Development of tolerance to the plasma amino acid-decreasing effect of ethanol in the rat.

Male Sprague-Dawley rats were treated for one month with daily intraperitoneal injections of ethanol (2 g kg-1), or saline. After this pretreatment, animals from each group were given acute doses of ethanol (2 g kg-1) or saline. Plasma amino acid concentrations and brain tyrosine, tryptophan, dopamine, 5-HT and 5-HIAA concentrations were measured in samples collected 1 h after the injections. Acute administration of ethanol induced a dramatic fall in the concentrations of 18 out of 20 plasma amino acids in animals pretreated with saline. In animals chronically pretreated with ethanol this decrease was much smaller. Furthermore, the decrease was significantly lower for 6 of the measured amino acids in the chronic ethanol group compared with the saline-treated control group. Tolerance to the plasma amino acid decreasing effect of ethanol had thus developed. This acquired tolerance might be explained by both pharmacokinetic and pharmacodynamic mechanisms. Chronic administration of ethanol induced increased concentrations of tyrosine and dopamine in the brain, probably due to increased transport of tyrosine into the brain caused by an increase in the ratio of tyrosine to large neutral amino acids in plasma.     

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

The investigation examined the mechanism of the increase in brain tryptophan concentration of rats treated with d-amphetamine. Certain well recognised influences upon brain tryptophan 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 tyrosine 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 alpha- and beta-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.     

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.     

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.     

Neuropharmacology: Amitriptyline and Clomipramine Increase the Concentration of Administered L-Tryptophan in the Rat Brain

The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood–brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan. Intraperitoneal administration of L-tryptophan alone (100 mg kg^?1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 ±0.7 to 100 ± 4.3 nmol g^?1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg^?1, i.p.) or clomipramine (25 mg kg^?1, i.p.) brain concentrations of tryptophan were increased even further, to 150 ±4.5 and 157 ± 10.2 nmol g^?1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14±0.003 to 0.42±0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 ±0.017 and 0.54 ±0.025, respectively. All these effects were statistically significant (P < 0.001). These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.     

Opiate-receptor mediated changes in monoamine synthesis in rat brain

The effects of morphine, β-endorphin, naloxone and naltrexone on the rate of tyrosine and tryptophan hydroxylation were investigated in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan (5-HTP) in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. The cerebral concentrations of tyrosine and tryptophan were also measured. Morphine (3–30 mg kg^?1) increased the accumulation of dopa dose-dependently (25–50%) in the dopamine-rich areas (limbic forebrain and corpus striatum). In the noradrenaline-predominant parts of the brain (containing hemispheres, diencephalon and lower brain stem) only the highest dose of morphine (30 mg kg^?1) significantly increased dopa formation (47%). Similarly to morphine, intracerebroventricularly injected β-endorphin (5–10 βg per rat) increased the formation of dopa. This increase was doubled in limbic forebrain, corpus striatum and cerebral hemispheres. Doses of 10 to 20 μg of β-endorphin were needed to increase dopa accumulation in the diencephalon and the lower brain stem. Naloxone antagonized the β-endorphin-induced increases in dopa. But naloxone and naltrexone (10–100 mg kg^?1) decreased the dopa formation in the dopamine-rich areas (about 20–25 %) but not in the noradrenaline-predominant areas. Morphine (30 mg kg^?1) and β-endorphin (5 μg per rat) increased the accumulation of 5-HTP whereas naloxone and naltrexone (10 mg kg^?1) tended to decrease its formation. Morphine and β-endorphine increased the concentrations of tyrosine and tryptophan, and naloxone decreased the cerebral tryptophan concentration. These results show that the effects of a narcotic agonist (morphine) and of pure narcotic antagonists (naloxone and naltrexone) on the synthesis of dopamine and 5-HT are opposite to each other. Furthermore, the effects of β-endorphine on brain monoamine synthesis are remarkably similar to those of morphine. Thus, it is probable that opiate receptors and their endogenous ligands are involved in the regulation of dopamine and 5-HT synthesis.     

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.     

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

The beta 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P less than 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 ED50 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 beta 2-antagonist, ICI 118,551, but not by the beta 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 beta 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.     

Neurochemical changes of the extracellular concentrations of glutamate and aspartate in the nucleus accumbens of rats after chronic administration of morphine

The effects of discontinuing a chronic morphine treatment on the concentrations of glutamate and aspartate were analyzed in the nucleus accumbens of unrestrained unanesthetized rats. The administration of naloxone or the cessation of morphine administration resulted in increased concentrations of glutamate and aspartate in this central nervous system area. These increased amino acid concentrations were observed a few minutes after naloxone administration and persisted in the controls 48 h after the last dose of the opiate. Morphine withdrawal was also studied in rats not injected with naloxone. In these latter animals, increased concentrations of glutamate and aspartate persisted in controls 96 h after the last dose of the opiate. Single doses of morphine, acamprosate or riluzole administered to rats previously withdrawn from chronic morphine treatment restored the amino acid concentrations to normal levels. These results suggest that the maintenance of increased levels of amino acids could be the expression of new adjustments in central nervous system neurotransmission after discontinuation of the chronic morphine treatment.     

An increase in tryptophan in brain may be a general mechanism for the effect of stress on sensitivity to pain

The role of the stress-induced increase in the uptake of tryptophan in brain in opioid-induced analgesia was investigated by modifying the uptake of amino acid in brain with injections of competing amino acids. Blockade of analgesia by valine (200 mg/kg, i.p.) alone, and by valine and tyrosine (100 mg/kg, i.p.), but not by valine and tryptophan (100 mg/kg, i.p.), was taken to indicate that an increase in the uptake of tryptophan in brain was involved in opioid-induced analgesia. Morphine-induced analgesia exhibited by rats that were habituated to the laboratory and not restrained did not involve an increase in the uptake of tryptophan in brain. However, a mild form of restraint, or exposure to a novel environment interacted with morphine to induce analgesia which involved an increase in the uptake of tryptophan in brain. These stressors did not affect sensitivity to pain in the absence of morphine. Analgesia induced by 3 hr of restraint, which was preventable by naltrexone (1 mg/kg, s.c.) but not reversible by naloxone (1 mg/kg, s.c.), also involved an increase in the uptake of tryptophan in brain. It is concluded that the endogenous opioid-induced analgesia that is induced by stress alone and analgesia induced by stress interacting with morphine, both depend on an increase in the uptake of tryptophan into the brain.     

Dependence of 5-HT and catecholamine synthesis on concentrations of precursor amino-acids in rat brain

Summary The short-term influence of varying concentrations of the precursors tryptophan and tyrosine on the formation of 5-hydroxytryptophan and Dopa, respectively, in three different rat-brain regions was investigated. The concentrations of the precursors were either increased by the intraperitoneal administration of the respective precursor or decreased by loading with large neutral amino acids competing with the precursors for the same carrier mechanisms.The formation of 5-hydroxytryptophan was found to depend on the level of tryptophan in the brain in a manner predicted from published kinetic data, except when large doses of non-precursor amino acids had been given (>300 mg/kg). In the latter case the hydroxylation of tryptophan was less rapid than expected. The apparent K _m of tryptophan hydroxylase calculated from these data was about 25 M, which is in reasonably good agreement with earlier published in-vitro and in-vivo data.The formation of Dopa likewise depended on the level of the precursor tyrosine in a predictable manner, in this case without any anomalous results after large doses of non-precursor amino acids. The apparent K _m of tyrosine hydroxylase was calculated from these invivo observations to be about 25 M, which is in fairly close agreement with published in-vitro data.It is concluded that under normal conditions tryptophan hydroxylase in the rat brain is about half-saturated with its amino-acid substrate, whereas tyrosine hydroxylase appears to be about 75% saturated.     

Acute and chronic effects of the trichothecene mycotoxin T-2 on rat brain regional concentrations of serotonin, tryptophan, and tyrosine

Female rats were given 1 acute dose or chronic doses (once every 48 hr for 28 days) of T-2 toxin (10 micrograms/kg ip) or vehicle. At necropsy, each brain was subdivided into cerebellum, cerebral cortex (including telencephalon and diencephalon), and brainstem (including mesencephalon, metencephalon, and myelencephalon). Acute systemic T-2 toxin administration increased cerebellar and brainstem tryptophan while serotonin, a tryptophan metabolite, was decreased correspondingly in these same brain regions. Chronic T-2 administration increased cerebellar tyrosine and serotonin concentrations, while cortical tryptophan concentrations were also increased. These results indicate that both acute and chronic administration of T-2 toxin cause differential changes in regional distribution levels of tyrosine, tryptophan, and serotonin.     

Study of the ameliorating effects of an enteral nutrient for liver failure on hepatic encephalopathy: effects of SF-1008C on plasma and brain free amino acids, intracerebral amine concentrations and electroencephalogram in portacaval shunted rats with ammonia loading

The ameliorating effects of an enteral nutrient for liver failure (SF-1008C), which is enriched with branched-chain amino acids (BCAA) and includes few aromatic amino acids (AAA), were investigated. The blood ammonia, plasma and brain free amino acids, intracerebral amine concentrations and electroencephalogram were measured in portacaval shunted rats with 10% ammonium acetate (3 ml/kg, i.p.) (PCS) as a model of hepatic encephalopathy. The blood ammonia and plasma free amino acid concentrations in PCS rats were significantly increased in comparison to sham-operated (Sham) rats. Thus, the plasma BCAA/AAA ratio in PCS rats was appreciably reduced. Concomitant with the abnormal plasma amino acid concentrations, the brain free amino acid concentrations in PCS rats were markedly increased in comparison to the Sham rats. Moreover, the intracerebral tryptophan (Trp) and 5-hydroxyindol acetic acid (5-HIAA) concentrations were significantly increased, and the intracerebral dopamine (DA) concentration was significantly decreased in the PCS rats. The intracerebral serotonin (5-HT) and norepinephrine (NE) concentrations were, however, hardly changed. A smaller voltage for the electroencephalogram was used in the PCS rats than in the Sham rats. Abnormal plasma and brain free amino acid concentrations in PCS rats were normalized by oral administration of SF-1008C, and the low voltage electroencephalograms in the PCS rats were suppressed. On the other hand, abnormal plasma and brain free amino acid concentrations in the PCS rats were hardly normalized by oral administration of ED-AC, an elemental diet based on an amino acid composition of egg protein. These results suggest that SF-1008C affects brain free amino acids, intracerebral amine concentrations and electroencephalogram by ameliorating abnormal plasma free amino acid concentrations. Moreover, there is a highly significant correlation between the plasma BCAA/AAA ratio and the brain BCAA/AAA ratio, and this finding suggests that the plasma free amino acid patterns reflect the brain free amino acid patterns.     

The effects of chlorpromazine on serum tryptophan,brain tryptophan uptake and brain serotonin synthesis in the rat

Following intraperitoneal injection of a single dose of chlorpromazine to rats, serum total tryptophan fell significantly, as did the concentration of serum total amino acids. At the same time there was a decrease in the binding of tryptophan to serum albumin, which was not attributable to any change in serum non-esterified fatty acid concentration. After repeated administration of chlorpromazine (over 10 days), serum tryptophan returned to normal within 4 days, as did the binding of tryptophan to serum albumin. However, serum total amino acid concentration remained depressed for at 10 days, returning to the control level immediately on cessation of administration of the drug. Cessation of chlorpromazine administration had no effect on serum tryptophan concentration or binding to serum albumin. Studies on brain tryptophan uptake and serotonin accumulation showed an increase in brain serotonin pool size following single or repeated chlorpromazine administration. Although serotonin accumulation was significantly correlated with tryptophan uptake into the brain, the increase in serotonin per unit increase in brain tryptophan uptake was less after 11 days repeated chlorpromazine administration than after a single dose. This suggests that some factor other than tryptophan availability is concerned in regulation of brain serotonin synthesis; this could be feed-back inhibition by serotonin.     

Toluene-induced Decrease in Rat Plasma Concentrations of Tyrosine and Tryptophan

Abstract: The organic solvent toluene is demonstrated to cause a decrease in rat plasma concentrations of tyrosine and tryptophan both after intraperitoneal injections and after inhalation. Tyrosine and tryptophan are precursors to neurotransmitters and are transported from plasma into the brain. As the concentrations of these amino acids in plasma could influence the monoamine synthesis in the brain, this phenomenon might be of importance for the pathophysiology behind solvent-induced effects on brain function.     

Dual action of methadone on 5-HT synthesis and metabolism

Summary The main purpose of these experiments was to compare the effects of methadone and morphine on cerebral 5-hydroxytryptamine (5-HT) synthesis and 5-hydroxyindoleacetic acid (5-HIAA) formation. In addition the rate of catecholamine synthesis and the concentrations of tyrosine and tryptophan in the brain were measured, as well as the effects of naloxone were investigated.Morphine (34 mg/kg, 2h) increased the synthesis of 5-HT and catecholamines, determined by measuring the accumulation of 5-hydroxytryptophan (5-HTP) and dopa in the whole brain of rats treated with an inhibitor of the aromatic l-amino acid decarboxylase (3-hydroxybenzylhydrazine hydrochloride, NSD 1015). Morphine also increased the cerebral 5-HIAA concentration both in rats treated with NSD 1015 or probenecid. Naloxone antagonized all these effects of morphine. A lower dose of naloxone was needed to antagonize the effect of morphine on 5-HT than on catecholamine synthesis, Similarly to morphine methadone (9 mg/kg, 2 h) increased the cerebral 5-HIAA concentration, but methadone alone did not alter the rate of formation of 5-HTP. However, in combination with naloxone methadone decreased the concentration of 5-HIAA and the accumulation of 5-HTP depending both on the dose of methadone and that of naloxone. Similarly to morphine, methadone stimulated and never reduced the catecholamine synthesis; naloxone antagonized this effect. Both morphine and methadone increased the cerebral concentrations of tryptophan and tyrosine and naloxone antagonized these effects. In addition naloxone alone (2+2 mg/kg, 1+2h) decreased the cerebral tyrosine concentration significantly suggesting that the opiate receptors are involved in the control of cerebral tyrosine concentration.Our results suggest that methadone similarly to morphine stimulates the cerebral 5-HT and catecholamine synthesis, and that these effects are most probably mediated via opiate receptors. However, when opiate receptors are blocked, methadone is able to decrease the cerebral 5-HT synthesis and cerebral 5-HIAA concentration probably via a feedback mechanism produced by blockade of 5-HT reuptake.     

Effect of low-dose lithium administration and subsequent withdrawal on biogenic amines in rat brain.

1 The effects of low-dose lithium administration (2 mEq/kg, daily) and its subsequent withdrawal have been examined with reference to changes in biogenic amine systems in several discrete regions of rat brain. 2 Increased levels of striatal tyrosine and midbrain tryptophan were found following lithium administration together with slight decreases in striatal tyrosine hydroxylase and midbrain tryptophan hydroxylase activities. Withdrawal resulted in a decrease in tyrosine content with increased tyrosine hydroxylase activity, whilst tryptophan levels and tryptophan hydroxylase activity were increased. 3 Lithium treatment and withdrawal resulted in altered levels of noradrenaline and dopamine, these changes being regionally variable. 3-Methoxy-4-hydroxyphenylglycol content was depressed in both treated and withdrawal rats as were 3,4-dihydroxyphenylacetic acid levels. Homovanillic acid decreased as a result of lithium treatment, but was greatly elevated in the withdrawal group. 4 5-Hydroxytryptamine content decreased in some brain regions following lithium treatment with return towards control values in withdrawal rats. 5-Hydroxyindoleacetic acid levels also displayed a regional variation as a result of lithium treatment and withdrawal. 5 The implications of these observations in elucidating the pharmacological effect of lithium treatment and its subsequent withdrawal are discussed.     

Methionine sulfoximine intensifies cancer anorexia.

Consistent anorexia was first observed 33 days after inoculating Fischer 344 rats with methylcholanthrene-induced sarcoma. Daily treatment of a similar group of rats with the glutamine synthetase inhibitor, methionine sulfoximine, elicited significant reductions of feeding by day 29 at a dose that had no effect on nontumor-bearing rats. Blood concentrations of ammonia were elevated in both groups of tumor-bearing rats and brain ammonia level was increased in the methionine sulfoximine-treated tumor-bearing rats. Forebrain concentrations of tyrosine, tryptophan, DOPAC and 5-HIAA were elevated in both groups of tumor-bearing rats. Since ammonia is detoxified through the glutamine synthetase reaction, these results suggest that blood and brain ammonia concentrations are more important than the neurochemical consequences of ammonia detoxification for the etiology of cancer anorexia.     

Tryptophan-free diet: a new means for rapidly decreasing brain tryptophan content and serotonin synthesis.

Changes in the synthesis rate of brain serotonin are positively correlated with changes in the concentration of brain tryptophan, indicating that the concentration of tryptophan in the whole brain reflects that at sites of serotonin synthesis. In turn, the concentration of brain tryptophan is positively correlated with that of free serum tryptophan (tryptophan is the only amino acid bound to serum proteins) and negatively to that of other amino acids competing with tryptophan for the same transport from blood to brain. Consistently, experiments in rats have shown that treatments which increase free tryptophan in serum (in respect to competing amino acids) also increase brain tryptophan and serotonin turnover. Conversely, the ingestion of diets containing all amino acids except tryptophan cause a dramatic fall in free serum tryptophan and a parallel decline in brain tryptophan and serotonin synthesis. In man the administration of an amino acid mixture lacking trytophan produces a marked depletion in serum tryptophan concentration.     

Isoprenaline increases brain concentrations of administered l-dopa and l-tryptophan in the rat

A small dose of isoprenaline or saline was administered intraperitoneally to rats 20 min before the administration of one of the amino acids l-dopa or l-tryptophan. Isoprenaline caused a marked increase in the brain concentration of the administered amino acid. Isoprenaline has previously been shown to cause a decrease in at least some of those plasma amino acids which compete with l-dopa and tryptophan for carrier-mediated transport into the brain. The effect of isoprenaline on the concentrations of dopa and tryptophan in the brain is suggested to be at least partly caused by a change in the relationship between endogeneous and administered amino acids. It is also possible that a direct effect of isoprenaline on the blood-brain barrier transport system contributes to the effect.The reported finding might be of clinical interest in view of the therapeutic importance of aromatic amino acids with a central site of action.