Changes in serotonin metabolism during food satiation in the mink and its effect on predatory aggression

Effect of single and protracted alimentary satiation on predatory aggression and content of serotonin and its metabolite 5-hydroxyindoleacetic acid in the amygdalar complex and hypothalamus was studied in mink--a representative of predators. A single alimentary satiation was not accompanied by any marked changes in serotonin metabolism and predatory behaviour. A long-term alimentary satiation significantly heightened the content of the 5-hydroxyindoleacetic acid in the lateral hypothalamus and amygdala without any changes in serotonin level, testifying to a high synthesis of serotonin with its simultaneous intensive destruction. Long-term satiation also greatly increased the latencies of aggression and killing the victim. It is suggested that serotonin is one of endogenous factors controlling predatory behaviour in predators, and this control is realized in interrelation with feeding behaviour.     

Interstrain differences in the serotonin and 5-hydroxyindoleacetic acid levels in the postnatal ontogeny of C57BL/6J and BALB/cLac strain mice

The content of serotonin and 5-hydroxy-indole-acetic acid (5-HIAA) was determined in the brain stem and hemispheres in 1 and 3 months old C57BL/6J and BALB/cLac mice. The characteristic dynamics of serotonin and its metabolite content related to the age was found in different brain regions and proved to be similar in both the strains, but the rate of serotonin system development in C57BL/6J mice was higher than in BALB/c Lac mice. An intensive catabolism of serotonin, possibly, related to the reaction to new environment was noted in the newborn animals. Sex differences in the rate of serotonin system maturation and serotonin and 5-HIAA content were shown for 12--16 days old mice: 12 days old males were characterized by more intensive metabolism than females while 16 days old males had less serotonin than females.     

Serotonin metabolism in the brain during sexual motivation and activation of the murine hypothalamo-hypophyseal-testicular system]

Serotonin metabolism was studied in male CBA mice during sexual arousal. It was shown that placement of a receptive female into a cage department separated from a male with a perforated partition, which prevented from the physical contact but allowed a male to see and smell a female, caused an elevation of serotonin metabolism. It was originally shown that 10-min female exposure produced in a male an increase in the level of the main serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain and its decrease in the hypothalamus. The catabolism coefficient (5-HIAA/serotonin ratio) also increased in the midbrain and decreased in the hypothalamus, while the serotonin content was unchanged. Longer sexual activation of male rats (for 20 min) resulted in an increase in the content of serotonin and 5-HIAA in the amygdala and olfactory bubs, while in the hippocampus only the level of 5-HIAA increased. Thus, for the first time, two stages were distinguished in male sexual arousal. They were determined according to the response of the pituitary-testicular system and involvement of serotonin in different brain regions.     

Selective effect of a maize diet in reducing serum and brain tryptophan contents and blood and brain serotonin levels.

The Maize diet used selectively lowers the tryptophan, serotonin and 5-hydroxyindoleacetic acid levels in the central nervous system without affecting catecholamine content. These changes are maximal as early as 48 hours after exposure to the Maize diet. The brain serotonin decrease is reversed to normal when the Maize diet is supplemented with Tryptophan, while nicotinic acid is ineffective. The maize diet seems to be a rapid and selective means of reducing brain serotonin content. The hypothesis that the psychic depression observed in patients with Pellagra may be related to an altered serotonin metabolism is discussed.     

A comparative study of serotonin metabolism in helminths and their hosts]

Studies have been made on the content of the main metabolite of serotonin, namely 5-hydroxyindoleacetic acid in parasitic worms from various classes. It was shown that 5-hydroxyindoleacetic acid level is lower than that of serotonin, which is taken as an indication of low catabolism of serotonin in worms. This tendency was observed in helminths from different taxonomic, ecological and age groups invading media with both low and high levels of serotonin metabolism.     

Use of genetic analysis to test the potential role of serotonin in alcohol preference.

The hypothesis that alcohol preference in mice is influenced by brain serotonin levels was tested using genetic analysis. Alcohol preference and static serotonin content were assessed in C57BL/Ibg (alcohol-preferring) and DBA/2 (alcohol-avoiding) mice, as well as in Fl and F2 generations obtained by crossbreeding. The two parental strains showed dissimilar alcohol preferences but identical concentrations of brain serotonin. Serotonin concentration segregated independently of alcohol preference in the F1 and F2 generations. These data provides strong evidence against the hypothesis that brain serotonin content influences alcohol preference. However, they do not preclude the possibility that differential alcohol influences on serotonin metabolism or turnover rate may result in differing preference for a alcohol.     

Genetics and phenogenetics of the hormonal characteristics of animals. VII. Correlation between brain serotonin and the hypothalamo-pituitary-adrenal system in domesticated and undomesticated silver foxes during emotional stress

Two groups of silver foxes, selected according their behaviour with respect to man and non-selected ones, were exposed to restriction-induced stress. It was found that changes in the level of brain serotonin and its main metabolite, 5-hydroxyindolacetic acid, and elevation of plasma corticosteroids concentration in domesticated (tame) silver foxes were much less pronounced than in non-domesticated (non-tame) animals. Positive relationship between type of behaviour, brain serotonin metabolism and pituitary-adrenal axis response to stress was observed. It is suggested that such correlative pattern as changed pituitary-adrenal axis responses in domesticated animals may be due to changes in metabolism of controlling this axis brain transmitter serotonin.     

Serotonin Decreases Cytoskeletal and Cytosolic Glycolytic Enzymes and the Levels of ATP and Glucose 1,6-Bisphosphate in Skin,Which Is Prevented by the Calmodulin Antagonists Thioridazine and Clotrimazole

Serotonin (5-hydroxytryptamine) is believed to play a pathogenic role in skin damage and various skin abnormalities; however, its mechanism of action remains unknown. We show here that intradermal injection of serotonin in rats induced a marked reduction in the activities of the glycolytic enzymes, phosphofructokinase (EC 2.7.1.11) and aldolase (EC 4.1.2.13), in both the cytoskeletal and cytosolic fractions from skin. Serotonin also decreased the levels of glucose 1,6-bisphosphate in skin, the powerful regulator of glucose metabolism. These serotonin-induced changes were accompanied by a marked decrease in ATP content in skin. All these pathological changes induced by serotonin were prevented by treatment with two structurally different calmodulin antagonists: thioridazine, an antipsychotic phenothiazine, or clotrimazole, from the group of the antifungal azole derivatives that were recently recognized as calmodulin antagonists. The present results suggest that calmodulin antagonists may be effective drugs in the treatment of skin damage under various pathological conditions and diseases in which serotonin levels are increased.     

Molecular Mechanisms of Actions of Interleukin-6 on the Brain,with Special Reference to Serotonin and the Hypothalamo-Pituitary-Adrenocortical Axis

Biological activities of the multifunctional cytokine, interleukin-6 (IL-6) include stimulation of B cell proliferation, immunoglobulin production, and initiation of the acute-phase response. IL-6 affects the CNS in that it activates the hypothalamo-pituitary-adrenocortical (HPA) axis and increases brain tryptophan and serotonin metabolism. IL-6 has been proposed as an important mediator of interaction between the neuroendocrine and immune systems. The peripheral and central effects of IL-6 are presumably mediated through its membrane receptor (IL-6R). IL-6, IL-6R and their respective mRNAs have been detected in several brain regions. Although the functions of cytokines overlap considerably, each displays its own characteristic properties. Expression of IL-6 in the brain has been observed in several CNS disorders, some of which have been associated with disorders of serotonin metabolism. It is proposed that interactions between IL-6 and brain serotonin is a complex process which involves corticotropin-releasing factor (CRF) and opioid peptides. It is likely that the molecular mechanisms underlying the actions of IL-6 on the HPA axis and its other brain functions involve the integrated effects of glutamate, Ca²⁺, 3,5-cyclic AMP, protein kinase C, and other metabolic pathways.     

Influence of Repeated Levodopa Administration on Rabbit Striatal Serotonin Metabolism,and Comparison Between Striatal and CSF Alterations

Parkinson's disease (PD) is characterized by decreased striatal dopamine, but serotonin (5-HT) is also reduced. Because 5-HT decreases following a single levodopa injection, levodopa has been suggested to contribute to PD's serotonergic deficits. However, in a recent study, rat striatal serotonin levels were reported to increase following 15-day levodopa administration. To address this issue, we administered levodopa (50 mg/kg) to rabbits for 5 days, then measured serotonin, its precursors tryptophan and 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindole-acetic acid (5-HIAA) in striatum and CSF. Striatal serotonin and tryptophan were unchanged, while 5-HTP and 5-HIAA increased 4- and 7-fold, respectively. CSF 5-HTP and 5-HIAA were also significantly increased. In levodopa-treated animals, 5-HTP concentrations were moderately correlated (r = 0.679) between striatum and CSF, while weak correlations were present between striatal and CSF concentrations of both serotonin and 5-HIAA. These results suggest that repeated levodopa treatment increases striatal serotonin turnover without changing serotonin content. However, levodopa-induced alterations in striatal serotonin metabolism may not be accurately reflected by measurement of serotonin and 5-HIAA in CSF.     

肠道微生物与血清素互作研究进展

肠道微生物在肠道稳态和大脑健康中发挥着举足轻重的作用.血清素是大脑的一种重要的单胺类神经递质,90％以上在结肠肠嗜铬细胞中由色氨酸代谢转化而来,在机体发挥广泛作用.近年来的研究表明,血清素对机体发挥的作用可能受到肠道微生物影响.肠道中某些微生物具有产生血清素的能力,同时,微生物群及其代谢产物(如丁酸)能通过影响色氨酸羟...     

Different influences of two types of diets commonly used for rats on a series of parameters related to the metabolism of central serotonin and noradrenaline

A commercial chow and a semipurified diet fed for 14 days to Sprague-Dawley male rats kept under standardized conditions of temperature, humidity, and light had different effects on a series of parameters related to the metabolism of central serotonin and noradrenaline. Rats fed the commercial chow had (1) a lower serum level of the six neutral amino acids (valine, isoleucine leucine, tyrosine, phenylalanine, and methionine) known to compete with tryptophan for its entry into the brain, (2) a higher ratio of tryptophan to the sum of the six neutral amino acids, (3) a lower ratio of tyrosine to the other five neutral amino acids, (4) a lower ratio of serotonin to 5-hydroxyindoleacetic acid in hypothalamus, (5) a higher tryptophan hydroxylase activity in raphe nuclei, and (6) a higher content of noradrenaline in hypothalamus. It is suggested that chow fed rats had a more active central serotonin metabolism in hypothalamus than rats fed the semipurified diet.     

Effect of ethanol on the concentration of serotonin in the brain of the rat and the excretion of 5-hydroxyindoleacetic acid

It is found that serotonin content in the brain areas and heart of rats with low alcohol motivation decreases after 5 months of chronic consumption of 48% ethanol solution in a dose of 4 g/kg; in animals with high alcohol motivation serotonin content decreases only in the hypothalamus. Under chronic alcoholization for 1 and 12 months no considerable changes were found in serotonin level of the studied tissues. 60 min after intraperitoneal administration of 20% ethanol solution in a dose of 3 g/kg in intact animals there occurs an increase of serotonin content in the brain hemispheres and heart and its decrease in the hypothalamus; in rat with low alcohol motivation after taking ethanol for 5 months this administration evokes a decrease of serotonin content in the hypothalamus and truncus cerebri; in rats with high alcohol motivation--its decrease in the hypothalamus. Excretion of 5-oxyindoleacetic acid with urine decreases 10 months after alcohol intoxication. When rats were not given ethanol after its chronic taking for 3 months serotonin oxidation was intensified for the first day, which was not observed after 7-month alcoholization of animals.     

Effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone in Wistar rats

The effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone (GnRH) during embryogenesis of Wistar rats was studied. The neurons producing GnRH were detected immunocytochemically on days 18 and 21 of embryonic development and on day 15 of postnatal development of rats with normal serotonin metabolism and rats in which the synthesis of serotonin was inhibited by p-chlorophenylalanine. The total number of GnRH neurons in serotonin deficiency was larger than in the case of its normal metabolism at all developmental stages studied. This is an indirect evidence for the inhibitory effect of serotonin on the formation of GnRH neurons. To confirm the morphogenetic effect of serotonin, we studied the rate of formation of GnRH neurons by injecting bromodeoxyuridine in the formation period of these neurons. It was found that serotonin deficiency had no effect on the time of formation of GnRH neurons: over 97% of neurons formed on days 11 to 15 of embryonic development both in the experimental and control groups. Note that, in serotonin deficiency, the maximum number of GnRH neurons formed one day later than in the normal state. Thus, serotonin inhibits the proliferation of GnRH neuron progenitor cells and thereby has a morphogenetic effect on the development of these neurons.     

The biochemical aspects of pineal gland functioning in the rat in ontogeny

We have studied metabolic pathways of serotonin in epiphysis of Wistar male rats at the age of 1; 1,5; 2; 3; 6; 12; 24 and 36 months. Epiphysis retains its functional activity throughout the life, however, serotonin metabolism in epiphysis undergoes marked changes. The main regulatory principle is the switch of serotonin metabolic pathways in the pineal gland. Most distinct changes between hydroxy- and methoxyindols in epiphysis have been observed during the periods of age-associated hormonal rearrangements like sexual maturation or involution of the gonad function at the old age.     

Morphofunctional changes in the pineal gland during adaptation to hypothermia

The influence of hypothermal stress (+4 degrees during 3 h) on the ways of serotonin metabolism in pineal gland and its structure has been studied in dynamics on adult male Wistar rats. It has been revealed that melatonin-producing epiphyseal function suffers from phase changes in dynamics of adaptation--significant rising during 15 min. after beginning of the experiment, rehabilitation up to normal--in 30 min, and fast suppressing--in 3 hrs. Suppressing of the functional pineal activity is not due to switched serotonin metabolism with melatonin and new indoles release, but to a partial pinealocytes breaking from their active function.     

Effects of sex factors and hemispheric localization on the involvement of serotonin from the frontal cortex, striatum, and nucleus accumbens into the processing of novel and repeatedly presented information in rats

The effects of novel or relevant (a single exposure to experimental chamber) and irrelevant (20 exposures to experimental chamber) stimuli on the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex, striatum, and nucleus accumbens in the left and right hemispheres were studied in male and female rats. It was found that 5-HT and 5-HIAA contents in the frontal cortex changed in response to neither relevant nor irrelevant stimuli. However, there were hemispheric difference in 5-HT and 5-HIAA in the frontal cortex of intact animals. The level of 5-HT in males and the level of 5-HIAA in females were higher in the left frontal cortex. In females, the level of 5-HIAA in the left striatum decreased in response to the novel stimulus. Sex differences in: a) 5-HT metabolism (increase in the level of 5-HIAA in males and increase in 5-HT in females) and b) lateralization (the striatal 5-HT metabolism in males changed bilaterally and only in the left hemisphere in females) were observed in reactions to irrelevant stimuli. Both in male and female rats, serotonin content in the nucleus accumbens changed only in response to the irrelevant stimuli. The 5-HT level increased in the left and right hemispheres independently of sex, but hemispheric difference was revealed only in females, in which the serotonin level was higher in the left nucleus accumbens. It is concluded that serotonergic neurotransmitter mechanisms are involved in hemispheric and sex differences in selective attention.     

Participation of the brain serotoninergic system in creating the stress reactivity of the hypophyseal-adrenal axis

The concentration of corticosteroids in the blood of rats was shown to increase in response to the immobilization stress at an earlier age than the brain serotonin metabolism changes. The level of corticosteroids in blood increased in response to the intraperitoneal serotonin injection also earlier than the reaction to the serotonin injection in the brain lateral ventricle sets up. The increase of the reaction of hypophysial-suprarenal system to stress during the period from the 12th till the 16th day of postnatal development coincided with the changes in serotonin metabolism in the brain stem and the reaction to serotonin injection in the brain lateral ventricle. It is suggested that the system of serotonin brain neurons connected with the hypophysial-suprarenal complex matures later tran the serotonin receptors in the periphery; the reaction to immobilization may be realized at the early developmental stages without the participation of brain serotonin.     

L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin

Nonalcoholic fatty liver disease is one of the most common liver diseases. L-tryptophan and its metabolite serotonin are involved in hepatic lipid metabolism and inflammation. However, it is unclear whether L-tryptophan promotes hepatic steatosis. To explore this issue, we examined the role of L-tryptophan in mouse hepatic steatosis by using a high fat and high fructose diet (HFHFD) model. L-tryptophan treatment in combination with an HFHFD exacerbated hepatic steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum alanine aminotransaminase levels, whereas L-tryptophan alone did not result in these effects. We also found that L-tryptophan treatment increases serum serotonin levels. The introduction of adenoviral aromatic amino acid decarboxylase, which stimulates the serotonin synthesis from L-tryptophan, aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced accumulation of lipid was further increased by serotonin treatment in cultured hepatocytes. These results suggest that L-tryptophan increases the sensitivity to hepatic steatosis through serotonin production. Furthermore, L-tryptophan treatment, adenoviral AADC introduction, and serotonin treatment induced phosphorylation of the mammalian target of rapamycin (mTOR), and a potent mTOR inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty acid with serotonin. These results suggest the importance of mTOR activation for the exacerbation of hepatic steatosis. In conclusion, L-tryptophan exacerbates hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR.     

Metabolism of tryptopan and serotonin by the chick pineal gland in organ culture.

Marked differences were seen between the metabolism of L-[3-14C] tryptophan and of [2-14C]serotonin by the intact chick pineal gland in organ culture. The major metabolite of tryptophan recovered by our procedures was melatonin, which accounted for about half the radioactivity recovered as metabolic products. In contrast, the principal product of serotonin metabolism recovered was hydroxyindoleacetic acid, and the yield of products derived through monoamine oxidase (EC 1.4.3.4) activity vastly exceeded that of melatonin. Metabolism of tryptophan yielded a much larger proportion of methlated metabolites among the products recovered than did metabolism of serotonin. However, the yield of methoxyindoleacetic acid from serotonin was greater than that from tryptophan. Serotonin formed endogenously and serotonin supplied exogenously appear to enter two or more largely distinct metabolic pools.