A STUDY OF PROPOSED DETERMINANTS OF BRAIN TRYPTOPHAN CONCENTRATION IN RATS AFTER PORTOCAVAL ANASTOMOSIS OR SHAM OPERATION

Liver 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.     

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 stress-related 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.     

EFFECTS OF CHRONIC PORTO-CAVAL ANASTOMOSIS ON BRAIN TRYPTOPHAN, TYROSINE AND 5-HYDROXYTRYPTAMINE

—Three weeks after porto-caval anastomosis, tryptophan and 5-hydroxyindolylacetic acid concentrations were-greatly increased in rat brain regions. 5-Hydroxytryptamine showed smaller increases. Midbrain tyrosine and muscle tyrosine and tryptophan concentrations were also increased. Striatal dopa-mine concentration was not significantly changed. Unlike previous results from acute liver failure, brain tryptophan changes in this chronic study did not simply reflect plasma-free tryptophan changes. Midbrain tryptophan/plasma-free tryptophan ratio and midbrain tyrosine/plasma tyrosine ratio both rose, suggesting increased effectiveness of uptake of these amino acids from plasma by brain. Corresponding muscle/plasma ratios were unaltered by the porto-caval anastomosis. Uptake of tryptophan from buffer by cerebral cortex slices was unaffected. Results on control animals illustrate the importance of plasma-free tryptophan in the normal physiological control of brain tryptophan.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

STUDIES IN VIVO ON THE RELATIONSHIP BETWEEN BRAIN TRYPTOPHAN, BRAIN 5-HT SYNTHESIS AND HYPERACTIVITY IN RATS TREATED WITH A MONOAMINE OXIDASE INHIBITOR AND L-TRYPTOPHAN

Abstract— The effect of l -tryptophan loading upon the amount of 5-HT accumulating in the brains of rats pretreated with a monoamine oxidase inhibitor was studied. The amount of brain 5-HT accumulated increased with increasing tryptophan dosages and brain tryptophan concentrations up to a tryptophan dose of 120 mg/kg body wt. and a brain tryptophan of about 70 μg/g brain. Above this dose and concentration no further increase in brain 5-HT accumulation occurred. After monoamine oxidase inhibition and tryptophan loading gross hyperactivity and hyperpyrexia occurred. Monoamine oxidase inhibition, tryptophan administration and intact aromatic amino acid decarboxylase activity were all collectively essential for the production of hyperactivity and hyperpyrexia. DL-Parachlorophenyl-alanine prevented both the occurrence of hyperactivity and the increased accumulation of, brain 5-HT. Indices of hyperactivity correlated with the amount of brain 5-HT accumulating in 1 h after tryptophan loading but not with the overall concentration of brain 5-HT, suggesting that hyperactivity was dependent upon the rate of 5-HT synthesis. Reserpine and tetra-benazine pretreatment speeded the onset and rate of development of the hyperactive state without altering the synthesis of brain 5-HT. It is suggested that when monoamine oxidase is inhibited and the rate of 5-HT synthesis is increased, granular uptake and storage of 5-HT and other rate-limiting mechanisms for 5-HT inactivation are unable to prevent 5-HT 'spilling over’to produce hyperactivity. The crucial dependence of 5-HT synthesis upon brain tryptophan concentration and the ability of intraneuronal metabolism, when monoamine oxidase activity is intact, to cope with increased 5-HT synthesis and prevent ‘spillover’, raise the possibility that brain 5-HT synthesis is normally in excess of functional needs, and suggest that intraneuronal metabolism and the intraneuronal organization of 5-HT pools are of more importance than synthesis in regulating the amount of 5-HT available for functional activity.     

EFFECT OF INCREASED RAT BRAIN TRYPTOPHAN ON 5-HYDROXYTRYPTAMINE AND 5-HYDROXYINDOLYL ACETIC ACID IN THE HYPOTHALAMUS AND OTHER BRAIN REGIONS

—Tryptophan was found at higher concentration in the rat hypothalamus than in other brain regions. This difference was explicable neither by regional differences in blood content nor by differences in tryptophan recovery from different weights of tissue. It was not due to interference by other known brain indoles. After food deprivation or tryptophan injection the tryptophan concentration rose in all regions. Total 5-hydroxyindole increases showed regional differences but relative changes were similar after both procedures. Increases in 5-hydroxytryptamine were clearest in midbrain + hippocampus. In general, 5-hydroxyindolylacetic acid increased more markedly than 5-hydroxytryptamine. The hypothalamus appeared refractory with negligible increases of both 5-hydroxyindoles upon either food deprivation or tryptophan administration even though hypothalamic tryptophan concentration rose considerably. Results are discussed in relation to other evidence suggesting special characteristics of 5-HT regulation in the hypothalamus.     

STIMULATION OF BRAIN SEROTONIN SYNTHESIS BY DIBUTYRYL-CYCLIC AMP IN RATS

Cyclic AMP and dibutyryl-cyclic AMP, a derivative of cyclic AMP resistant to phosphodiesterase inactivation, were injected into the lateral ventricles of rats. These nucleotides did not change the level of brain 5-HT but increased the brain level of its principal metabolite, 5-hydroxyindoleacetic acid. Cyclic AMP was less potent than dibutyryl-cyclic AMP. Butyrate and 5′-AMP were inactive. The effect of dibutyryl cyclic AMP on 5-HT metabolism was studied both in vivo and in vitro. The rate of synthesis of 5-HT was measured by the rate of accumulation of 5-hydroxyindoleacetic acid after the transport of this acid out of the brain was blocked with probenecid. The rate of synthesis of brain 5-HT increased from 0-38 μg/g/h in control rats to 0-65 μg/g/h after dibutyryl-cyclic AMP. In addition cyclic AMP and dibutyryl-cyclic AMP markedly increased brain tryptophan, while AMP was inactive. Since brain tryptophan hydroxylase has a K_m for its substrate that is much higher than the concentrations of tryptophan normally present in the brain, it is likely that the increase in the rate of synthesis of brain 5-HT is secondary to the cyclic AMP induced increase in the levels of brain tryptophan. In vitro studies revealed that dibutyryl-cyclic AMP increased the uptake of radioactive labelled tryptophan into slices of rat brain stem and the formation of 5-HT and 5-hydroxyindoleacetic acid.     

Blood 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury

Following a study of oxidative tryptophan metabolism to kynurenines, we have now analysed the blood of patients with either Huntington's disease or traumatic brain injury for levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and melatonin. There were no differences in the baseline levels of these compounds between patients and healthy controls. Tryptophan depletion did not reduce 5-HT levels in either the controls or in the patients with Huntington's disease, but it increased 5-HT levels in patients with brain injury and lowered 5-HIAA in the control and Huntington's disease groups. An oral tryptophan load did not modify 5-HT levels in the patients but increased 5-HT in control subjects. The tryptophan load restored 5-HIAA to baseline levels in controls and patients with brain injury, but not in those with Huntington's disease, in whom 5-HIAA remained significantly depressed. Melatonin levels increased on tryptophan loading in all subjects, with levels in patients with brain injury increasing significantly more than in controls. Baseline levels of neopterin and lipid peroxidation products were higher in patients than in controls. It is concluded that both groups of patients exhibit abnormalities in tryptophan metabolism, which may be related to increased inflammatory status and oxidative stress. Interactions between the kynurenine, 5-HT and melatonin pathways should be considered when interpreting changes of tryptophan metabolism.     

Brain catecholaminergic and tryptophan responses to restraint are attenuated by nitric oxide synthase inhibition

Increases in the brain concentrations of tryptophan and in serotonin (5-HT) metabolism are commonly observed in animals under stress. Previous experiments indicated that the increase in brain tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) observed in response to administration of endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) were largely prevented by pretreatment with N-nitro-L-arginine methylester (L-NAME), an inhibitor of NO synthase (NOS). Therefore we tested whether the increases in tryptophan and 5-HT metabolism observed following restraint and footsthock were similarly affected. Mice were injected with L-NAME (30 mg/kg) or saline and restrained for 40 min. Restraint caused increases in concentrations of tryptophan and the catabolites of dopamine (DA), norepinephrine (NE) and 5-HT in the medial prefrontal cortex, hypothalamus, and brain stem. The L-NAME pretreatment significantly attenuated, but did not prevent, the changes in tryptophan and catecholamine metabolism, with a very small effect on the increase in plasma corticosterone. When mice pretreated with L-NAME were subjected to 30 min footshock, the NOS inhibitor had no statistically significant effects on the increases in DA, NE and 5-HT metabolism, but tended to attenuate the increases in tryptophan. We interpret these results to indicate that NOS plays a relatively small role in the cerebral neurochemical responses to restraint and footshock, but the role in the restraint-induced changes was greater than that in the footshock-induced ones. The attenuation of the restraint-related effects on the catecholamines most probably reflects a contribution to the CNS responses from peripheral vascular changes which are likely to be limited by the inhibition of NOS.     

METABOLISM OF A TRYPTOPHAN LOAD IN THE HYPOTHALAMUS AND OTHER BRAIN REGIONS

Abstract— Results confirm previous findings that after injecting rats with 50mg/kg tryptophan the percentage increase of 5-hydroxytryptamine metabolism (as shown by 5-hydroxyindolylacetic acid changes) is particularly small in the hypothalamus. However, 15–30 min after tryptophan injection (when brain 5-hydroxytryptamine changes were maximal) percentage 5-hydroxytryptamine increases in the hypothalamus and in the rest of the brain were comparable. The small 5-hydroxyindolylacetic acid changes in the hypothalamus are consistent with a long 5-hydroxytryptamine turnover time therein as indicated by experiments using pargyline or probenecid and by the relatively small increases of 5-hydroxytryptamine after injecting tryptophan into tranylcypromine treated rats. When 5-hydroxytryptamine synthesis was partially inhibited by p -chlorophenylalanine and tryptophan was injected, there was a large percentage rise of hypothalamic 5-hydroxytryptamine but the concentration found in rats given neither drug was not attained and 5-hydroxyindolylacetic acid showed little change. Elsewhere in the brain 5-hydroxytryptamine attained concentrations comparable to those in rats given neither drug and 5-hydroxyindolylacetic acid rose considerably. Results are discussed in relation to the contributions made to brain 5-hydroxytryptamine turnover by functional and non-functional metabolism.     

The role of liver tryptophan pyrrolase in the opposite effects of chronic administration and subsequent withdrawal of drugs of dependence on rat brain tryptophan metabolism.

1. Chronic administration of morphine, nicotine or phenobarbitone has previously been shown to inhibit rat liver tryptophan pyrrolase activity by increasing hepatic [NADPH], whereas subsequent withdrawal enhances pyrrolase activity by a hormonal-type mechanism. 2. It is now shown that this enhancement is associated with an increase in the concentration of serum corticosterone. 3. Chronic administration of the above drugs enhances, whereas subsequent withdrawal inhibits, brain 5-hydroxytryptamine synthesis. Under both conditions, tryptophan availability to the brain is altered in the appropriate direction. 4. The chronic drug-induced enhancement of brain tryptophan metabolism is reversed by phenazine methosulphate, whereas the withdrawal-induced inhibition is prevented by nicotinamide. 5. The chronic morphine-induced changes in liver [NADPH], pyrrolase activity, tryptophan availability to the brain and brain 5-hydroxytryptamine synthesis are all reversed by the opiate antagonist naloxone. 6. It is suggested that the opposite effects on brain tryptophan metabolism of chronic administration and subsequent withdrawal of the above drugs of dependence are mediated by the changes in liver tryptophan pyrrolase activity. 6. Similar conclusions based on similar findings have previously been made in relation to chronic administration and subsequent withdrawal of ethanol. These findings with all four drugs are briefly discussed in relation to previous work and the mechanism(s) of drug dependence.     

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

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.     

24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: Implications for caffeine-induced depression

Caffeine injected at doses of 20, 40 and 80 mg/kg increased brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in rat brain. In view of a possible role of 5-HT in caffeine-induced depression the effects of repeated administration of high doses of caffeine on brain 5-HT metabolism are investigated in rats. Caffeine was injected at doses of 80 mg/kg daily for five days. Control animals were injected with sahne daily for five days. On the 6th day caffeine (80 mg/kg) injected to 5 day sahne injected rats increased brain levels of tryptophan, 5-HT and 5-HIAA. Plasma total tryptophan levels were not affected and free tryptophan increased. Brain levels of 5-HT and 5-HIAA but not tryptophan decreased in 5 day caffeine injected rats injected with sahne on the 6th day. Plasma total and free tryptophan were not altered hi these rats. Caffeine-induced increases of brain tryptophan but not 5-HT and 5-HIAA were greater in 5 day caffeine than 5 day sahne injected rats. The findings are discussed as repeated caffeine administration producing adaptive changes in the serotonergic neurons to decrease the conversion of tryptophan to 5-HT and this may precipitate depression particularly in conditions of caffeine withdrawal.     

PLASMA AND BRAIN TRYPTOPHAN CHANGES IN EXPERIMENTAL ACUTE HEPATIC FAILURE

An experimental model for acute hepatic failure in man was obtained in pigs by hepatic devascularization. After operation, liver function was grossly impaired, movements became inco-ordinated and coma ensued. Most animals died 5½–8½ h after operation. Plasma unesteritied fatty acid and free (but not total) tryptophan concentrations rose markedly after operation and correlated significantly with each other. Brain tryptophan concentration increased and correlated significantly with plasma free tryptophan concentration. Increased tryptophan was found in the four brain regions studied (hypothalamus, thalamus, caudate and cortex) and was associated with raised 5-hydroxytryptamine turnover as indicated by raised 5-hydroxyindolylacetic acid concentration. Results are discussed in relation to altered tryptophan metabolism in human hepatic coma and to investigations of the influence of plasma unesterified fatty acid and free tryptophan changes on brain tryptophan metabolism in the rat.     

REGIONAL BRAIN STUDY OF INDOLEAMINE METABOLISM IN THE RAT IN ACUTE HEPATIC FAILURE

Abstract— Tryptophan, 5-hydroxytryptamine and 5-hydroindoleacetic acid were found to be greatly increased in various parts of the brains of rats in acute hepatic failure following two stage hepatic devascularization. However, the increases in 5-hydroxytryptamine and 5-hydroxyindoleacetic acid varied by region and are not explicable solely in terms of increased concentrations of tryptophan. The results are discussed in terms of differences in the regional metabolism of 5-hydroxyindoleamines. Plasma free fatty acids, albumin, total tryptophan and free tryptophan were measured in plasma in hopes of elucidating the mechanism responsible for the cerebral elevation of tryptophan. Increased plasma free tryptophan appears sufficient to explain the rapid increase in brain tryptophan. The relationship between these results and recent observations in hepatic encephalopathy is discussed.     

Stress-and Endotoxin-Induced Increases in Brain Tryptophan and Serotonin Metabolism Depend on Sympathetic Nervous System Activity

Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock- and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on beta- as opposed to alpha-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to 5-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.     

Effects of Long-Term Low Dietary Tryptophan Intake on Determinants of 5-Hydroxytryptamine Metabolisn in the Brains of Young Rats

Abstract: The relationship between plasma and brain tryptophan (TRP) concentrations and brain 5-hydroxytryptamine (5-HT) metabolism was studied in weanling rats fed diets containing either 0.4 g or 1.45 g TRP/ 100 g casein hydrolysate. Both groups gained weight comparably though food intakes were generally higher in the low-TRP group. Severe depletion of plasma total and free TRP and of brain TRP, 5-HT, and 5-hydrox-yindoleacetic acid (5-HIAA) occurred within 1 day of feeding the 0.4% TRP diet. Levels became stable after 7 days. The decreased brain TRP concentration of the rats on the 0.4% TRP diet did not cause a compensatory rise of the tryptophan hydroxylase (TRP OHase) activity in vitro. In the low-TRP group, neither plasma free TRP nor total TRP correlated significantly with brain TRP and although plasma TRP/large neutral amino acid (NAA) ratios (TRP/NAA) correlated significantly ( P < 0.05) with the time course of brain TRP, this statistical relationship depended almost completely on the variation of the TRP values alone. In the higher TRP group none of these correlations were significant. A plot of mean plasma free TRP versus brain TRP gave two distinct regression lines with similar slopes and corresponding to values before and after 7 days on the diet. The time course of brain 5-hydroxyindole concentrations did not parallel those of brain TRP and suggested that changes of TRP OHase activity also had an influence on 5-HT synthesis.     

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.     

Increased central serotonergic activity associated with nocturnal anorexia induced by Walker 256 carcinoma

The role of brain serotonin levels in Walker 256 tumor induced anorexia was investigated. Total and free plasma tryptophan, regional brain serotonin and 5-hydroxyindoleacetic acid were determined at night, and their relationship to nocturnal anorexia assessed by linear regression analysis. No significant difference in tryptophan, serotonin, or 5-hydroxyindoleacetic acid levels was detected between pair fed and tumor bearing rats exhibiting a 20% reduction of nighttime food intake. Tumor bearing rats with a 40% reduction in food intake had higher nighttime plasma free tryptophan and regional 5-hydroxyindoleacetic acid levels than their pair fed malnourished controls. These results indicate that increased plasma free tryptophan and elevated serotonin metabolism may not be the initial dysfunction responsible for nocturnal anorexia. However, it may contribute to the decreasing nocturnal food intake in severely anorexic tumor rats.