Increased Brain Tryptophan Research Articles

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.

Serotoninergic mechanisms and obesity

Brain serotonin appears to be an excellent target for designing drugs to treat obesity. The prototype drug dexfenfluramine accelerates the onset of satiety and suppresses “carbohydrate craving,” the tendency to consume large quantities of snacks rich in carbohydrates and fats but not proteins. The drug works by blocking serotonin’s reuptake into presynaptic terminals; its metabolite norfenfluramine also releases serotonin into synapses and activates certain postsynaptic serotonin receptors. Dopaminergic drugs such as amphetamine and phentermine suppress the appetite but apparently lack macronutrient specificity. The special importance of serotoninergic neurons in feeding behavior derives in part from the fact that eating per se affects the production and release of serotonin. This is because dietary carbohydrates, acting via insulin—which lowers plasma concentrations of the large neutral amino acids (LNAA)—increase the uptake of tryptophan in the brain; this in turn increases the substrate saturation of tryptophan hydroxylase, the key enzyme that converts this amino acid to serotonin. Paradoxically, dietary proteins—which, unlike carbohydrates or fats, do contain tryptophan—decrease tryptophan’s uptake in the brain (because they cause disproportionately great increases in blood levels of the other LNAA, which compete with tryptophan for brain uptake), and thus fail to increase brain tryptophan or serotonin levels. Brain serotonin also is critically involved in controling mood, and many patients learn that they can improve their mood by eating carbohydrate-rich, protein-poor foods, particularly as snacks. This carbohydrate craving transiently ameliorates their depressive symptoms, but predisposes to weight gain, a phenomenon readily observed in people with seasonal affective disorder syndrome, premenstrual syndrome, or nicotine withdrawal.

Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism

Neuroendocrine and neurochemical responses were studied following administration of recombinant mouse IL 6 (mIL 6) to mice. Intravenous (iv) or intraperitoneal (ip) injection of mIL 6 caused a rapid and short-lived activation of the hypothalamo-pituitary- adrenocortical (HPA) axis, as indicated by increases in plasma ACTH and corticosterone, with peak responses around 30 60 min. These responses contrast with those to ip mIL-1b which is substantially more potent and induces a greater response which does not peak until about 2 h following ip administration. Unlike IL-1 and lipopolysaccharide (LPS), IL-6 had no detectable effect on norepinephrine metabolism. However, tryptophan concentrations were elevated in most brain regions studied 1 2 h following iv mIL-6, and 2 h following ip mIL-6, significantly later than the peak HPA response. 5-hydroxyindoleacetic acid (5-HIAA) and the ratio of 5-HIAA to serotonin (5-HT) were elevated at around the same time in the brain stem, and occasionally in other brain regions. These responses were observed at doses of mIL-6 as low as 0.25 μg, and near maximal effects were achieved by 0.5 μg. Recombinant human IL-6 elicited similar responses, but was significantly less potent. Heat-treated mIL-6 elicited none of the responses. Serum amyloid A protein (SAA) concentrations were not elevated until 4 h after iv or ip mIL-6 administration, suggesting that the neuroendocrine and neurochemical changes were not secondary to an acute phase protein response. Intracerebroventricular injection of mIL-6 also elevated tryptophan and 5-HIAA in the hypothalamus and brain stem. Pretreatment of mice with the cyclooxygenase inhibitor, indomethacin, or the nitric oxide synthase inhibitor, N-v-nitro-L-arginine methyl ester (L-NAME) did not attenuate the mIL-6 induced neuroendocrine or neurochemical responses. However, the ganglionic blocking drug, chlorisondamine, prevented the increases in tryptophan and 5-HIAA:5-HT ratios. IL-6 may contribute to the HPA and indoleaminergic responses to LPS and IL-1. It is possible that the increases of tryptophan and serotonin metabolism may contribute to some of the biological effects of IL-6.

P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia

P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia

Plasma tryptophan levels and anorexia in liver cirrhosis.

Increased brain tryptophan (TRP) availability for serotonin synthesis may play a role in the pathogenesis of anorexia. Since in chronic liver failure, increased plasma and cerebrospinal fluid TRP concentrations are characteristically reported, we hypothesize that also in liver cirrhosis increased brain TRP availability may constitute the pathogenic mechanism of anorexia. To test this hypothesis, the association between anorexia and plasma TRP was investigated. Anorexia and plasma amino acid concentrations were evaluated in 16 patients with liver cirrhosis and compared with those obtained in 13 healthy volunteers. According to a questionnaire, 11 cirrhotic patients were considered as anorectic. In these patients, brain TRP availability was significantly higher than in nonanorectic patients and controls. Increased brain TRP availability is also associated with anorexia in liver cirrhosis, and supports the hypothesis that increased serotonergic activity may constitute the common pathogenic mechanism for anorexia associated with different diseases.

Studies on the pharmacological properties of oxindole (2-hydroxyindole) and 5-hydroxyindole: are they involved in hepatic encephalopathy?

It has been repeatedly described that plasma or CSF tryptophan concentrations increase in experimental animal models of liver impairment and in patients suffering from hepatic encephalopathy or hepatic coma (Hirayama, 1971; Curzon et al. 1973; Sourkes, 1978; ONO et al. 1996). It has also been demonstrated that the administration of large doses of tryptophan to patients affected by hepatic disorders or to dogs with a portocaval shunt may lead to coma (Sherlock, 1975; Rossi-Fanelli et al. 1982). On the basis of the widely agreed assumption that increased brain tryptophan concentrations signify increased 50Htryptamine turnover, several years ago, a number of investigators proposed that an increased stimulation of 50H-tryptamine receptors plays a key role in the neurological and psychiatric symptoms associated with liver diseases (Cummings et al. 1976). Tryptophan may be metabolized not only into 50H-tryptamine, but also into quinolinic or kynurenic acids, neuroactive compounds which are able to interact with glutamate receptors of the NMDA type (see: Stone, 1993 for a review). Approximately ten years ago, we observed that quinolinic acid was indeed increased in the rat brain with portocaval anastomosis or in patients who had died in hepatic coma (Moroni et al. 1986; Moroni et al. 1986a). We therefore proposed that “..quinolinic acid should be added to the list of compounds possibly involved in the pathogenesis and symptomatology of brain disorders associated to liver failure.” Other groups have recently confirmed that quinolinic acid is indeed increased in the blood and brain of rat models suffering from either acute or chronic liver failure. The concentration of quinolinic acid in the brain, however, does not seem to correlate with the neurological symptoms observed in these liver disorders. Furthermore, it is possible that quinolinic acid synthesis occurs mostly in macrophages or other periphalopathy may be “minor” (Bergquist et al. 1995; Basile et al. 1995).

Cracking the riddle of cancer anorexia

During tumor growth, anorexia and reduced food intake are among the major causes leading to malnutrition and eventually cachexia, which negatively affect patients' outcome. Consistent evidence from our laboratories in rats and humans indicates a key role for ventromedial hypothalamic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan levels (the precursor of serotonin) lead to increased cerebrospinal fluid tryptophan concentrations and increased VMH serotonin synthesis, which then mediates the occurrence of anorexia. However, recent data strongly suggest that factors other than tryptophan supplied to the central nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 infusion in normal rats causes changes in food intake and its determinants, meal number and meal size, similar to those characterizing cancer anorexia, thus supporting the involvement of this cytokine in the development of anorexia. Interestingly, IL-1 and the VMH serotonergic system appear to be closely linked: peripherally infused IL-1 increases brain tryptophan and serotonin concentrations, while intracerebrally infused IL-1 increases neuronal firing rate and serotonin release. We therefore hypothesize that during tumor growth, increased production/secretion of IL-1 occurs, which facilitates the tryptophan supply to the brain. IL-1 can then also act on the VHM itself, where IL-1 receptors exist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic neuronal firing rate and serotonin release, while peripherally acting IL-1 is critical in supplying the hypothalamus with the precursor, tryptophan, in order to maintain the high rate of serotonin synthesis. Also, additional factors recently proposed as mediators of anorexia (including neuropeptide Y and nitric oxide) appear to be part of the hypothesized pathogenic mechanism.

Phosphorylation and Activation of Tryptophan Hydroxylase by Exogenous Protein Kinase A

The catalytic subunit of protein kinase A increases brain tryptophan hydroxylase activity. The activation is manifested as an increase in Vmax without alterations in the Km for either tetrahydrobiopterin or tryptophan. The activation of tryptophan hydroxylase by protein kinase A is dependent on ATP and an intact kinase and is inhibited specifically by protein kinase A inhibitors. Protein kinase A also catalyzes the phosphorylation of tryptophan hydroxylase. The extent to which tryptophan hydroxylase is phosphorylated by protein kinase A is dependent on the amount of kinase used and is closely related to the degree to which the hydroxylase is activated. These results suggest that a direct relationship exists between phosphorylation and activation of tryptophan hydroxylase by protein kinase A.

The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat

The effects of a novel inhibitor 680C91 (( E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1 H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent ( K i = 51 nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT 1A,1D,2A and 2C receptors at a concentration of 10 μM. 680C91 had no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of l-[ring-2- 14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C91, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.

Serum Amino Acid Concentrations in Nine Athletes Before and After the 1993 Colmar Ultra Triathlon

The amino acid imbalance hypothesis should explain the fatigue originating in the brain during sustained exercise or over-training as a branched-chain (BCAA)/aromatic amino acids (AAA) imbalance with increased brain tryptophan uptake and 5-hydroxytryptamine synthesis. The serum amino acid profile was determined in 9 ultra-triathletes before and after completing the 1993 Colmar ultra-triathlon to additionally analyse the extent of this amino acid imbalance during such an extreme prolonged contest lasting more than 23 hours. The summed serum concentration of 25 amino acids decreased by 18% from 3962 +/- 846 to 3255 +/- 694 umol.l-1 likely reflecting a catabolic state of the organism with a decrease in 18 individual amino acids by 9-56%, an increase in cystine (+38%), methionine (+24%), tyrosine (+10%), phenylalanine (+12%), free tryptophan (+74%), and constant glutamine, leucine and total tryptophan levels. Since plasma volume increased by approximately 7.6% with a 3.3 kg body mass decrease in the athletes during the ultra triathlon, a decrease in intra-cellular water with an extra-cellular fluid increase is hypothesized. This decrease in cellular hydration state is seen as a protein-catabolic signal.

Stress, serotonergic function, and mood in users of oral contraceptives

The relationship between stress and changes in insulin levels, plasma ratio of tryptophan to other large neutral amino acids (LNAAs), mood, and food intake was investigated in women taking monophasic oral contraceptives containing progestagens. Subjects experiencing high levels of stress displayed significant decreases of insulin and tryptophan to other LNAAs ratios, before and after the consumption of a standard meal during the pill-free period as compared with the period of pill use. The decline of the tryptophan to other LNAAs ratio was accompanied by worsening of mood. In a control group of subjects experiencing low levels of stress there was no relationship between insulin and tryptophan to other LNAAs ratio, nor between tryptophan to other LNAAs ratio and mood. These results suggest that the combination of stress and alterations in sex hormones may be responsible for mood changes during the pill-free period in women taking oral contraceptives.

Effects of chlorisondamine and restraint on cortical [ 3H]ketanserin binding, 5-HT 2A receptor-mediated head shakes, and behaviours in models of anxiety

A recent study has indicated that ganglionic transmission mediates acute restraint-elicited increases in brain tryptophan (5-HT precursor) levels, 5-HT synthesis and (possibly) release. Because restraint-induced release of 5-HT has been shown to be associated with a paradoxical increase in cortical 5-HT 2A receptor binding, we have examined the influence of 5-HT synthesis/release upon cortical 5-HT 2A receptor binding and 5-HT 2A receptor-mediated head shakes in 3-hr restrained rats pretreated with the ganglionic blocker chlorisondamine. In keeping with past reports regarding the effects of restraint and ganglionic blockade upon anxiety, we have also measured the behavioural effects of restraint and/or chlorisondamine in two animal models of anxiety, the elevated plus-maze and the social interaction test. Chlorisondamine pretreatment (2.5 mg/kg, 20 min beforehand) prevented restraint-elicited defaecation and body weight decreases. Although stress amplified the head shake response to the injection of the 5-HT 2A/5-HT 2C receptor agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 1 or 2 mg/kg 2 hr after the end of restraint), cortical [ 3H]ketanserin binding remained unaltered. Chlorisondamine treatment was inactive, except for the amplification of the head shake response to DOI (2 mg/kg) in restrained rats. When exposed to the social interaction test, neither restraint nor chlorisondamine affected social interaction, locomotion, or rearings. In the elevated plus-maze, the percent number of open arms entered and the total number of arms enterd were decreased by acute restraint, whilst chlorisondamine pretreatment was inactive.

Foot shock-induced changes in blood and brain serotonin and related substances in rats.

The effects of electric foot shock on peripheral and central serotonergic systems in rats have been studied. We have focused on the time course alterations with particular attention being paid to changes in 5-HT, 5-HIAA, tryptophan concentrations and 5-HIAA/5-HT ratios in blood and various parts of the brain, observed within 1 h following stress application. Blood and brain (7 regions) samples were taken immediately after electric foot shock, 30 min, 1 and 24 h later. In the blood stress induced a rise in tryptophan level as well as rises in 5-HT, 5-HIAA levels and 5-HIAA/5-HT ratio within 1 h following stressful treatment. Tryptophan concentration was found to be increased in every part of the brain within 1 h after electric foot shock application. In striatum it remained higher even after 24 h. 5-HT level showed a significant rise only in medulla, while hypothalamus was the sole region where a fall in 5-HT was found. In other parts of the brain 5-HT level remained unaffected by stress. 5-HIAA content increased in almost every brain area studied except cerebellum and striatum. 5-HIAA/5-HT ratios shared the same pattern of changes. Briefly, foot shock altered 5-HT turnover in various brain regions, in particular within the first hour following stress application, whereas delayed response to stress was rarely observed. Increased brain tryptophan level seems to be necessary to cope with the enhanced 5-HT metabolism caused by stress, reflecting as a rise in 5-HIAA concentration and 5-HIAA/5-HT ratio.

5-HT 1C/5-HT 2 receptor blockade prevents 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane-, but not stress-induced increases in brain tryptophan

We have previously shown that acute administration of the 5-HT 1C/5-HT 2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI), elevates brain tryptophan levels. The present work aimed to investigate the mechanisms responsible for this elevation. Acute s.c. administration of a 2-mg/kg dose of DOI increased brain tryptophan levels but did not affect either plasma free tryptophan, plasma total tryptophan, brain 5-HT, or brain 5-hydroxyindoleacetic acid. Pretreatment with the 5-HT 1C/5-HT 2 receptor antagonist, LY 53857, prevented the DOI-induced increase in brain tryptophan levels, whilst the increase was reduced by the 5-HT 2 receptor/ α 1-adrenoceptor antagonist, ketanserin, and to a lesser extent, by the ganglionic blocker, chlorisondamine. On the other hand, pretreatment with either the peripherally acting 5-HT 1C/5-HT 2 receptor blocker, BW 501C67, the 5-HT uptake enhancer, tianeptine, the 5-HT uptake blocker, paroxetine, or the β 2-adrenoceptor antagonist, ICI 118.551, proved ineffective. Lastly, pretreatment with LY 53857 did not affect the immobilization-induced elevation in brain tryptophan levels. It is concluded that the elevation in brain tryptophan levels induced by DOI but not that induced by stress is due to central 5-HT 1C and 5-HT 2 receptor stimulation.

Accumulation of Brain Tryptophan in Rats after Administering Various Fats or Fatty Acids.

The intragastric administration of various kinds of fat (corn oil, lard, safflower oil, perilla oil, and fish oil) or fatty acids (oleic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) caused a significant increase in brain tryptophan (especially with fish oil or DHA), and also in serum insulin. However, at 2 h after administering the fats or fatty acids, brain serotonin was not increased in accordance with the increase of brain tryptophan. As a result of determining the time-dependent changes in brain 5-hydroxyindoles, brain serotonin and 5-HIAA gradually increased, and showed significant increases at 6 hand 4 h after the administration of fish oil, respectively. These results suggest that there was a fairly long time-lag for the changes in brain 5-hydroxyindoles to appear after being induced by the administration of fats or fatty acids.

Restriction of Maternal Dietary Carbohydrate Decreases Fetal Brain Indoles and Glycogen in Rats

In spite of evidence that dietary carbohydrate can increase brain tryptophan and 5-hydroxytryptamine in adult rats, the possible influence of maternal dietary carbohydrate on fetal brain indoles has received little attention. We studied the effect of graded levels (0, 4, 12 and 60%) of maternal dietary fructose or glucose fed throughout pregnancy on fetal brain glycogen and indoles. The diets were isoenergetic and met the NRC energy requirements for pregnant rats. The results demonstrated that low maternal dietary carbohydrate, with adequate energy intake, reduced fetal brain weight and concentrations of glycogen, tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. There were no significant differences between glucose and fructose feeding at any dietary carbohydrate level for any fetal brain measurements, showing that it was the level and not the type of dietary carbohydrate that was important. Significant correlations between fetal brain 5-hydroxytryptamine and brain glycogen, and between fetal brain 5-hydroxytryptamine and brain weight, suggested that lowered brain 5-hydroxytryptamine was only one symptom of disrupted brain development in fetuses of dams fed low levels of carbohydrate. The results show that dietary carbohydrate restriction during pregnancy can have adverse effects on fetal brain development, glycogen levels, and neurotransmitter synthesis even when maternal dietary protein and energy intake are adequate.

The role of interleukin-1 and tumor necrosis factor α in the neurochemical and neuroendocrine responses to endotoxin

Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor α (TNFα). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1α or IL- 1β on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNFa, TNFβ, IL-6, and interferon-a injected intraperitoneally failed to activate the HPA axis, but mouse TNFa was effective by this route, and human TNFα, TNFβ, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNFα, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNFα are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis.

The effect of aflatoxin B1 exposure on serotonin metabolism: response to a tryptophan load.

Semi-chronic exposure of ICR male Mice to Aflatoxin B1 (AFB1) in non-toxic doses decreased brain serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) and catecholamines without altering tryptophan (TRP) or tyrosine (TYR) levels. A TRP load (300 mg/kg, i.p. x 2 hours) slightly increased brain TRP levels while causing a slight decrease in 5-HT and 5-HIAA in control animals. A TRP load in AFB1 treated mice increased brain 5-HT and 5-HIAA. The TRP load caused a further reduction in brain catecholamines without altering TYR levels. Exposure to AFB significantly increased lung TRP levels without altering 5-HT or 5HIAA levels. TRP loading increased lung TRP concentrations in control mice. However, in AFB1 treated mice the increase was not significantly elevated above the level caused by AFB1 treatment alone. Lung 5-HT or 5-HIAA levels in control or AFB1 treated mice are not significantly altered by TRP loading. These experiments demonstrate that AFB1 alters brain and lung TRP metabolism.

The 5-HT 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl) 2-aminopropane increases brain tryptophan levels in the rat

Earlier studies have indicated that the sympathoadrenal system and the corticotropic axis control brain levels of tryptophan (Trp), the precursor of 5-hydroxytryptamine (5-HT). We investigated the effects of 5-HT receptor agonists known to activate the sympathoadrenal system and/or the corticotropic axis on plasma and brain Trp levels. Neither the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.5 mg/kg s.c.), nor the 5-HT 1C receptor agonist 1-(3-chlorophenyl) piperazine (mCPP, 2.5 mg/kg s.c.) affected plasma and brain Trp levels. The 5-HT 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl) 2-aminopropane (DOI, 0.5–2 mg/kg s.c.) increased brain Trp levels, an effect which was significant for the two highest doses used (1.5–2 mg/kg s.c).

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.