Tryptophan Pyrrolase Activity Research Articles

Effect of Protein Intake and Cold Exposure on Selected Liver Enzymes Associated with Amino Acid Metabolism

Two experiments were conducted to examine the possibility that increased activities of some enzymes in cold-exposed animals could be substrate-induced rather than a direct effect of cold, since the cold-exposed animals increase appreciably their food intake.Two groups of cold-exposed rats were allowed to eat only as much protein as their warm mates, and their extra energy requirement was met by sugar or fat. Another cold-exposed group of animals was allowed to eat the complete diet freely.After a 4-week cold exposure, the activities of 5 liver enzymes involved in amino acid metabolism were markedly increased in all groups of cold-exposed rats. However, the activities of 3 of these enzymes, arginase, glutamic-oxalacetic and glutamicpyruvic transaminase were increased only as a result of a cold-induced higher protein intake. In contrast, the activities of tryptophan pyrrolase and tyrosine-α-ketoglutaric transaminase were increased by cold per se. The data demonstrate that both substrate-induced and cold-induced enzymatic changes occur in cold-exposed animals.

Alteration in plasma corticosterone levels following long term oral administration of lead produces depression like symptoms in rats

Lead toxicity is known to induce a broad range of physiological, biochemical and behavioral dysfunctions that may result in adverse effects on several organs, including the central nervous system. Long-term exposure to low levels of lead (Pb(2+)) has been shown to produce behavioral deficits in rodents and humans by affecting hypothalamic-pituitary-adrenal (HPA) axis. These deficits are thought to be associated with altered brain monoamine neurotransmission and due to changes in glucocorticoids levels. This study was designed to investigate the effects of Pb(2+)exposure on growth rate, locomotor activity, anxiety, depression, plasma corticosterone and brain serotonin (5-HT) levels in rats. Rats were exposed to lead in drinking water (500 ppm; lead acetate) for 5 weeks. The assessment of depression was done using the forced swimming test (FST). Estimation of brain 5-HT was determined by high-performance liquid chromatography with electrochemical detection. Plasma corticosterone was determined by spectrofluorimetric method. The present study showed that long term exposure to Pb(2+) significantly decreased the food intake followed by the decrease in growth rate in Pb(2+)exposed rats as compared to control group. No significant changes in open field activity were observed following Pb(2+)exposure while significant increase in anxiogenic effect was observed. Increased plasma corticosterone and decreased 5-HT levels were exhibited by Pb(2+)exposed rats as compared to controls. A significant increase in depressive like symptoms was exhibited by Pb(2+)exposed rats as compared to control rats. The results are discussed in the context of Pb(2+) inducing a stress-like response in rats leading to changes in plasma corticosterone and brain 5-HT levels via altering tryptophan pyrrolase activity.

New developments on the serotonin hypothesis of depression: shunt of tryptophan

Since the late 1960s, the serotonin deficiency, as demonstrated in major depression, was related to an increased activity of the liver enzyme tryptophan-pyrrolase stimulated by an excess of circulating corticosteroids, which would shift the metabolism of tryptophan from serotonin to kynurenine production. The finding that the kynurenine causes different effects in central nervous system suggested that an up-regulation of the tryptophan-kynurenine pathway determined not only a deficiency of serotonin, but could also play a role in the development of anxiety, psychotic symptoms and cognitive impairment associated with depression. This review aims to evaluate the different hormonal and genetic factors regulating the metabolism of tryptophan via kynurenine, and to highlight how this metabolic pathway may be involved in depression pathogenesis. Rate-limiting enzymes of kynurenine formation are two: tryptophan 2,3-dioxygenas (TDO) activated by stress hormones, and indoleamine 2,3-dioxygenase (IDO), activated by proinflammatory cytokines. The increased expression of the genes that produce inflammatory cytokines (interferon-gamma and tumor necrosis factor alpha) would determine a genetic predisposition to develop depression by up-regulating the IDO pathway, while environmental stressors would activate TDO via hormonal activation. Therefore, it can be reasonably assumed that the pathway of tryptophan-kynurenine represents one of the main melting points of the interaction between genetic and environmental factors involved in the pathophysiology of depression, as well as new targets for future antidepressant strategies.

Dual Effect of Exogenous Progesterone on the Activity of Tyrosine Aminotransferase in the Liver of Female Rats

An as yet undescribed biphasic response of liver tyrosine aminotransferase (TAT) activity to a single administration of a microcrystallic watery suspension of 25 mg of progesterone (Agolutin Depot, SPOFA Praha) is described in adult female rats subjected to immobilization stress for 150 min. Exaggeration of the stress induced increase of TAT activity 3 and 8 h after hormone administration and its suppression 20 h after it was observed. The stress induced serum corticosterone increase is not correlated with the described changes, however, in non-stressed animals an increased TAT activity at 3 and 8 h after progesterone injection tightly follows the increased plasma corticosterone values. No statistically significant changes were found with respect to liver tryptophan pyrrolase activity.

Activation of Liver Tryptophan Pyrrolase Mediates the Decrease in Tryptophan Availability to the Brain after Acute Alcohol Consumption by Normal Subjects

We have previously suggested that acute ethanol consumption by normal subjects decreases the availability of circulating tryptophan (Trp) to the brain by activating liver Trp pyrrolase, the first and rate-limiting enzyme of the (major) kynurenine pathway of Trp degradation. The aim of the present study was to examine this hypothesis further by measuring plasma levels of kynurenine metabolites following alcohol consumption. After an overnight fast and a light breakfast, each of 10 healthy subjects received one of five drinks (placebo and doses of ethanol of 0.2, 0.4, 0.6 and 0.8 g/kg body weight in tonic water) on five different occasions. Blood samples were withdrawn 2 h later and plasma was analysed for concentrations Trp, competing amino acids (CAA) and kynurenine metabolites. Along with the depletion of plasma Trp and the decrease in its availability to the brain, as expressed by the ratio of [Trp]/[CAA], plasma kynurenine was elevated by doses of ethanol of 0.2-0.8 g/kg body weight. The ratio% of [kynurenine]/[Trp], an index of the expression of Trp pyrrolase activity, was also increased by all doses of ethanol. We conclude that activation of liver Trp pyrrolase mediates the depletion of plasma Trp and the decrease in its availability to the brain induced by acute ethanol consumption.

Inhibition of tryptophan pyrrolase activity in restraint female rats following medroxyprogesterone administration.

To determine the effects of Medroxyprogesterone (hormonal contraceptive) in restraint stressed female rats in relation to tryptophan metabolism. Pre-clinical study. Department of Biochemistry, University of Karachi. The investigation was carried out in the year 2003. Female Albino Wistar rats (150-200 gm body wt) were selected and divided into four groups (n=5 in each group). Rats were injected intraperitoneally either vehicle or Medroxyprogesterone (25mg/kg/ml) and were immediately subjected to 2 hours restraint stress while respective controls remained in their home cages. In restraint stress group, hepatic holo and total tryptophan pyrrolase activities were increased. Liver tryptophan, total serum tryptophan and albumin concentration were decreased. Brain tryptophan, 5HT and 5HIAA concentrations were increased. Medroxyprogesterone administration in unrestraint rats inhibited holo, total and apo enzyme activities with increases in liver tryptophan concentrations. Effect of restraint stress following Medroxyprogesterone administration when compared with drug injected unrestrained group showed increase in holo and total tryptophan pyrrolase activities with decrease in liver tryptophan concentrations. Brain tryptophan, 5HT and 5HIAA levels were increased. Results when compared with vehicle injected stressed-rats showed that total and apo tryptophan pyrrolase activities were decreased. Liver tryptophan, serum tryptophan and albumin concentrations were increased but brain tryptophan metabolism was not effected. It is concluded that Medroxyprogesterone inhibits stress induce increases in peripheral tryptophan metabolism and increases plasma tryptophan. Although stress induced increases in brain indoles were not effected by the drug at two hours, further studies on time course effects of this drug will be needed to explore its possible anxiolytic effects.

Inhibition of tryptophan - pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats.

To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine (SSRI) on tryptophan metabolism in rats. A pre-clinical study. Clinical Biochemistry Research Laboratory, Department of Biochemistry, University of Karachi. The investigation was carried out during 2000 to 2001. Male Wistar rats (150-200 g body wt) were selected and divided into control and test groups (n = 5) for comparison. In in-vitro (10 - 1000mM) as well in-vivo (0.5-30 mg/kg body wt.) studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase (tryptophan-2,3-dioxygenase; EC 1.13.11.11) activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum (total and free) and liver L-tryptophan concentrations. Similarly, serum non-estrified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.

Tryptophan degradation during and after gestation.

In mice, activation of indoleamine-(2,3)-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, is required to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. On the other hand, postpartum blues and depression appear to be related to reduced availability of tryptophan and serotonin. In healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy and postpartum. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor, two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy. The data confirm earlier results and suggest significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were found, correlating significantly to the kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation has ceased. By contrast, still increased kynurenine concentrations and also increased kyn/trp suggest continuing turnover of tryptophan. Because also ALT was increased postpartum, abnormal activity of hepatic tryptophan pyrrolase and possibly other enzymes could be involved. We conclude that the decrease of tryptophan during pregnancy might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process, rather it seems related to abnormal activity of liver enzymes.

Longitudinal study of tryptophan degradation during and after pregnancy

In mice, activation of indoleamine-2,3-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, was found to be necessary requirement to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. In plasma from 20 healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy (1 specimen at each trimester of gestation) and postpartum (week 6). None of the women had any signs of infection at the time of plasma sampling, but the study population was otherwise unselected. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor (sTNF-R55), two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy, data suggesting significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were observed, correlating significantly to kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation returned to baseline. By contrast, still increased kynurenine concentrations and also increased kyn/trp point to continuing catabolism of tryptophan. Postpartum elevation of liver enzyme ALT may suggest that increased activity of hepatic tryptophan pyrrolase could be involved in increased conversion of tryptophan despite low degree of immune activation. We conclude that IDO is activated in pregnancy and that the decrease of tryptophan might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process.

Rat liver tryptophan pyrrolase activity and gene expression during alcohol withdrawal.

Rat liver tryptophan (Trp) pyrrolase activity and gene expression were studied in relation to the alcohol-withdrawal syndrome (AWS). Both activity and gene expression were enhanced after withdrawal of ethanol-containing liquid diets and the time-course of these changes mirrored that of development and intensity of the behavioural disturbances of the AWS. By contrast, no correlation was observed between the AWS-induced behaviour and changes in activity of another hepatic glucocorticoid-inducible enzyme, tyrosine aminotransferase, and a negative correlation was noted between behaviour and the gene expression of this latter enzyme and also of that of the hepatic glucocorticoid receptor. We suggest that the metabolic consequences of activation of liver Trp pyrrolase during alcohol withdrawal may play a role in the behavioural features of the AWS.

Coordinate up-regulation of CYP1A1 and heme oxygenase-1 (HO-1) expression and modulation of δ-aminolevulinic acid synthase and tryptophan pyrrolase activities in pyridine-treated rats

To determine the changes in heme metabolism associated with induction of cytochrome P450 expression by pyridine, we compared the time course of CYP1A expression with the time course of (i) expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3), (ii) activity of δ-aminolevulinic acid synthetase (ALAS) (EC 2.3.1.37), and (iii) heme saturation of tryptophan pyrrolase (TPO) (EC 1.13.11.11) in tissues of rats administered a single 100 or 150 mg/kg i.p. dose of pyridine. Both mRNA and protein of HO-1 and CYP1A1 were induced in the liver, kidney, and lung, with the induction of HO-1 mRNA preceding and paralleling that of CYP1A1 mRNA in the liver and lung but not kidney. Induction of CYP1A1 mRNA expression peaked within 9–12 hr and returned to control levels by 24 hr in all tissues examined, whereas induction of HO-1 mRNA expression was sustained for 48 hr in the lung and liver. In contrast to the transient up-regulation of CYP1A1 mRNA, increased microsomal CYP1A1 protein was sustained in all three tissues. Similar to the induction of HO-1 expression, lipid peroxidation was stimulated by pyridine treatment in the kidney, lung, and liver, but with the stimulation being more persistent in the liver and lung than in the kidney. Increased hepatic CYP1A1 or CYP1A2 activity was preceded by increased activities of HO-1 and ALAS. Pyridine treatment negatively modulated heme saturation of hepatic TPO. The findings indicate that pyridine stimulates the synthesis, utilization, and degradation of heme in a coordinate manner, and suggest that these alterations in heme metabolism may contribute to CYP1A1 induction by pyridine.

Tryptophan metabolism in alcoholism.

Studies of tryptophan (Trp) metabolism in relation to the serotonin status in alcoholism are of 2 types: (1) those related to the pharmacological effects of ethanol; (2) those concerning the serotonin status in the absence of alcohol intake. In experimental animals, acute and chronic ethanol administration and subsequent withdrawal exert a variety of effects on brain serotonin synthesis and turnover mediated by corresponding changes in Trp availability to the brain secondarily mainly to modulation of liver Trp pyrrolase (TP) activity. Alcohol-preferring mice and rats exhibit a central serotonin deficiency caused by, or in some cases associated with, a higher TP activity. Liver TP also appears to be a target of ethanol in man and evidence has recently emerged that alcoholics with positive family history are serotonin-deficient because of a lower availability of circulating Trp to the brain. Acutely, ethanol depletes brain serotonin in normal subjects, which may explain alcohol-induced aggression in susceptible individuals and also the incidence of depression in alcoholism. Trp availability to the brain is increased before the appearance of the alcohol-withdrawal syndrome in man, raising the possibility that the associated behavioural disturbances may involve the excitotoxic Trp metabolite quinolinate. Further studies of the Trp and serotonin status in relation to these important clinical features of alcohol dependence and alcoholism may therefore yield fruitful results.

Body weight loss and changes in tryptophan homeostasis by chlorinated dibenzo-p-dioxin congeners in the most TCDD-susceptible and the most TCDD-resistant rat strain.

We compared the effects of 2,3,7,8-tetra (TCDD), 1,2,3,7,8-penta (PeCDD), 1,2,3,4,7,8-hexa (HxCDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) on brain serotonin metabolism, plasma tryptophan and liver tryptophan pyrrolase activity in two rat strains, TCDD-sensitive Long-Evans (Turku AB; L-E) and TCDD-resistant Han/Wistar (Kuopio; H/W). Previously it was shown that L-E rats exhibit the expected rank order of potency for CDDs in terms of acute toxicity with TCDD being the most potent, followed by PeCDD, HxCDD and HpCDD. In contrast, to H/W rats HxCDD was the most toxic and TCDD the least toxic of these congeners. In the present study, the CDDs decreased body weight in L-E rats in the following order of potency: TCDD > PeCDD > HxCDD > HpCDD. The same rank order was recorded for elevations in brain tryptophan and plasma free tryptophan concentrations as well as for inhibition of the main hepatic tryptophan metabolizing enzyme, tryptophan pyrrolase. By contrast, in H/W rats HxCDD was the most effective congener in producing loss of body weight, followed by HpCDD, PeCDD and TCDD. This was also true of changes in tryptophan homeostasis. These findings imply that in TCDD-susceptible L-E and TCDD-resistant H/W rats the potency of dioxin congeners in inducing acute toxicity highly correlates with their ability to disrupt tryptophan homeostasis. However, there may not be a direct causal relationship between body weight loss and altered tryptophan homeostasis, because the magnitudes of these two phenomena were not consistently parallel across the dioxin congeners tested.

Tryptophan metabolism in male Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats.

Parameters of tryptophan (Trp) and related metabolism were compared in male Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats. Liver Trp pyrrolase activity was 38-58% higher in sP than in sNP rats, and this was associated with a greater expression of the enzyme mRNA as measured by multiprobe oligonucleotide solution hybridization. Moderately (about 10-19%), but significantly, lower concentrations of free serum, total serum, and brain Trp were also observed in sP compared with sNP rats. Concentrations of whole brain 5-hydroxytryptamine (5-HT) and its major metabolite 5-hydroxyindol-3-yl-acetic acid (5-HIAA) were, however, 14-21% higher in sP rats. Serum corticosterone concentration was 18% higher in sP rats. We conclude that alcohol preference in Sardinian rats is associated with increased liver Trp pyrrolase activity and mRNA expression leading to a decrease in Trp availability to the brain. Although a simple serotonin deficiency could not be demonstrated in the whole brain, the possibility could not be ruled out that a deficiency may be present in discrete areas of the brain of the sP rat.

Tryptophan pyrrolase gene expression in an alcohol preferring and non-preferring mouse strain.

There is considerable evidence that the level of cerebral serotonin plays a key role in the volitional consumption of ethanol in both man and animals. Naive alcohol-preferring C57BL/6J mice have been shown to have a lower cerebral serotonin content compared to the non-preferring CBA/Ca mouse strain. This has been attributed to the enhancement of hepatic tryptophan pyrrolase activity in C57 mice. Activity and/or expression of tryptophan pyrrolase may be an important biological determinant of alcohol preference. We have investigated the possible mechanism/s underlying this strain difference in tryptophan pyrrolase activity by assaying both mRNA levels encoding for the tryptophan pyrrolase gene and by mutational analysis of tryptophan pyrrolase cDNA. We were unable to demonstrate any difference in tryptophan pyrrolase mRNA levels between naive C57 and CBA mice. Tryptophan pyrrolase mRNA levels were increased following starvation in C57 mice and following glucocorticoid administration in both C57 and CBA mice. Heteroduplex mutational analysis failed to detect any tryptophan pyrrolase cDNA sequence heterogeneity between these mice strains.

PREVENTION BY CYCLOHEXIMIDE OF THE AUDIOGENIC SEIZURES AND TRYPTOPHAN METABOLIC DISTURBANCES OF ETHANOL WITHDRAWAL IN RATS

Cycloheximide (20 mg/kg body wt, given intraperitoneally at-1 and 3 h after withdrawal of an ethanol-containing liquid diet) prevents the activation of liver tryptophan pyrrolase, the consequent inhibition of synthesis of brain 5-hydroxytryptamine, and the audiogenic seizures observed at 7 h after alcohol withdrawal. We suggest that a rapidly-turning-over protein mediates the alcohol withdrawal syndrome and discuss the possible role of liver tryptophan pyrrolase.

Effects of chronic administration and subsequent withdrawal of ethanol-containing liquid diet on rat liver tryptophan pyrrolase and tryptophan metabolism.

An investigation of the effects of chronic administration of ethanol by the liquid diet procedure and its subsequent withdrawal on tryptophan (Trp) metabolism and disposition was performed in rats. Treatment with the control liquid diet caused an enhancement of liver Trp pyrrolase activity and mRNA abundance. These effects are not due to the starvation associated with this feeding procedure, because they occur in rats maintained on the liquid diet ad libitum. Chronic ethanol administration in the liquid diet did not further influence the above increased expression of Trp pyrrolase mRNA but caused inhibition of pyrrolase activity in competition with the effects of the diet. The control liquid diet decreased liver Trp concentration, but exerted no significant effects on other aspects of Trp disposition. The most striking and robust finding was a highly significant elevation in both Trp pyrrolase activity and mRNA expression at 7 h following discontinuation of ethanol availability, at which time there were demonstrable behavioural signs of ethanol withdrawal. The increase in Trp pyrrolase mRNA during alcohol withdrawal may be caused by corticosterone, whose circulating concentration was also increased. The changes in Trp pyrrolase activity during ethanol withdrawal were associated with significant alterations in Trp disposition including decreased brain Trp concentration and 5-hydroxytryptamine synthesis and turnover. These alterations may play a pivotal role in the behavioural manifestations of ethanol withdrawal including the hyperexcitement underlying audiogenic seizures. We suggest that rat Trp pyrrolase gene regulation may be an important biological determinant of the ethanol withdrawal syndrome and requires further study, and that the use of the liquid diet procedure in Trp metabolic studies requires inclusion of adequate controls and special attention to the effects of the liquid diet itself.

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.

Tryptophan metabolism and disposition in relation to alcohol and alcoholism.

Tryptophan (Trp) metabolism and disposition in relation to alcohol and alcoholism are briefly reviewed. The changes observed could generally be classified into those: (1) exerted by acute or chronic alcohol administration and/or subsequent withdrawal; (2) already present in the absence of alcohol consumption, such as in naive alcohol-preferring animals or in abstinent alcoholics. In normal rats, acute ethanol administration activates liver Trp pyrrolase and exerts a biphasic effect on brain 5-HT (5-hydroxytryptamine or serotonin) synthesis, whereas chronic ethanol administration and subsequent withdrawal exert opposite effects on 5-HT synthesis mediated by corresponding changes in liver Trp pyrrolase activity. A cerebral 5-HT deficiency has been demonstrated in the alcohol-preferring C57BL mouse strain and in a number of alcohol-preferring rat lines, the mechanism of which is understood only in two models; the C57B1 mouse strain has a higher liver Trp pyrrolase activity and the P rat line from Indiana has a lower density of serotonergic fibres in cerebral cortex. In man, acute ethanol intake lowers circulating [Trp] and its availability to the brain, almost certainly by activating liver Trp pyrrolase. Some evidence exists for possible inhibition of pyrrolase activity in non-abstinent chronic alcoholics. Evidence in recently abstinent alcoholics suggests that Trp availability to the brain may be impaired and that this may be particularly so in patients with positive family history. Exploration of this latter possibility may be important in understanding the biological basis of predisposition to alcoholism.

Decrease in Circulating Tryptophan Availability to the Brain After Acute Ethanol Consumption by Normal Volunteers: Implications for Alcohol-Induced Aggressive Behaviour and Depression

Acute ethanol consumption by fasting male volunteers decreases circulating trytophan (Trp) concentration and availability to the brain as determined by the ratio of (Trp) to the sum of its five competitors ([Trp]/[CAA]ratio). These effects of alcohol are specific to Trp, because levels of the 5 competitors are not increased. The decrease in circulating (Trp) is not associated with altered binding to albumin and may therefore be due to enhancement of hepatic Trp pyrrolase activity. It is suggested that, under these conditions brain serotonin synthesis is likely to be impaired and that, as a consequence, a possible strong depletion of brain serotonin in susceptible individuals may induce aggressive behaviour after alcohol consumption. The possible implications of these findings in the relationship between alcohol and depression are also briefly discussed.