term and in the early puerperium indicates inflammation-induced degradation of tryptophan along the kynurenine pathway; and 3) that depressive and anxiety symptoms in the early puerperium are (causally) related to an increased catabolism of tryptophan into kynurenine, a phenomenon which probably results from immune activation.

Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression.

There is now evidence that the availability of plasma tryptophan is decreased during pregnancy and the puerperium and also in patients with major depression and inflammation. The aims of the present study were to examine: (i) the effects of pregnancy and delivery on plasma tryptophan and the amino acids known to compete for the same cerebral uptake mechanism (CAAs), valine, leucine, tyrosine, phenylalanine and isoleucine; (ii) the relationships between the availability of plasma tryptophan and postpartum depression or anxiety; and (iii) the relationships between the availability of plasma tryptophan to the brain and inflammatory markers, such as serum interleukin-6 (IL-6), interleukin-1 receptor-antagonist (IL-1RA) and the leukaemia inhibitory factor receptor (LIF-R). The above variables were measured in 13 healthy non-pregnant and in 98 pregnant women 3 to 6 days before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the state version of Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Plasma tryptophan and the tryptophan/CAA ratio were significantly lower at the end of term and after delivery than in the plasma of non-pregnant, healthy women. The tryptophan/CAA ratio was significantly lower in the early puerperium than at the end of term. There were no significant relationships between the availability of plasma tryptophan and either post-partum depression or changes in the STAI or ZDS scores in the early puerperium. The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R. The results show that the reduction in the availability of plasma tryptophan from the end of term to the early puerperium is related to immune activation; and that the lowered availability of plasma tryptophan is not related either to depressive or anxiety symptoms in the early puerperium or to post-partum depression ensuing some months later.

Serotonergic markers and lowered plasma branched-chain-amino acid concentrations in fibromyalgia

The aims of the present study were to examine serotonergic markers, i.e. [ 3H]paroxetine binding characteristics and the availability of plasma tryptophan, the precursor of serotonin (5-HT), and the plasma concentrations of the branched chain amino acids (BCAAs), valine, leucine and isoleucine, in fibromyalgia. The [ 3H]paroxetine binding characteristics, B max and K d values, and tryptophan and the competing amino acids (CAA), known to compete for the same cerebral uptake mechanism (i.e. valine, leucine, isoleucine, phenylalanine and tyrosine), were determined in fibromyalgia patients and normal controls. There were no significant differences in the [ 3H]paroxetine binding characteristics ( B max and K d) between fibromyalgia and control subjects. There were no significant differences in plasma tryptophan or the tryptophan/CAA ratio between fibromyalgia patients and normal controls. In the fibromyalgia patients, there were no significant correlations between [ 3H]paroxetine binding characteristics or the availability of tryptophan and myalgic or depressive symptoms. Patients with fibromyalgia had significantly lower plasma concentrations of the three BCAAs (valine, leucine and isoleucine) and phenylalanine than normal controls. It is hypothesized that the relative deficiency in the BCAAs may play a role in the pathophysiology of fibromyalgia, since the BCAAs supply energy to the muscle and regulate protein synthesis in the muscles. A supplemental trial with BCAAs in fibromyalgia appears to be justified.

Suicidal behaviour in schizophrenia: A retrospective study

The aims of the present study were to examine (1) the inflammatory response system (IRS), through measurements of serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130 (the soluble form of the IL-6 transducer signal protein), CC16 (Clara Cell protein; an endogenous anti-cytokine), IL-1R antagonist (IL-1RA), IL-8 and sCD14; and (2) the availability of plasma total tryptophan to the brain in chronic alcoholic patients without apparent liver disease (AWLD). Detoxified AWLD patients had significantly lower plasma tryptophan and serum CC16 and significantly higher serum IL-1RA and IL-8 concentrations than normal volunteers. There were significant correlations between the availability of tryptophan to the brain and serum IL-6, IL-8 and IL-1RA (all negative) and CC16 (positive). The results suggest that (1) there is, in detoxified AWLD patients, an activation of the monocytic arm of cell-mediated immunity and a lowered anti-inflammatory capacity of the serum; and that (2) lower availability of plasma tryptophan to the brain in detoxified AWLD patients is related to activation of the IRS. Lower CC16 may be one factor predisposing chronic alcoholic patients toward infectious disorders. © 1998 Elsevier Science Ireland Ltd

Relationships of plasma tryptophan availability to course of illness and clinical features of alcoholism: a preliminary study.

Serotonergic (5-HT) mechanisms may be involved in impulse control (including antisocial behavior) across psychiatric syndromes. Age of onset may differentiate alcoholics on psychopathological characteristics associated with impulse control, especially mood disturbance, hostility, and a broad range of antisocial behaviors. Thus, there may be a predictable relationship between markers of 5-HT function and age of onset-related characteristics. We tested the hypothesis that there would be a predictable relationship between the ratio of plasma tryptophan to large neutral amino acids (i.e. TRYP/LNAA ratio), a marker of 5-HT function, age of onset and related psychopathological characteristics associated with impulse control. Fifty-eight male and female DSM-IV diagnosed alcoholics attending an outpatient treatment center completing a comprehensive psychopathological assessment, and from whom blood samples were obtained. Plasma TRYP/LNAA ratio was positively correlated with symptoms of dysphoria, and negatively associated with harm avoidance on Cloninger's Temperament and Character Inventory. Low tryptophan availability was associated with antisocial-type personality characteristics. Interestingly, the few (nine) subjects who had both early onset alcoholism and antisocial personality disorder had a higher plasma tryptophan but similar TRYP/LNAA ratio to the others. These data suggest that a low plasma TRYP/LNAA ratio is associated with susceptibility to anxiety, antisocial-type personality characteristics, and an early age of onset for alcoholism. In contrast, a high plasma TRYP/LNAA ratio is associated with a later onset of alcoholism and dysphoria.

Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer's disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT.

The aims of this study were to examine the plasma availability of tryptophan, the precursor of 5-hydroxytryptamine (5-HT), and serum cytokines, such as interleukin-6 (IL-6) and IL-8, in normal elderly volunteers and in patients with Alzheimer's disease (DAT). Elderly normal volunteers (mean age = 78.3 +/- 5.7 years) had a significantly lower tryptophan/competing amino acids (valine + leucine + isoleucine + phenylalanine + tyrosine) ratio than younger subjects (mean age = 32.9 +/- 8.1 years). In normal volunteers, there were significant and inverse relationships between age and either plasma tryptophan or the tryptophan/competing amino acids ratio, and between the availability of tryptophan to the brain and serum IL-6 or IL-8. DAT patients had significantly higher serum IL-6, but not IL-8, than age-matched normal volunteers. There were no significant differences in the availability of tryptophan to the brain between DAT patients and age-matched normal volunteers. The results suggest that: 1) in normal humans, the availability of plasma tryptophan to the brain decreases with age, and with activation of the immune system; and 2) increased production of IL-6 may play a role in the pathogenesis of DAT.

The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression

Background: It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions. Aims and Methods: The aims of the present study were to examine: (i) immune-inflammatory markers, i.e. serum interleukin-6 (IL-6), IL-8, IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA), gp130, and prostaglandin E2 (PGE2) production by mitogen-stimulated whole blood and the availability of plasma tryptophan in patients with primary sleep disorders, major depression and healthy volunteers; and (ii) the relationships between the availability of tryptophan and indicators of the immune-inflammatory response system. Results: Mitogen-stimulated release of PGE2, and serum IL-6 and IL-8, were significantly increased in both depressed and sleep disordered patients compared to normal controls. Serum IL-1RA was significantly higher in depressed patients than in normal controls. Patients with depression and sleep disorders had a significantly lower availability of tryptophan than normal controls. There were significant and inverse relationships between the availability of plasma tryptophan and serum IL-1RA, IL-6 and IL-8. Conclusions: The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.

Serotonin-immune interactions in detoxified chronic alcoholic patients without apparent liver disease: activation of the inflammatory response system and lower plasma total tryptophan

The aims of the present study were to examine (1) the inflammatory response system (IRS), through measurements of serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130 (the soluble form of the IL-6 transducer signal protein), CC16 (Clara Cell protein; an endogenous anti-cytokine), IL-1R antagonist (IL-1RA), IL-8 and sCD14; and (2) the availability of plasma total tryptophan to the brain in chronic alcoholic patients without apparent liver disease (AWLD). Detoxified AWLD patients had significantly lower plasma tryptophan and serum CC16 and significantly higher serum IL-1RA and IL-8 concentrations than normal volunteers. There were significant correlations between the availability of tryptophan to the brain and serum IL-6, IL-8 and IL-1RA (all negative) and CC16 (positive). The results suggest that (1) there is, in detoxified AWLD patients, an activation of the monocytic arm of cell-mediated immunity and a lowered anti-inflammatory capacity of the serum; and that (2) lower availability of plasma tryptophan to the brain in detoxified AWLD patients is related to activation of the IRS. Lower CC16 may be one factor predisposing chronic alcoholic patients toward infectious disorders. © 1998 Elsevier Science Ireland Ltd

The Effects of Dieting on Plasma Tryptophan Concentration and Food Intake in Healthy Women

Wolfe, B. E., E. D. Metzger and C. Stollar. The effects of dieting on plasma tryptophan concentration and food intake in healthy women. Physiol Behav 61(4) 537–541, 1997.—Although many people diet, relatively few dieters are successful in maintaining weight loss. The extent to which dieting behavior might dampen satiety responses normally mediated by the neurotransmitter serotonin remains uncertain. This study tested the hypothesis that dieting behavior decreases the availability of plasma tryptophan (TRP) and the ratio of TRP to other branched-chain amino acids (BCAA) that compete for entry into the central nervous system (CNS). This effect could diminish the CNS concentration of TRP, the amino acid precursor for serotonin synthesis, thus interfering with serotonin-mediated influences on food intake. Using a fixed-order design, 15 healthy, normal-weight women were studied longitudinally during an ad lib dietary intake phase and a subsequent reduced-calorie diet phase. Physiological and behavioral measures were collected at baseline, at the end of the ad lib-intake phase, and at the end of the 4-week study diet phase. Food intake was measured by a single-item test meal. Plasma TRP and TRP:ΣBCAA significantly decreased following the study diet compared to baseline (p < 0.05). Change in TRP and TRP:ΣBCAA significantly correlated with decrease in body weight (p < 0.01). No significant relationship was observed between postdiet change in TRP or TRP:ΣBCAA ratio and postdiet change in test meal food intake, with covariation for weight loss. The observed decreases in plasma TRP and TRP:ΣBCAA extend previous reports suggesting that dieting behavior may diminish central serotonin function through a reduction in precursor availability.

Dieting decreases plasma tryptophan and increases the prolactin response to d-fenfluramine in women but not men

We studied the effect of 3 weeks of moderate calorie restriction on 5-HT-mediated prolactin (PRL) release in healthy volunteers using the 5-HT-releasing agent d-fenfluramine. In women, dieting significantly lowered plasma total and free tryptophan (TRP) and increased the PRL response to d-fenfluramine. None of these measures were altered in men who dieted. These findings add to the data indicating that dieting alters brain 5-HT function in women, perhaps as a consequence of reducing the availability of plasma TRP.

Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss

Plasma total tryptophan (TRP) concentration was significantly lower in 31 patients with major depression compared to a healthy control group. The ratio of plasma TRP concentration to that of other branch chain amino acids (the TRP: BCAA ratio) was also decreased. Further analysis revealed that the decrease in plasma TRP and TRP: BCAA ratio was most apparent in patients with major depression and melancholia. Overall, women but not men had significantly decreased plasma tryptophan concentrations, perhaps because of a contributory effect of weight loss; this latter effect, however, could not be distinguished clearly from a diagnosis of melancholia. Our data suggest that in some depressed patients, reductions in plasma tryptophan availability may contribute to abnormalities in brain 5-hydroxytryptamine function.

Tryptophan availability: The importance of prepartum and postpartum dietary protein on brain indoleamine metabolism in rats

Alterations in brain tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations occurred in rats as a consequence of dietary protein insufficiencies during prenatal and/or postnatal development. Rats born to dams fed normal (25% casein) or low (8% casein) protein diets starting 5 weeks prior to conception were cross-fostered at birth to dams of the opposite diet. At 21 days of age, their indoleamine metabolism was compared to that of unswitched rats of each diet group. All animals subjected to protein malnutrition during either the prenatal and/or postnatal developmental periods had similar elevations in brain tryptophan, amine, and metabolite concentrations compared to developmentally well-nourished pups. Although the three groups of animals which experienced protein deprivation displayed similar increases in brain indoleamine concentrations, this resulted from different modifications in peripheral metabolic processes controlling free plasma tryptophan availability. For both the prenatal/postnatal and postnatal only protein-deprived pups, lactational malnutrition produced increases in free tryptophan availability for brain metabolism by decreasing a major determinant of this process (the tryptophan to albumin ratio) as a result of the significant lowering of total tryptophan and albumin concentrations in plasma. Animals experiencing protein deficiencies during prepartum existence only, showed increases in free tryptophan availability due to permanent alterations in constituents (total tryptophan, albumin, and nonesterified fatty acid concentrations) affecting the competition between nonesterified fatty acids and tryptophan for binding on albumin that were not reversed by adequate postpartum nutrition. Overall, the present data demonstrate that the nutritional status with respect to the amount of dietary protein during prepartum and postpartum development has an important role in determining subsequent brain tryptophan metabolism.

Tryptophan availability: Relation to elevated brain serotonin in developmentally protein-malnourished rats

Developmental changes in tryptophan, serotonin, and 5-hydroxyindoleacetic acid in many brain regions were examined in normal and protein-malnourished rats from birth to age 30 days. The malnourished rats, whose dams received a diet low in protein starting 5 weeks prior to conception, showed significantly elevated brain tryptophan, serotonin, and 5-hydroxyindoleacetic acid at most ages examined. Brain tryptophan concentrations for both groups of animals showed a positive correlation with their respective unbound plasma tryptophan concentrations. Although the malnourished animals showed lower total plasma tryptophan concentrations than the control group, the amount of free plasma tryptophan available for brain metabolism was significantly higher in the malnourished rats. This was due, in part, to a decrease in the molar ratio of bound tryptophan to albumin in the malnourished animals. In addition, those malnourished rats had lower albumin levels and higher concentrations of nonesterified fatty acids as compared to the normal animals, causing more tryptophan to be available as the free form in plasma. Overall, the present results demonstrate that rearing rats on a diet low in protein but adequate in all other respects significantly elevates brain tryptophan and amine concentrations, probably as a consequence of developmental alterations in plasma tryptophan availability.

Effect of aminophylline on tryptophan and other aromatic amino acids in plasma, brain and other tissues and on brain 5-hydroxytryptamine metabolism.

1 Aminophylline and other methylxanthines increase brain tryptophan and hence 5-hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated. 2 At lower doses (greater than 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain. 3 Plasma unesterified fatty acid did not increase when aminophylline (109 mg/kg i.p.) was given to nicotinamide-treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred. 4 The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose. 5 The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenyllanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose. 6 The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected. 7 The aminophylline-induced increase of the ratio of brain tryptophan of plasma free tryptophan no longer occurred when the drug was given to animals injected with the beta-adrenoreceptor blocking agent propranolol or the diabetogenic agent streptozotocin. 8 The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.

The control of tryptophan metabolism.

This volume as a whole describes enzyme induction mechanisms and the influences of enzyme induction upon metabolism and its control. The present chapter deals with various ways in which the metabolism of a single amino acid tryptophan is controlled. While processes influencing this include induction, the de novo synthesis of enzymes which metabolize tryptophan is only one of a variety of ways in which its metabolism is apportioned between various pathways. For example, altered activity of existing enzyme molecules and altered availability of plasma tryptophan for metabolism are also important. The roles of these factors will therefore be discussed as well as that of induction. Mechanisms of a less specific nature such as altered availability of tissue amino acid pools are described in detail elsewhere (Munro, 1970) and will not be dealt with here.KeywordsTryptophan MetabolismTryptophan LevelTryptophan ConcentrationPlasma TryptophanFree TryptophanThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.