Brain Tryptophan Concentrations Research Articles

Effect of isoprenaline infusion on the distribution of tryptophan, tyrosine and isoleucine between brain and other tissues

Intravenous infusion of anaesthetized rats with the β-adreno-receptor agonist isoprenaline decreased plasma total tryptophan concentration and increased both plasma free and brain tryptophan concentrations. Muscle tryptophan and also tyrosine concentrations showed moderate significant decreases, but concentrations in liver and kidney did not alter significantly. Plasma tyrosine concentration fell and brain tyrosine concentration rose, but these changes were less marked than those of tryptophan. Isoprenaline infusion considerably increased egress of 14C-tryptophan from plasma and moderately increased egress of 14C-isoleucine, but did not alter egress of 14C-tyrosine. However, 5 min after pulse injection of any of the above 14C-labelled amino acids, the isoprenaline-infused rats had higher brain counts than control animals. Results are consistent with previous evidence that increased availability of tryptophan to the brain can occur in stressful situations.

Effects of enkephalins and two enzyme resistant analogues on monoamine synthesis and metabolism in rat brain

Methionine-enkephalin and leucineenkephalin, administered into the lateral ventricle of intact rats, increased the accumulation of DOPA by a naloxone-sensitive mechanism in different brain regions after inhibition of the aromatic l-amino acid decarboxylase. Because of the rapid enzymatic degradation of both enkephalins large doses (500 μg) were required to enhance brain catecholamine synthesis. The two enzyme resistant enkephalin analogues d-Ala2-methionine enkephalin amide (DALA (4–256 μg) and FK 33-824 (0.003–1 μg) also increased the synthesis of DOPA, dose-dependently and by naloxone-sensitive mechanisms, but at much lower dosage level. The enkephalins markedly enhanced the brain tyrosine concentration but this effect was not antagonized by naloxone, probably because the enzymatic cleavage releases tyrosine from the administered peptides. In contrast, neither DALA nor FK 33-824 increased the brain tyrosine concentration. The formation of 5-HTP and the brain tryptophan concentration were also increased by the enkephalins, although these effects were not blocked by naloxone. The enkephalin analogues, however, enhanced the formation of 5-HTP and the brain tryptophan concentration by naloxonesensitive mechanisms. All four peptides accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine after inhibition of monoamine synthesis. The results suggest that endogenous enkephalins, through the activation of opiate receptors, are involved in the short-term regulation of central monoaminergic systems.

Effect of doxepin on serotonin metabolism in rat brain and serotonin uptake by human blood platelets

1. 1. Application of doxepin, an antidepressant with tertiary amine group, in a dose of 60 mg/kg i.p. produced a marked increase in the concentration of rat brain tryptophan and slight, but statistically significant elevation in serotonin (5-HT) concentration. 2. 2. Two hours after the doxepin injection no change in the steady state level of brain 5-hydroxyindoleacetic acid (5-HIAA) was observed. However, in rats treated with pargyline, an inhibitor of monoamine oxidase (MAO), doxepin retarded 5-HIAA decline. Moreover, in rats receiving probenecid, a drug that blocks elimination of acidic metabolites from central nervous system (CNS), doxepin decelerated the rate of 5-HIAA accumulation. 3. 3. In vitro doxepin inhibited the uptake of 5-HT into human blood platelets. 4. 4. Our data indicate, that doxepin exerts its effect on brain serotoninergic neurons by same or similar mechanisms as the other tricyclic antidepressants with tertiary amine in side chain, i.e. by inhibition of 5-HT reuptake mechanism.

Effect of food restriction on serotonin metabolism in rat brain.

The brain concentration of 5-hydroxytryptamine (5-ht) and 5-hydroxyindoleacetic acid (5-HIAA) increased in rats maintained on restricted volume of low-protein or normal-protein diet, whereas these two agents decreased in rats fed low-protein diet ad libitum. In these two food-restricted groups brain 5-HT and 5-HIAA concentrations were not correlated with brain tryptophan hydroxylase activity, but the concentrations correlated closely with cerebral tryptophan concentrations. The cerebral tryptophan concentration in the two food-restricted groups was not consistent with the total or free tryptophan concentration in plasma. In these restricted rats cerebral tryptophan concentration was elevated, and, unlike the plasma tryptophan, it showed no diurnal variation. These results suggested that tryptophan uptake into the brain from plasma was enhanced by limiting food volume intake. Tryptophan uptake was increased by glucagon injection without changing the plasma tryptophan level, but injection of hydrocortisone or insulin had little or no effect on tryptophan concentration in either the plasma or brain. D-Glucose injection elevated plasma tryptophan concentration but decreased brain tryptophan concentration.

TRYPTOPHAN TRANSPORT ACROSS THE BLOOD‐BRAIN BARRIER DURING ACUTE HEPATIC FAILURE

Abstract— Tryptophan transport across the blood‐brain barrier was studied using a single injection dual isotope label technique, in the following three conditions: normal rats, rats with portacaval shunts, and rats with portacaval shunts followed 65 h later by hepatic artery ligation. In both normal rats and those with acute hepatic failure the tryptophan transport system was found to be comprised of two kinetically distinct components. One component was saturable and obeyed Michaelis‐Menten kinetics (normal: Vmax= 19.5 nmol.min−1.g−1. Km= 113 μM; hepatic failure: Vmax, = 33.8 nmol.min−1.g−1, Km= 108 μM), and the second was a high capacity system which transported tryptophan in direct proportion to concentration over the range tested (normal: K= 0.026 ml.min−1.g−1; hepatic failure: K= 0.067 ml.min−1.g−1). Since the saturable low capacity component transports several neutral amino acids, and their collective plasma concentration is high in relation to the individual Kms, tryptophan transport by this component is reduced by competitive inhibition under physiological conditions. Thus it was calculated that in normal rats approx 40% of tryptophan influx occurs via the high capacity system. During acute hepatic failure transport via both components was increased substantially, approximately doubling the rate of tryptophan penetration of the blood‐brain barrier at all concentrations tested. The contribution by the high capacity component became even more significant than in normal rats, accounting for about 75% of all tryptophan passage from plasma to brain. Brain tryptophan content was 29.9 nmol/g in normal rats and rose to 45.2 nmol/g in rats with portacaval shunts and 50.5 nmol/g in those with acute hepatic failure, correlating with the increased rate of tryptophan transport. In a previous study we found that plasma competing amino acids were greatly increased during acute hepatic failure. Calculations predict that these increased concentrations would cause a reduction in tryptophan transport by the low capacity system. However, because of the increase in the rate of transport by the high capacity component, net tryptophan entry across the blood‐brain barrier was actually increased. This increased rate of transport clearly contributes to the increased content of brain tryptophan found during hepatic failure.

The effect of morphine and some other narcotic analgesics on brain tryptophan concentrations.

An acute dose of morphine increased brain tryptophan in mice. This effect was not prevented by naloxone nor was it produced by other narcotic analgesics. Dextrorphan, but not levorphanol, had a similar effect to morphine. A large dose of tryptophan had no effect on the antinociceptive action of morphine in mice. Morphine increased brain tryptophan in rats. This effect was prevented by naloxone. A large dose of tryptophan antagonised the antinociceptive action of morphine in the rat.

Neurotensin and its amide analogue [Gln4]-neurotensin: effects on brain monoamine turnover.

Intracerebroventricularly administered neurotensin and [Gln4]-neurotensin (50-200 microgram) increased the formation of Dopa in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. For both neuropeptides these increases were dose dependent (20-150%). In the corpus striatum [Gln4]-neurotensin was twice as active as neurotensin and it tended to be more active also in other brain regions. The brain tyrosine concentrations were also increased. [Gln4]-neurotensin (100-200 microgram) following inhibition of the aromatic L-amino acid decarboxylase, increased the accumulation of 5-hydroxytryptophan in all brain regions by 30-60%. In contrast, neurotensin was completely inactive. In both cases the brain tryptophan concentrations were increased. Both neurotensin and [Gln4]-neurotensin also accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine after inhibition of monoamine synthesis. These results show an increased brain monoamine turnover induced by both neuropeptides.

A study of proposed determinants of brain tryptophan concentration in rats after portocaval anastomosis or sham operation.

AbstractLiver dysfunction was produced in rats by surgical portocaval anastomosis (PCA), and the time‐course of changes in brain tryptophan and 5‐HT metabolism studied in relation to plasma changes possibly influencing brain tryptophan concentration.Brain tryptophan and 5‐hydroxyindolylacetic acid (5‐HIAA) levels were increased greatly and maximally on the day after PCA and remained high. 5‐HT changes were less marked but had a similar time‐course. Plasma total tryptophan was little changed but plasma free tryptophan was raised. The latter change showed a similar time‐course to that of brain tryptophan but was not large enough to account completely for it. Sham operation was followed by significant but transient increases in plasma free tryptophan, brain tryptophan and 5‐HIAA but these were much smaller than after PCA.Brain tryptophan did not correlate with plasma total tryptophan either in control or PCA rats but it correlated significantly with plasma free tryptophan in both groups. However brain levels were much higher in PCA rats than in controls with similar plasma free tryptophan levels at all times from the first day after operation. The increase of brain tryptophan in anastomosed rats not accounted for by plasma free tryptophan was explained neither by insulin changes nor by an increase of the insulin/glucagon ratio nor by changes in plasma concentrations of those amino acids which compete with tryptophan for entry into brain. The results therefore indicate an unknown influence on brain tryptophan concentration in PCA rats. As tyrosine changes in brain and plasma after PCA were very similar to those of tryptophan this influence may not be specific to tryptophan. Results suggest that under the conditions used brain tryptophan concentrations of both PCA and control rats are more influenced by changes of plasma free tryptophan concentration than by changes of plasma concentrations of competing amino acids.

Modification by monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice.

A single injection of phenelzine 100 mg kg-1 given 18 h before, decreased the analgesia and hypothermia induced by morphine, but potentiated the analgesic and hypothermic effects of pethidine, when the analgesics were administered either intraperitoneally, or intracerebroventricularly. The modification of pethidine analgesia and hypothermia, but not morphine analgesia, was antagonized by methysergide (10 mg lg-1, s.c.). The LD50 of pethidine, but not that of morphine, was 30-40% lower in mice treated with phenelzine tranylcypromine or iproniazid 6 h before the test. The increased lethality of a single dose of pethidine induced by phenelzine was also prevented by methysergide. Pretreatment of mice with 100 mg kg-1 phenelzine was followed by a significant rise in both brain tryptophan and 5-hydroxytryptamine (5-HT) concentrations which lasted for 24 h. Therefore, the changes in pethidine effects could have been due to raised brain tryptophan and 5-HT concentrations.

Effect of d-amphetamine on tryptophan and other aromatic amino acids in brain

This investigation examined the mechanism of the increase in brain tryptophan concentration of rats treated with d-amphetamine. Certain well recognised influences upon brain trytophan have been excluded as responsible. Thus, the effect is not associated with changes in the plasma concentrations of NEFA or free tryptophan. It is probably not due to a tryptophan-specific mechanism, because amphetamine increases the ratio of brain/plasma concentrations not only of tryptophan but also of tryrosine and phenylalanine. The concentration ratios for liver/ plasma also rose, as did the liver tryptophan concentration, but these changes were less striking than for brain. Both α- and β-adrenergic blocking drugs opposed the changes in brain, but in different ways. Thus, after treatment of rats with phentolamine, amphetamine decreased the plasma concentrations of the three aromatic amino acids; however, as the brain concentrations were little altered, the brain/plasma concentration ratios rose. Propranolol (and the dopamine blocker pimozide) opposed the increases of the ratios, so that the brain concentrations again altered little. The increased brain/plasma ratios resulting from the administration of amphetamine were associated with hyperthermia. Propranolol, pimozide and the diabetogenic drug streptozotocin opposed the changes in both plasma and brain; phentolamine affected neither. Despite the increase in brain tryptophan caused by amphetamine this drug had relatively little concurrent effect on 5HT synthesis. Experiments with adrenergic blockers suggest that the small rise of plasma insulin after the injection of amphetamine into rats did not cause the brain changes; these are probably a consequence of hyperthermia. The findings with streptozotocin suggest that the hyperthermic effect of amphetamine is manifested only in states of normal insulin secretion.

Effects of clofibrate on plasma tryptophan, growth hormone, and prolactin and on brain tryptophan and serotonin in prepubertal rats

The effects of clofibrate administration (200 mg/kg, po) on somatic growth, plasma levels of lipids, tryptophan, growth hormone (GH), and prolactin (PRL), as well as on brain concentrations of tryptophan and 5-hydroxytryptamine (5-HT) were studied in prepubertal male rats. The drug did not significantly alter ponderal growth, but an appreciable reduction of tail length was observed in rats treated for 30 days. Triglyceride concentrations in plasma showed a 43% diminution after 30 days of treatment, whereas free fatty acid (FFA) levels were not modified. Clofibrate administration for 7, 15, or 30 days caused a fall in total tryptophan and a significant increase of the free fraction in plasma with no change in brain tryptophan levels. Brain 5-HT was generally unaffected but a marked elevation of this parameter was noted in rats treated for 15 days. Plasma GH and PRL concentrations remained unaltered. It may be concluded from these findings that the slight reduction of somatic growth, the diminution of triglycerides, and the increase of free tryptophan in plasma, induced by chronic clofibrate treatment, are not associated with variations in brain tryptophan and 5-HT levels or with modifications of plasma GH and PRL titers.

Effects of insulin and streptozotocin-induced diabetes on brain tryptophan and serotonin metabolism in rats.

Abstract—Previous work by other authors has shown hat insulin administration increases brain tryptophan levels and serotonin (5–HT) metabolism. The present study partially replicates these results and tests whether these effects could be due to insulin‐induced hypoglycemic stress, since stressers such as immobilization or food deprivation also increase brain tryptophan and 5‐HT metabolism. Ingestion of a dextrose solution by rats administered insulin (2 I.U./kg) prevents the extreme fall in blood glucose concentration and rise in plasma corticosterone following insulin injections alone. This treatment, however, produces a larger increase in brain tryptophan (30%) than insulin‐injected rats allowed only tap water. The greater accumulation of brain tryptophan may reflect an additive effect of the endogenously released insulin to that exogenously administered, since ingestion of the dextrose solution could trigger insulin secretion. In addition, brain tryptophan and 5‐HT metabolism were measured in streptozotocin‐diabetic rats maintained on several different feeding schedules to control for the effects of hyperphagia. All groups of diabetics showed significant decreases of approx 30% in brain tryptophan concentrations, while 5‐HT metabolism was unchanged. This deficit in brain tryptophan is reversed within 2 h after insulin administration (2 I.U./kg). These results indicate that changes in brain tryptophan and 5‐HT metabolism following insulin injections are not due to hypoglycemic stress, and that brain tryptophan is low in diabetics but increases above normal after administration of insulin. The results are discussed with respect to the effects of insulin on plasma levels of the neutral amino acids and a possible direct effect of insulin on the uptake of tryptophan by brain.

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.

Fatty acid and tryptophan changes on disturbing groups of rats and caging them singly

The effects of disturbing groups of 24 hr fasted rats on plasma unesterified fatty acid (UFA) and tryptophan concentrations and brain tryptophan concentrations were investigated. Removing rats from cages rapidly increased plasma UFA and corticosterone and decreased plasma and whole blood tryptophan of cage mates. The disturbance also appeared to influence biochemical values of rats in other cages within the same chamber. Effects specific to individual cages were also suggested. In subsequent experiments 24 fasting rats caged together were rapidly transferred to 24 separate cages and killed at intervals. Plasma UFA rose to a maximum by 12 min and then tell toward initial values. Plasma total tryptophan concurrently fell then rose. Its percentage in the free (ultrafilterable) state, and in some experiments the absolute values of free tryptophan rose then fell. When the latter rise was marked then brain tryptophan and the 5-HT metabolite 5-hydroxyindoleacetic acid rose. Tyrosine changes were negligible. Thus altered brain tryptophan level and 5-HT metabolism may be associated with plasma tryptophan changes caused by brief environmental disturbance.

Role of free serum tryptophan on brain tryptophan concentration after oral glucose administration

Role of free serum tryptophan on brain tryptophan concentration after oral glucose administration

Environmental, Toxicological, and Related Aspects of Tryptophan Metabolism with Particular Reference to the Central Nervous System

AbstractIX. SUMMARYTryptophan is unique among the amino acids as it is present largely in the plasma bound to albumin. The binding is decreased by various drugs and unesterified fatty acids. As synthesis of the latter substance is influenced by sympathetic nervous activity, the binding of plasma tryptophan can be markedly dependent on changes of environmental and internal milieu. One consequence of these relationships is that changes of plasma tryptophan binding may lead to changes of brain tryptophan concentration and, thus, to altered synthesis of the neurotransmitter 5-hydroxytryptamine and, hence, to the possibility of altered behavior. Other mechanisms, such as competition between tryptophan and other plasma amino acids for uptake by the brain, can also influence brain tryptophan concentration.Various components of behavior such as sleep, motor activity, food intake, pain sensitivity, and aggression respond to changes of brain 5-hydroxy -tryptamine synthesis. In general, these behavioral parameters i...

Tryptophan concentrations in rat brain. Failure to correlate with free serum tryptophan or its ratio to the sum of other serum neutral amino acids.

Groups of rats were deprived of food overnight and then given free access to diets designed to raise (carbohydrate) or lower (carbohydrate and large neutral amino acids) brain tryptophan concentrations. Similar diets were supplemented with 40% fat and fed to other groups. All animals were killed 2h after food presentation. Sera from animals fed carbohydrate plus fat contained 2.5 times as much free tryptophan concentrations did not differ. Similarly, sera from rats fed on carbohydrate, large neutral amino acids, and 40% fat contained 5 times as much free tryptophan as those from rats given this meal without fat, but brain tryptophan concentrations increased by only 26%. Correlations were made between brain tryptophan and (1) free serum tryptophan, (2) the ratio of free serum tryptophan to the sum of the other large neutral amino acids in serum that compete with it for uptake into the brain, (3) total serum tryptophan or (4) the ratio of total serum tryptophan to the sum of its circulating competitors. The r values for correlations (3) and (4) (i.e. those involving total serum tryptophan) were appreciably higher than those for correlations (1) and (2). Brain tyrosine concentrations also were found to correlate well with the ratio of serum tyrosine to the sum of its competitors. Competition for uptake into the brain among large neutral amino acids (represented here by serum ratios) thus appears to determine the changes in the brain concentrations of these amino acids under physiological conditions(i.e. after food consumption). Total, not free, serum tryptophan is the relevant index for predicting brain tryptophan concentrations.

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.

Effects of methylmercury on brain biogenic amines in the developing rat pup

Neonatal rat pups were dosed ip with methylmercury chloride, 5 mg/kg/day, on Days 5, 6, and 7 after birth. Peak brain concentrations of methylmercury were observed 1–3 days after the last injection. The t 1 2 of methylmercury in the brain was 6.6 days. This nonlethal dose produced an initial decrease (on Day 8) in brain 5-HT, 5-HIAA, NE, and DA in the rat pups. Subsequently, the concentrations of these brain constituents increased toward, and then exceeded, control values by Day 15. The initial decreases in the monoamine concentrations were associated with high amounts of methylmercury in the brain, while increased concentrations were seen when the amount of the poison was low. After Day 15 no consistent trends were observed in brain catecholamine concentrations after methylmercury treatment; large deviations from control were noted. Serotonin, on the other hand, continued to rise above control and remained elevated until the end of the experiment (Day 60). This monoamine was further studied with respect to early methylmercury exposure. Methylmercury-treated rat pups displayed decreases in brain tryptophan content, tryptophan hydroxylase activity, and serotonin turnover rate on Day 8 of the experiment. The rat pups matured normally, and no overt signs of the early poisoning were observed.

THE EFFECT OF l‐DOPA AND AN INHIBITOR OF PERIPHERAL DECARBOXYLATION ON GLUCOSE METABOLISM IN BRAIN1

Abstract– The effect of the administration of l‐DOPA plus an inhibitor of peripheral l‐aromatic amino acid decarboxylase (aromatic‐l‐amino‐acid carboxy‐lyase; EC 4.1.1.28) on the metabolism of glucose in brain was studied by administering [U‐I4C]glucose (20μCi) to three groups of rats: (1) rats that had been injected with l‐DOPA (200mg/kg) 28min earlier; (2) rats that had been similarly injected with l‐DOPA and also with N‐(d,l‐seryl)‐N′‐(2,3,4‐trihydroxybenzyl)hydrazine (50 mg/kg), an inhibitor of l‐aromatic amino acid decarboxylase, 30min before the l‐DOPA; and (3) appropriate controls. The flux of 14C from glucose in plasma to those amino acids that are in equilibrium with the tricarboxylic acid cycle intermediates was reduced by treatment with l‐DOPA and reduced further by treatment with l‐DOPA and the decarboxylase inhibitor. Concentrations of glucose in brain and in plasma were increased after treatment with l‐DOPA; these increases were attenuated if the inhibitor was given before the l‐DOPA. After treatment with l‐DOPA, there were decreases in the concentration of aspartate, tryptophan, and tyrosine in brain. After the administration of l‐DOPA and the decarboxylase inhibitor, the concentrations in brain of alanine, glutamate, tyrosine, and phenylalanine were greater, and the concentrations of aspartate, leucine, lysine, histidine, arginine, and tryptophan were less than in control rats.