Increase In 5-hydroxyindoleacetic Acid Research Articles

Gut microbiota-derived 5-hydroxyindoleacetic acid from pumpkin polysaccharides supplementation alleviates colitis via MAPKs-PPARγ/NF-κB inhibition

Polysaccharides from Pumpkin (Cucurbita moschata Duchesne) (PPs) have many pharmacological activities, including anti-oxidant, immune, and intestinal microbiota regulation. These activities have provided some reminders of its potential therapeutic effect on ulcerative colitis (UC), but this has not yet been confirmed. This study preliminarily confirmed its significant anti-UC activity superior to Salicylazosulfapyridine. The average molecular weight of PPs was 3.10 × 105 Da, and PPs mainly comprised Mannose, Rhamnose, Galacturonic acid, Galactosamine, Glucose, and Xylose with molar ratios of 1.58:3.51:34.54:1.00:3.25:3.02. PPs (50, 100 mg/kg) could significantly resist dextran sodium sulfate induced UC on C57BL/6 mice by improving gut microbiota dysbiosis, such as the changes of relative abundance of Bacteroides, Culturomica, Mucispirillum, Escherichia-Shigella, Alistipes and Helicobacter. PPs also reverse the abnormal inflammatory reaction, including abnormal level changes of TNF-α, IFN-γ, IL-1β, IL-4, IL-6, IL-10, and IL-18. Metabolomic profiling showed that PPs supplementation resulted in the participation of PPAR and MAPK pathways, as well as the increase of 5-hydroxyindole acetic acid (5-HIAA) level. 5-HIAA also exhibited individual and synergistic anti-UC activities in vivo. Furthermore, combination of PPs and 5-HIAA could also elevate the levels of PPARγ in nuclear and inhibit MAPK/NF-ĸB pathway in the colon. This study revealed that PPs and endogenous metabolite 5-HIAA might be developed to treat UC.

Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.

Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.

Dynorphin a (1-13) alleviated stress-induced behavioral impairments in mice.

In this study we investigated whether κ-opioid receptor stimulation by dynorphin A (1-13), a potent fragment of endogenous peptide, attenuated repeated stress-induced behavioral impairments in mice. In order to reduce the motivation to escape, mice were preexposed to inescapable electric footshock (day 0), and then dynorphin A (1-13) was administered to mice prior to the stress from the next day for 4 d (days 1-4). Dynorphin A (1-13) (1500 pmol/5 µL intracerebroventricular (i.c.v.)) attenuated the repeated stress-induced escape failures from the shock, and this improvement was inhibited by the pretreatment of nor-binaltorphimine (4.9 nmol/kg subcutaneously (s.c.)), a κ-opioid receptor antagonist. In the neurochemical experiments, we detected an increase in 5-hydroxyindoleacetic acid (5-HIAA) content, but not in serotonin (5-HT) content, and an increase in the 5-HIAA/5-HT ratio was observed in the amygdala of the group with footshock compared with the group without shock. Additionally, the changes in 5-HIAA content and the ratio were reversed by dynorphin A (1-13). However, there were no differences in 5-HT or 5-HIAA content or their ratios in the hippocampus among the three groups. These results suggest that dynorphin might alleviate the stress-induced behavioral impairments accompanied by regulation of the 5-HTergic system in the brain.

ALTERATION OF 5-HIAA LEVELS IN FRONTAL CORTEX AND DORSAL RAPHE NUCLEUS IN RATS TREATED WITH COMBINED ADMINISTRATION OF TRYPTOPHAN AND ETHANOL

The present studies sought to investigate the effect of tryptophan alone or coadministration of tryptophan and ethanol on the interaction of central frontal cortex and dorsal raphe nucleus serotonergic functional activities by utilizing in vivo microdialysis. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, a metabolite of serotonin (5-HT), in the dorsal raphe nucleus, but not in the frontal cortex. Coadministration of tryptophan and ethanol caused very marked increases in 5-hydroxyindoleacetic acid (5-HIAA) levels in both the frontal cortex and the dorsal raphe nucleus, although ethanol (1.25 g/kg) did not change 5-HIAA levels in both areas. Moreover, the application of WAY100635 (10 muM), 5-HT(1A) antagonist, into the frontal cortex after coadministration caused a marked increase in 5-HIAA levels in the frontal cortex and a decrease in the levels in the dorsal raphe nucleus, although WAY100635 alone had no effect on these levels. This may suggest that WAY100635-induced increase of 5-HIAA levels in the frontal cortex resulted from negative feedback following the blockade of serotonergic 5-HT(1A) autoreceptors, and that this increase in 5-HIAA levels decreased 5-HIAA levels in the dorsal raphe nucleus by preventing the activation of dorsal raphe 5-HT(1A) autoreceptors. WAY100635 into the dorsal raphe nucleus did not significantly change 5-HIAA levels in both areas. This may indicate that the blockade of dorsal raphe 5-HT(1A) autoreceptors by WAY100635 resulted in unchanged 5-HIAA levels in the frontal cortex. Behavioral sign of teeth-chattering was markedly observed following the coadministration and in combination with WAY100635. These results may suggest that the increased 5-HIAA levels in both areas after coadministration are indicative of the interrelation via activation of serotonergic neurons, and that the increased levels are partly responsible for behavioral activation of rats.

Antidepressant evaluation of polysaccharides from a Chinese herbal medicine Banxia-houpu decoction.

Banxia-houpu decoction, a traditional Chinese medicine has been used in the treatment of depression. The present study confirmed that oral administration of polysaccharides from Banxia-houpu decoction, exhibited a reduction in the immobility time in the tail suspension and in the forced swimming tests in mice in a time-dependent manner. This effect at a dose of 320 mg/kg was more potent than that at a dose of 640 mg/kg. The polysaccharides from Banxia-houpu decoction were active in animal models of depression with comparable effects to known antidepressants. The oral administration of the polysaccharides at a low dose for 4 weeks resulted in a significant increase in the monoamine neurotransmitter 5-hydroxytryptamine (5-HT) and dopamine (DA) levels in whole mouse brain, but produced no significant increase in 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) concentrations. The effect of polysaccharides on the brain neurotransmitter levels appeared to be quite different from the effect of fluoxetine, a serotonin specific reuptake inhibitor. The results indicate that the mode of action of polysaccharides from Banxia-houpu decoction in depression might be related to both 5-HT and DA systems.

Effects of nimodipine on biogenic amines in discrete brain areas.

Discrete brain sections were obtained from rats after once or repeatedly given intraperitoneal nimodipine at doses ranging from 2.5 to 40 mg/kg. The single or the last treatment was carried out at 2-8 h before killing. The biogenic amine and metabolite content of the tissue samples were determined by high-performance liquid chromatography with electrochemical detection. The nimodipine-induced effects, chiefly regarding the brainstem, the thalamus-midbrain and the striatum, consisted of both an increase in 5-hydroxyindoleacetic acid (5-HIAA) levels and a decrease in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Since the 5-HIAA/5-hydroxytryptamine (5-HT) ratio was increased, whereas the DOPAC/dopamine (DA) and HVA/DA ratios were decreased, it was argued that nimodipine activated the serotonergic and inhibited the dopaminergic systems. The first effect was enhanced by fasting and, likewise, by drug administration repeated for 5 days, while the second was not affected by fasting, but disappeared after 5 days' treatment. The data obtained appeared to substantiate the usefulness of nimodipine to treat some disorders of the central nervous system.

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.

NEUROCHEMICAL CHANGES CORRELATED WITH BEHAVIOR MAINTAINED UNDER FIXED‐INTERVAL AND FIXED‐RATIO SCHEDULES OF REINFORCEMENT

Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed-ratio schedule of food presentation. Only one schedule was in effect during an experimental session, and each was correlated with a different keylight stimulus and location (left vs. right). The different schedule components alternated across days or weeks. Cerebrospinal fluid was collected from chronically implanted intracerebroventricular cannulae following sessions with the different schedules, as well as following sessions in which reinforcement was withheld (extinction), when response-independent food was delivered, and when the experimental chamber was dark and there were no scheduled events. Metabolites of the neurotransmitters serotonin, norepinephrine, and dopamine were assayed in cerebrospinal fluid using high-performance liquid chromatography with electrochemical detection. Compared to the fixed-ratio condition, responding maintained under the fixed-interval schedule resulted in consistently higher levels of the serotonin metabolite 5-hydroxyindoleacetic acid and of the dopamine metabolite homovanillic acid in all pigeons. Levels of 3-methoxy-4-hydroxyphenylethylene glycol, a metabolite of norepinephrine, and dihydroxyphenylacetic acid, another dopamine metabolite, were also higher in 3 of the 4 pigeons following exposure to the fixed-interval schedules when compared to levels of these metabolites after exposure to the fixed-ratio schedule. Extinction of fixed-ratio responding resulted in large increases in 5-hydroxyindoleacetic acid compared to levels of this metabolite under the fixed-ratio schedule, whereas this serotonin metabolite decreased during extinction of responding under the fixed-interval schedule. Control procedures suggested that the neurochemical changes were not related to the rate of responding but were a function of the specific experimental conditions. Distinctive neurochemical changes that accompany schedule-controlled responding show the sensitivity of the neurochemical environment to behavioral contingencies and demonstrate further the profound impact that such contingencies have on biobehavioral processes.

Kynurenine Pathway Measurements in Huntington's Disease Striatum: Evidence for Reduced Formation of Kynurenic Acid

Recent evidence suggests that there may be overactivation of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors in Huntington's disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16-sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p less than 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.

In vivo neurochemical effects of tail pinch

Tail pinch in the rat gives rise to a well characterised pattern of behaviour which includes gnawing, licking and eating. We have used both in vivo voltammetry and microdialysis to monitor neurochemical changes which accompany the behavioural response to a 5-min tail pinch. Tail pinch resulted in a increase of extracellular 5-hydroxytryptamine and a smaller and more delayed increase of 5-hydroxyindole acetic acid in the hippocampus. In the striatum there was a rise of both extracellular dopamine and ascorbate. With a recently developed constant potential voltammetric technique we can continuously monitor changes in extracellular ascorbate. Using this technique we found a very rapid rise in ascorbate current during a 5-min tail pinch; the current began to decline as soon as the clip was removed. The high time resolution of the technique also allowed us to record similar ascorbate changes during a 0.5-s tail pinch.

Regional brain monoamine levels and utilization in middle-aged rats

Significant changes in monoamine levels and utilization were noted in certain brain regions of middle-aged Fisher 344 rats when compared with young adult controls. In the prefrontal cortex and septum, 3, 4 dihydroxyphenylglycol (MHPG) and the MHPG/norepinephrine (NE) ratio were decreased. The septum also showed increases in dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) but there was a decrease in the DOPAC/DA ratio. The striatum showed an increase in the MPHG/NE ratio and an increase in DOPAC. The hippocampus and thalamus showed an increase in 5-hydroxyindoleacetic acid (5HIAA). This demonstrates that selected neurotransmitter systems in the brain are altered at an early stage of senescence. This could lead to ensuing neurological deficits.

Effect of restraint stress and anxiolytics on 5-HT turnover in rat brain.

In male Tuck AHA rats, restraint stress had no effect on 5-hydroxytryptamine (5-HT) levels in the frontal cortex, amygdala, hypothalamus and hippocampus, but produced a significant increase in 5-hydroxyindoleacetic acid (5-HIAA) levels in the amygdala after 120 and 180 min, and in the hypothalamus after 180 min. This apparent increase in turnover was not paralleled by a concomitant increase in the rate of 5-HT synthesis, as determined by measuring the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of amino acid decarboxylase with m-hydroxybenzylhydrazine (NSD-1015). 5-HTP accumulation was, however, increased in the frontal cortex after 180 min. In naive rats, buspirone (0.1-2.5 mg/kg, s.c.) produced a dose-dependent decrease in 5-HTP accumulation in all four brain regions, while chlordiazepoxide, in doses up to 10 mg/kg (s.c.) had no effect. The increase in 5-HT synthesis in the frontal cortex following 180 min restraint stress was inhibited by pretreatment with buspirone, when administered at 2.5 mg/kg (s.c.) 30 min prior to the stress period, but not by chlordiazepoxide at 10 mg/kg (s.c.).

Facilitating Effect of Insulin on Brain 5-Hydroxytryptamine Metabolism

In this study we investigated the effect of insulin on striatal 5-hydroxytryptamine and tryptamine in streptozotocin-diabetic and in normal rats. Streptozotocin-diabetic rats show a reduction in rat striatal tryptophan, 5-hydroxytryptamine, and 5-hydroxyindole acetic acid, an effect observed at 7 or 14 days after the treatment began. In addition, the accumulation of striatal tryptamine in pargyline-treated rats was reduced at 14 days. Insulin administration produced an increase in rat striatal tryptophan concentration that was observed within 2 h following its administration. By 6 h, however, the striatal tryptophan concentrations were significantly reduced. No changes in rat striatal 5-hydroxytryptamine were observed following the insulin administration, but the treatment induced significant increases in 5-hydroxyindole acetic acid that were observed at 2, 3, 4, and 6 h after insulin administration. The administration of insulin to diabetic rats had a tendency to reverse the decreases in 5-hydroxytryptamine metabolism observed in these animals. Treatment with tryptophan (12-25 mg kg-1) markedly increased rat striatal tryptophan, but did not affect 5-hydroxytryptamine metabolism, an effect that was only observed after the administration of higher doses (50-100 mg kg-1). This is in contrast to the effect of insulin that produces a lesser increase in striatal tryptophan accompanied by an increase in 5-hydroxytryptamine metabolism, indicating that in addition to the increase in tryptophan availability that it produces, it also possesses some other facilitatory effect on 5-hydroxytryptamine metabolism.

Effect of ischemia on hydroxylase cofactor (tetrahydrobiopterin) and monoamine neurotransmitters in rat brain.

Hydroxylase cofactor, monoamine neurotransmitters and their metabolites were measured in ischemic rat brain produced by four-vessel occlusion for 30 and 60 min periods. Slight reduction of hydroxylase cofactor activity was observed in the ischemic cortex after 60 min. Dopamine increased in the brainstem, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased throughout the brain. Decrease in norepinephrine was observed in the whole brain. Decrease in serotonin and increase in 5-hydroxyindoleacetic acid, a metabolite of serotonin, was observed in the ischemic cerebral cortex. The present study has revealed that there appears to be no significant relationship between hydroxylase cofactor activity and monoamine levels in the ischemic brain. Thus, the hydroxylase cofactor does not play a main role in regulating monoamine synthesis in the acute phase of brain ischemia.

α2-adrenoceptors modulate kainic acid-induced limbic seizures

We have tested several compounds interfering with the brain monoamine (noradrenaline, dopamine, serotonin) and acetylcholine systems for their effects on limbic seizures produced by systemically (s.c.) injected kainic acid as well as on neurochemical changes in amygdala/pyriform cortex resulting from the kainic acid treatment. The characteristic neurochemical changes induced by s.c. kainic acid were a decrease in noradrenaline and an increase in 5-hydroxyindoleacetic acid in the acute phase (3 h after kainic acid injection) suggesting strongly increased neurotransmitter turnover in noradrenergic and serotonergic neurons. This was followed by a reduction of glutamic acid decarboxylase and choline acetyltransferase activities during the chronic phase (3 days) of the kainic acid action, indicating destruction of GABAergic and cholinergic neurons. The compounds tested in this model of limbic epilepsy included l-propranolol, prazosin, clonidine, yohimbine, metergoline, atropine and haloperidol. Among these compounds the α 2-adrenergic agonist clonidine (0.1 mg/kg, i.p.) exhibited a powerful protective action on kainic acid-induced limbic seizures as well as on the neurochemical changes in the amygdala and pyriform cortex. In addition, the adrenoceptor antagonists prazosin ( α 1) and propranolol (β) as well as the dopamine receptor antagonist haloperidol had significant - but less potent - protective actions upon kainic acid-induced seizures and subsequent neurochemical changes. On the other hand, yohimbine ( α 2-antagonist) and metergoline (serotonin-antagonist) potentiated the limbic seizure syndrome and no effect was found with atropine. The experiments suggest a possible pathophysiological involvement of α-adrenergic receptors in limbic seizures induced by the excitotoxin kainic acid.

Effect of a new eburnamine derivative, RU 24722, on the turnover of monoamines in mouse brain: Selective and reversible decrease of noradrenaline

A new eburnamine derivative, is RU 24722, structurally similar to vincamine and is known to cause a specific and reversible decrease of noradrenaline in rat brain. The effects of RU 24722 on the turnover of monoamines in mouse brain were investigated. The noradrenaline level in mouse brain was significantly decreased after administration of RU 244722 10 mg/kg i.p. with significant increases in 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The levels of these compounds returned to the control levels within 5 h. The levels of d dopamine, serotonin, 5-hydroxyindoleacetic acid and histamine were not affected by this dose of RU 24722. Higher doses of RU 24722 (25 and 50 mg/kg) decreased the concentration of serotinin significantly with a significant increase in 5-hydroxyindoleacetic acid. There were no differences between the patterns of changes in the forebrain, midbrain and hindbrain. These results indicate that RU 24722 increased the turnover of noradrenaline and dopamine i in mouse brain at the dose of 10 mg/kg and the turnover of serotonin was also increased only at higher doses.

PLATELET SEROTONIN RELEASE IN RHEUMATOID ARTHRITIS: A STUDY IN FOOD-INTOLERANT PATIENTS

Serotonin and 5-hydroxyindoleacetic acid levels in platelet-rich plasma were determined in serial samples obtained before and up to 6 h after food-challenge in 7 patients showing inflammation of the joints after ingestion of certain foods. Exacerbation of arthritis was associated with a fall in serotonin levels and a subsequent increase in 5-hydroxyindoleacetic acid. These data suggest that serotonin may be released from platelets during food challenges and that platelet serotonin release may contribute to joint inflammation.

Effect of omental transposition on to the brain on the cortical content of norepinephrine, dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in experimental cerebral ischaemia.

Local cerebral ischaemia causes a significant decrease in norepinephrine, dopamine, 5-hydroxytryptamine in the cortical brain tissue of rabbits, associated with an increase in 5-hydroxyindoleacetic acid. Previous transposition of the omentum on to the brain surface maintains, to a large extent, physiological levels of these metabolites. This study stresses the role of the transposed omentum in reducing the effects of experimental occlusion of a major cerebral artery.

Effect of fusaric acid on aggression, motor activity, and brain monoamines in mice

The effects of fusaric acid (FA), a dopamine-β-hydroxylase (DβH) inhibitor, were determined on aggression, motor activity, and brain monoamines at doses of 3.2 to 60 mg/kg following administration of dietary supplements of L-tyrosine or balanced protein to male albino mice. Compared to saline injected control animals, both aggression and motor activity were reduced by the highest doses of FA. Somewhat more reduction in aggression was observed in animals administered dietary supplements of casein compared to those given the tyrosine supplement. Treatment with FA at doses of 30 to 60 mg/kg decreased brain norepinephrine and dopamine, and decreased brain tyrosine in animals fed the tyrosine supplement. In contrast, FA increased 5-hydroxytryptamine, and caused marked increases in 5-hydroxyindoleacetic acid at the highest doses. The data suggest that the neurochemical effects of FA may not be the same in rats and mice.

The importance of 5-hydroxytryptamine turnover for the analgesic effect of morphine in the chicken

A new method for testing analgesia in young chicks is described. It consists of shining a light on the chick's head till the chick senses the heat and moves. The report in the literature that chickens require very large doses of morphine to produce analgesia was only partly confirmed. Three strains (called A, B & C) were tested. Only 57% of the chicks showed analgesia after morphine 100mg/kg in strain C, whereas all chicks responded to 30mg/kg in strain B and to 15mg/kg in strain A. The subcutaneous ED 50 was 80 mg/kg in C, 17.5 mg in B and 5.6 mg in A. Except for the first days of life, the analgesic responses are not age-dependent (tested up to 48 days). The relationship between 5-hydroxytryptamine turnover in the brain and analgesic effect of morphine was examined in the three strains. Only strain A showed an increase in 5-hydroxyindole acetic acid (of 31%, P < 0.01, in the cerebral hemispheres, and of 23%, P < 0.05, in the optic lobes) and in this respect resembled the mammals. It can be concluded that the phenomenon of the interaction of morphine with 5-hydroxytryptamine-containing neurones, which enhances the analgesic effect of morphine in the mammalian brain, occurs in some strains of chicks but is absent in others. The strain in which it was found had a sensitivity to morphine which approached that seen in mammals.