Increased Brain Tryptophan Research Articles

?-Adrenergic Effects on Plasma and Brain Large Neutral Amino Acids Are Unaltered by Chronic Administration of Antidepressants

Effects of isoproterenol (3 mg kg-1, i.p. for 60 min) and salbutamol (3, 10 mg kg-1, i.p. for 60 min) on large neutral amino acid concentrations in rat plasma and brain were assessed. Phenylalanine, leucine, isoleucine, and valine were measured by gas chromatography with electron-capture detection; tyrosine and tryptophan were measured by HPLC with electrochemical detection. These drugs induced increases in brain tryptophan, tyrosine, phenylalanine, and valine and decreases in plasma tryptophan, tyrosine, leucine, isoleucine, and valine. Effects of salbutamol (3 mg kg-1, i.p. for 60 min) were assessed following chronic administration of phenelzine sulfate and desipramine.HCl (each drug 10 mg kg-1 per day, s.c. via Alzet 2ML4 osmotic minipumps for 28 days). There were no effects of these antidepressants on basal levels of large neutral amino acids in brain and plasma. In both brain and plasma, salbutamol-induced changes in large neutral amino acids were unaffected by these antidepressants. The results indicate that beta-adrenoceptor-regulated availability of plasma and brain large neutral amino acids is unaffected by chronic administration of tricyclic or monoamine oxidase inhibitor antidepressants.

Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat

1 The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat. 2 Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg-1 dose. 3 Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine. 4 Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase-inhibitory mechanism. Cerebral 5-hydroxytryptamine (5-HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg-1. With larger doses, decreased 5-HT turnover, probably as a result of 5-HT uptake inhibition, was the more dominant feature. 5 Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non-esterified fatty acids or glucose. 6 It is concluded that, in addition to inhibiting brain 5-HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5-HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.

Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan

Previous morphological studies reported that serotonergic neurons appear in rats in the second half of prenatal life. Initially the biochemical differentiation of these neurons before birth was studied. Both serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) wese detected in the fetal brain on day 15 of gestation. During prenatal development an increase was detected in the brain levels of 5-HT (200% higher on day 19 than on day 15) and 5-HIAA (700% higher on day 19 than on day 15). Oral administration of tryptophan to pregnant rats induced a dose-related increase of tryptophan concentration in different fetal tissues, including brain. The increase in tryptophan tissue concentration was detected for low doses (50 mg/kg) and remained unsaturated after administration of high doses (1000 mg/kg). This observation suggests that the placental barrier is not effective to block the influx of high levels of tryptophan to the fetus. Tryptophan concentration in the brain is 300% higher than in the carcass and 600% higher than in the placenta. These data suggest a mechanism to assume a role in concentrating of tryptophan in the brain. Finally, it was found that an increase in brain tryptophan induced changes in both serotonin and 5-HIAA brain levels, but did not modify tyrosine, dopamine or norepinephrine levels. Thus, under physiological conditions, tryptophan hydroxylase activity in prenatal brain is probably not saturated by its substrate tryptophan.

Changes in plasma amino acid and subjective sleepiness ratings in humans after consumingL-tryptophan/maltodextrin mixes

In animals, there is some evidence that increasing brain tryptophan (TRP) levels can increase brain serotonin (5-HT) synthesis and facilitate sleep onset. The plasma ratio of TRP to the other large neutral amino acids (TRP/LNAA ratio) must at least triple before detectable increases in brain 5-HT occur. In young men, consumption of 500 mg TRP combined with a carbohydrate (CHO) load will triple this ratio. In a study on 72 volunteers with mild insomnia, using subjective ratings of sleep onset and quality, this combination significantly decreased sleep latency. We noticed, however, that young women seemed to be particularly responsive to the sleepiness-inducing effects of TRP/CHO mixes. The present study was designed to examine more closely the effects of TRP/CHO mixes on subjectively rated sedation in young women and to check if their plasma amino acid response differs from that of men. On three evenings, nine healthy young women consumed 0, 500, or 1000 mg TRP combined with 30 g of maltodextrin. Blood samples were collected at 0, 30, 60, 90 and 120 minutes. Sleepiness was rated during the evening. The study was carried out double-blind, and each woman received all 3 treatments balanced across days. Plasma TRP/LNAA ratios tripled after 500 mg and quadrupled after 1000 mg of TRP. All women reported a marked increase in sleepiness with TRP. We conclude that young women do seem to be more sensitive than men to the sedating effect of TRP/CHO mixes but their plasma amino acid responses are similar.

Effects of the β 2-adrenoceptor agonist clenbuterol on tyrosine and tryptophan in plasma and brain of the rat

The β 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P < 0.01). By comparison, decreases in plasma tryptophan and increases in brain tyrosine were small and often nonsignificant. Amino acid levels measured in different brain regions revealed that the elevations were similar among the cerebellum, striatum, and cortex. These effects were partially blocked by propanolol but not by atenolol. The ed 50 was estimated from dose-response curves to be about 0.05 mg/kg for both the decrease in plasma tyrosine and the increase in brain tryptophan. The effects of low doses of clenbuterol were prevented completely by propranolol. Peripheral organs displayed strikingly different patterns of change in amino acid concentrations. Only the spleen had any accumulation of tryptophan, but that was much less than in brain. In contrast, tyrosine and tryptophan were decreased in heart and unaltered in liver; tyrosine was decreased in lung. The elevation in brain tryptophan levels was attenuated by the β 2-antagonist, ICI 118,551, but not by the β 1-antagonist, betaxolol; but the reduction in plasma tyrosine was unaffected by either drug. The serotonin antagonist, methysergide, failed to block the effects of clenbuterol. We conclude that changes in amino acid concentrations produced by clenbuterol are mediated by β 2-adrenoceptor stimulation. Although the increases in brain tyrosine and tryptophan were similar to increases in the plasma ratios of these amino acids to the sum of the other large neutral amino acids competing for transport into the brain, the disparity between the effects of ICI 118,551 in brain and plasma suggests that clenbuterol may also have a direct action in brain to regulate levels of aromatic amino acids. Since clenbuterol has been purported to have an antidepressant effect and since other antidepressants also increase brain tryptophan, this may be a common feature of antidepressant drug action.

Changes in plasma and brain tryptophan and brain serotonin and 5-hydroxyindoleacetic acid after footshock stress

Brain concentrations of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and plasma amino acids were measured after 15 or 30 minutes of intermittent footshock. Footshock treatment significantly decreased the content of 5-HT in prefrontal cortex and hypothalamus, but not brainstem at 15 min, but the decreases were reversed by 30 min. 5-HIAA, the major catabolite of 5-HT, increased in prefrontal cortex after 15 min, and in prefrontal cortex and hypothalamus after 30 min footshock. 5-HIAA:5-HT ratios were increased at both timepoints in all three brain regions. Concomitant changes in the ratios of 3,4-dihydroxyphenylacetic acid (DOPAC) to dopamine and 3-methoxy,-4-hydroxyphenylethyleneglycol (MHPG) to norepinephrine were also observed. Brain concentrations of tryptophan increased progressively during the footshock in all three brain regions. Plasma concentrations of both tryptophan and tyrosine were also significantly increased, while those of histidine and lysine were decreased. It is possible that the stressrelated changes in 5-HT metabolism are due to increased plasma tryptophan, in turn causing increased brain tryptophan and 5-HT synthesis. However, the transient decreases in 5-HT suggest a footshock-induced increase of 5-HT release, depleting existing stores of 5-HT, that are replenished by the increased systemic availability of tryptophan

Carbohydrate ingestion and brain serotonin synthesis: Relevance to a putative control loop for regulating carbohydrate ingestion, and effects of aspartame consumption

The ingestion of a meal of carbohydrates by fasting rats rapidly increases brain tryptophan level and serotonin (5-HT) synthesis. The rise in brain tryptophan level follows from an increase in tryptophan transport into brain, the consequence of an insulin-induced reduction in the blood levels of several amino acids that compete with tryptophan for brain uptake. In contrast, ingesting protein with carbohydrate does not stimulate brain tryptophan uptake or 5-HT synthesis, because the blood levels of tryptophan's transport competitors are increased, not reduced. These observations form the biochemical basis of a current proposal for a regulatory loop governing meal-to-meal appetite for carbohydrates. This review briefly analyzes the experimental basis for the carbohydrate appetite regulatory loop, and finds it wanting. It also considers the proposal that the ingestion of the artificial sweetener aspartame might disrupt the putative regulatory loop for carbohydrate intake regulation, and thus promote rather than help to limit carbohydrate appetite, and finds this hypothesis unrealistic as well. In general, the conclusion is that while single meals do readily influence brain tryptophan uptake and 5-HT synthesis, it is presently unclear what role such neurochemical effects of food ingestion have in the control of specific appetites.

The Effects of Caffeine and Caffeine-containing Beverages on the Disposition of Brain Serotonin in Rats

Caffeine and caffeine-containing beverages (instant coffee, black tea, green tea, or oolong tea) caused a significant decrease in serum tryptophan, and significant increases in brain tryptophan, serotonin, and 5-hydroxyindole acetic acid over those in rats fed a control diet. Adenosine supplementation partially counteracted the increase of brain serotonin caused by caffeine. These results are interpreted as indicating that caffeine-containing beverages may have some nutritional and behavioral effects.

Inhibition of rat Liver Tryptophan Pyrrolase Activity and Elevation of Brain Tryptophan Concentration by Administration of DL-α-Amino-β-Pyridinepropanoic Acid (Pyridylalanine) Analogs

Single doses of DL-alpha-amino-beta-(2-pyridine)propanoic acid (2-PA, 100 mg/kg) significantly decreased the holoenzyme and apoenzyme activities of rat liver tryptophan pyrrolase (TP) and increased brain tryptophan, serotonin (5-HT) and 5-hydroxyindole-3-ylacetic acid concentrations. 2-PA had no inhibitory effect on either of the enzyme activities in vitro, but its expected metabolites were effective. Single doses of DL-alpha-amino-beta-(3-pyridine)propanoic acid (3-PA, 100 mg/kg) decreased only the holoenzyme activity and elevated brain tryptophan and its metabolites levels in rats. 3-PA and its metabolite, 3-pyridylpyruvate, inhibited only the holoenzyme activity in vitro. DL-alpha-Amino-beta-(4-pyridine)propanoic acid (4-PA) caused significant changes in liver TP (holo- and apoenzyme forms) activity and brain tryptophan concentration only after repeated administration (100 mg/kg/day). 4-PA was a weak inhibitor of the holoenzyme, but its metabolites apparently inhibited the holo- and apoenzyme activities in vitro. These findings suggest that PA analogs (and/or their metabolites) increased brain tryptophan (and hence 5-HT synthesis) by directly inhibiting liver TP activity.

The effects of caffeine and caffeine-containing beverages on the disposition of brain serotonin in rats.

Caffeine and caffeine-containing beverages (instant coffee, black tea, green tea, or oolong tea) caused a significant decrease in serum tryptophan, and significant increases in brain tryptophan, serotonin, and 5-hydroxyindole acetic acid over those in rats fed a control diet. Adenosine supplementation partially counteracted the increase of brain serotonin caused by caffeine. These results are interpreted as indicating that caffeine-containing beverages may have some nutritional and behavioral effects.

Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat.

Rats were trained to run on a horizontal treadmill for 2 h at 20 m/min. This activity considerably increased plasma free tryptophan (TRP) (+70%) but did not alter plasma total TRP levels and had little or no effect on plasma concentrations of the other large neutral amino acids (LNAAs) that compete with TRP for entry into the brain. Brain TRP levels increased by 80%. The only other brain LNAA to be affected by exercise was threonine, which rose moderately. The results indicate that increased plasma free TRP was specifically responsible for the increase of brain TRP after 2 h of exercise. Brain lysine was also increased whereas glycine, alanine, and gamma-aminobutyric acid were decreased. The differences between the present findings and those previously obtained following 2 h immobilization stress are discussed.

Regional Brain Amino Acid and Neurotransmitter Derangements During Abdominal Sepsis and Septic Encephalopathy in the Rat

Regional amino acids and brain neurotransmitters were studied in 33 normal and 32 rats with sepsis (induced by cecal ligation and puncture) infused with different amino acid formulations. The brain amino acid pattern during sepsis showed increased concentrations of most essential and six of the nonessential amino acids. The most consistent finding was the accumulation of indoleamines in all six brain regions studied during sepsis; increased brain tryptophan levels presumably resulted in enhanced metabolism of serotonin (5HT), increased production of 5-hydroxyindoleacetic acid (5HIAA), and a high 5HT/5HIAA ratio. Infusion of branched-chain amino acid-enriched formulas restored brain amino acid and neurotransmitter profiles, decreasing levels of tryptophan, tyrosine, 5HIAA, and 5HT/5HIAA ratios while increasing norepinephrine levels in some regions. These alterations in brain neurotransmitter metabolism may be at least partially responsible for the development of septic encephalopathy.

Effects of aspartame and glucose administration on brain and plasma levels of large neutral amino acids and brain 5-hydroxyindoles

Administration of the artificial sweetener aspartame (l-aspartylphenylalanylmethyl ester, 200 mg/kg) by gavage to rats caused large increments in brain and plasma levels of phenylalanine and its product tyrosine. Glucose administration (3 g/kg, by gavage, a dose sufficient to cause insulin-mediated reductions in plasma levels of the large neutral amino acids leucine, isoleucine, and valine) also elevated brain phenylalanine and tyrosine, and enhanced the increments caused by the aspartame, nearly doubling the rise in brain phenylalanine. Each animal's brain phenylalanine or tyrosine levels were highly correlated (r = 0.97 and 0.99, respectively) with its plasma phenylalanine or tyrosine ratios, affirming that aspartame's effects on the brain amino acids result from the changes it produces in plasma composition. As described previously, glucose consumption increased brain tryptophan levels, and consequently, brain levels of the 5-hydroxyindoles serotonin and 5-hydroxyindoleacetic acid. Aspartame alone had no effect on these compounds but completely blocked the changes in 5-hydroxyindoles caused by glucose. Each animal's brain level of tryptophan (r = 0.89) and 5-hydroxyindoles (r = 0.74) was also significantly correlated with its plasma tryptophan ratio, affirming that the effects of glucose or aspartame on these brain constituents also result from the changes they produce in plasma composition. The aspartame-glucose combination also reduced brain levels of leucine, isoleucine, and valine to a significantly greater extent than aspartame or glucose alone. These observations indicate that high aspartame doses can generate major neurochemical changes in rats, especially when consumed along with carbohydrate-containing foods. However, they should not in any way be interpreted as demonstrating that aspartame significantly affects the human brain.

Evidence that stress augments morphine analgesia by increasing brain tryptophan

Morphine analgesia measured by the tail withdrawal test was examined in rats that were either restrained or left free during testing. It was found that restraint potentiated morphine analgesia and decreased the latency of the peak analgesic effect. Methysergide, a serotonin antagonist, and valine, which prevents the increase in brain tryptophan induced by restraint, blocked the effect of restraint on morphine analgesia. Valine did not alter analgesia in unrestrained rats. An increase in brain tryptophan uptake induced by stress is suggested as a possible mechanism by which stress can interact with pain modulation systems.

Stress-induced release of 5-HT in the hippocampus and its dependence on increased tryptophan availability: an in vivo electrochemical study

We have previously shown that in vivo voltammetry can be used to study the release of 5-hydroxyindoles in the rat hippocampus. Immobilization stress is believed to be associated with increased release of 5-HT in the rat brain; we have now studied the effect of immobilization stress using this technique. The electrochemical peak at 0.35 V recorded in the dorsal hippocampus of the rat was increased by the time of the first sweep following immobilization, i.e. within 5 min, and remained significantly elevated for more than 3 h of immobilization. The increase was biphasic, a peak at 30 min being followed by a slower increase from 60 min. We have shown that valine, a large neutral amino acid which competes with tryptophan for brain uptake, prevents the stress-induced increase of brain tryptophan. Administration of valine 60 min prior to immobilization markedly attenuated both phases of the stress-induced increase in signal. Tryptophan administration with the valine prevented its inhibitory effect, and restored the full biphasic response to stress. Tyrosine administration with the valine did not prevent, but potentiated its inhibitory effect. In addition prior (48 h) treatment with p-chlorophenylanine, an inhbitor of 5-HT synthesis, subastantially attenuated the increased signal in response to stress, while α-methyl- p-tyrosine, an inhibitor of catecholamine synthesis, did not. It is concluded that 5-hydroxyindole release in the hippocampus is increased by immobilization stress, and that this increase is substantially dependent on increased synthesis of 5-HT. This in turn normally depends upon increased availability of tryptophan, the 5-HT precursor. Failure to increase brain tryptophan in stress may therefore compromise serotonergic responses to stress. The potential relevance of this mechanism for stress precipitated disorders in humans is discussed.

Corticosteroid response to stress depends upon increased tryptophan availability.

Prior administration of valine to rats has been shown previously to prevent restraint stress-induced increases in brain tryptophan and 5HT turnover. The present study demonstrates that the accompanying attenuation of the corticosteroid response to this stress is substantially reversed by administration of tryptophan with the valine. Tyrosine is not effective in reversing this attenuation, and in fact itself attenuates the corticosteroid response to the stress when given alone. It is concluded that at least part of the corticosteroid response to restraint stress is mediated by an increase in serotonergic activity that is dependent on increased supply of the precursor, tryptophan, and that this can be antagonised by either of two amino acids which compete with tryptophan for access to the brain. Implications for stress-associated human disorders are discussed.

Behavioural and biochemical effects of tryptophan, tyrosine and phenylalanine in mice.

Behaviour was observed in mice given L-tryptophan, L-tyrosine or L-phenylalanine and then placed either in an open field or in water in a narrow cylinder. Animals placed in water (swim test) soon assume a characteristic immobile posture. Most antidepressants, including pharmacologically atypical ones, decrease immobility in the swim test while many decrease or do not affect activity in the open field test. Tryptophan increased immobility in the swim test, but did not affect open field activity and thus did not exhibit the normal profile of activity for an antidepressant. Tyrosine decreased immobility in the swim test and markedly increased activity in the open field test, an action similar to the psychostimulants amphetamine and caffeine. Phenylalanine decreased immobility in the swim test, but did not affect open field activity. Thus, its behavioural effects are similar to those of an antidepressant. As expected, tryptophan increased brain tryptophan and serotonin in a dose-related fashion. Tyrosine did not alter dopamine or noradrenaline levels, while phenylalanine lowered dopamine, noradrenaline and serotonin. These biochemical data do not fully explain the behavioural results.

Acute effects of caffeine injection on neutral amino acids and brain monoamine levels in rats

The injection of caffeine (100 mg/kg, i.p.) into male rats acutely increased brain levels of trytophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). Blood levels of glucose, nonesterified fatty acids (NEFA) and insulin also increased, while those of the aromatic and branched-chain amino acids fell. Serum tryptophan levels either did not fall, or increased. Consequently, the serum ratio of trypthopahn to the sum of other large neutral amino acids (LNAA) increased. Less consistently noted were increases in serum free tryptophan levels. Brain tyrosine levels were not appreciably altered by caffeine, nor was the serum tyrosine ratio. In dose-response studies, 25 mg/kg of caffeine was the minimal effective dose needed to raise brain tryptophan, but only the 100 mg/kg dose elevated all three indoles in brain. In no experiments did caffeine, at any time or dose, alter brain levels of dopamine or norepinephrine. Caffeine thus probably raises brain tryptophan levels by causing insulin secretion, and thereby changing plasma amino acid levels to favor increased tryptophan uptake into brain. The rises in brain 5-HT and 5-HIAA may follow from the increase in brain tryptophan, although further data are required clearly to establish such a mechanism.

Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by administration of antidepressants

The apoenzyme activity of rat liver tryptophan pyrrolase is decreased in vitro by 16–100% by concentrations of many antidepressants of 0.01–1 mM. Apo-(tryptophan pyrrolase) activity is also decreased by 37–86% at 2hr after administration of a 10 mg/kg dose of many antidepressants. This inhibition appears to be due to the prevention of the conjugation of the apoenzyme with its cofactor haem. Brain tryptophan concentration is elevated by 19–39% at 3.5 hr after administration of the above dose of antidepressants. Isocarboxazid is the only antidepressant tested that affects neither liver pyrrolase activity nor brain tryptophan concentration. The non-antidepressants chlorpromazine, β-flupenthixol, mefenamic acid and pargyline are also ineffective in both respects. The increase in brain tryptophan concentration caused by administration of mianserin, viloxazine, desipramine or tranylcypromine is associated with an accumulation of tryptophan in the liver and an increased availability of the circulating amino acid to the brain. It is suggested that antidepressants increase brain tryptophan concentration by inhibiting liver tryptophan pyrrolase activity. The results are briefly discussed in relation to the therapeutic effects of the drugs.

The functional importance of increased brain tryptophan in the serotonergic response to restraint stress

The increase in brain tryptophan induced by restraint stress in rats has been shown to be prevented by prior administration of valine, 200 mg/kg (i.p.). Brain 5-hydroxytryptamine (5-HT) was not depleted, but the stress-induced increase in 5-hydroxyindoleaeetic acid (5-HIAA) was prevented. A 5-HT-mediated functional response to stress, elevated plasma corticosterone, was however significantly attenuated by valine pretreatment, but was not affected by valine treatment alone. This suggests that the increase in 5-HIAA in brain is not merely secondary to increased brain tryptophan but indicates an increase in functional 5-HT activity, which is in turn at least partly dependent on the increase in brain tryptophan. Measurement of kynurenine levels in the same animals indicated an increase in synthesis in stress, but did not support the hypothesis that competition occurs between the kynurenine and 5-hydroxyindole pathways of tryptophan metabolism in brain.