5-hydroxyindoleacetic Acid Concentrations Research Articles

Preliminary study on the mechanism underlying the interaction of balance dysfunction and anxiety disorder.

This study aims to explore the anxiety-related behavioral changes and the concentration alterations of monoamine neurotransmitters in balance/anxiety-related nuclei of intratympanic gentamicin (GT)-induced balance disorder models. GT was administrated intratympanically in the adult male Sprague-Dawley rats to establish the vestibular impaired animal model. Rotarod was applied to test the vestibular function, and elevated plus maze and open field test were harnessed to evaluate the anxiety level. Monoamines and their metabolites were assayed by high-performance liquid chromatography. Rotarod test revealed that 6 days after GT administration, the average latency decreased significantly compared with the control group. Three days after GT administration, the travel distance and the central zone time obtained from open field and the duration of open arm stay and the times of open arm entries from elevated plus maze were apparently lower than those of the control group, whereas no significant differences were noted between 2-week group and the control group. Three days after GT administration, the concentration of norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) within medial vestibular nucleus (MVN); the concentration of NE, serotonin (5-HT), and 5-HIAA within locus coeruleus (LC); and the concentration of NE, 5-HT, 5-HIAA, and 3,4-dihydroxyphenylacetic acid within dorsal raphe nucleus (DRN) increased significantly compared with the control group. Two weeks after the administration, the concentrations of part of the neurotransmitters were lower than those of the 3-day group, indicating the rapid activation and slow deactivation of MVN-LC and MVN-DRN pathways. Vestibular impairment could lead to elevated anxiety level. The elevated anxiety levels might be attributed to increased monoamine concentrations within MVN, LC, and DRN.

Predator stress-induced depression is associated with inhibition of hippocampal neurogenesis in adult male mice

Stress has been suggested to disturb the 5-hydroxytryptamine system and decrease neurogenesis, which contribute to the development of depression. Few studies have investigated the effect of predator stress, a type of psychological stress, on depression and hippocampal neurogenesis in adult mice; we therefore investigated this in the present study. A total of 35 adult male Kunming mice were allocated to a cat stress group, cat odor stress group, cat stress + fluoxetine group, cat odor stress + fluoxetine group, or a control group (no stress/treatment). After 12 days of cat stress or cat odor stress, behavioral correlates of depression were measured using the open field test, elevated plus maze test, and dark-avoidance test. The concentrations of hippocampal 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were measured using high-performance liquid chromatography-electrochemical detection. Neurogenesis was also analyzed using a bromodeoxyuridine and doublecortin double-immunostaining method. Cat stress and cat odor stress induced depression-like behaviors; this effect was stronger in the cat stress model. Furthermore, compared with the control group, cat stress mice exhibited lower 5-hydroxytryptamine concentrations, higher 5-hydroxyindoleacetic acid concentrations, and significantly fewer bromodeoxyuridine+/doublecortin+-labeled cells in the dentate gyrus, which was indicative of less neurogenesis. The changes observed in the cat stress group were not seen in the cat stress + fluoxetine group, which suggests that the effects of predator stress on depression and neurogenesis were reversed by fluoxetine. Taken together, our results indicate that depression-like behaviors induced by predator stress are associated with the inhibition of hippocampal neurogenesis.

Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy

Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures.

Cerebrospinal fluid 5-HIAA concentrations correlate with cardiac uptake of 123I-MIBG during myocardial scintigraphy in drug naïve Parkinson's disease.

We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = - 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.

Bioconversion of Tyrosine and Tryptophan Derived Biogenic Amines by Neuropathogenic Bacteria.

The biochemical potential of pathogenic bacteria may cause alteration in the neurophysiological environment; consequently, neuroendocrine and immune responses of the host are modulated by endogenously produced metabolic products of neuropathogenic bacteria. The present study was designed to detect the derived biogenic amines in spent culture media of Bacillus cereus (Bc), Clostridium tetani (Ct), Listeria monocytogenes (Lm), and Neisseria meningitidis (Nm). Overnight grown culture in different culture media i.e., Nutrient broth (NB), Luria basal broth (LB), Brain Heart Infusion broth (BHI), and human serum supplemented RPMI 1640 medium (RPMI) were used to prepare filter-sterilized, cell-free cultural broths (SCFBs) and subjected to high performance liquid chromatography with electrochemical detection (HPLC-EC) along with the control SCFBs. Comparative analysis of biogenic amines in neuropathogenic bacterial SCFBs with their respective control (SCFB) revealed the complete degradation of dopamine (DA) into its metabolic products by Bc, Ct, and Nm, whereas Lm showed negligible degradation of DA. A relatively high concentration of 5-hydroxyindol acetic acid (5HIAA) by Bc in NB and LB indicated the tryptophan metabolism by the serotonin (5HT) pathway. Our study suggests that microbial endocrinology could help unravel new perspectives to the progression of infectious diseases.

Low Inherent Sensitivity to the Intoxicating Effects of Ethanol in Rhesus Monkeys with Low CSF Concentrations of the Serotonin Metabolite 5-Hydroxyindoleacetic Acid.

Type 2 alcoholism is characterized by low serotonin system functioning and has a high degree of heritability, with offspring of alcoholics often showing a reduced response to the intoxicating effects of ethanol (EtOH), which is thought to be marker for future alcohol use disorders (AUDs). As such, an important aim of studies investigating the origins of AUDs is to understand the relationship between serotonin system functioning and level of intoxication. A nonhuman primate model was used to evaluate observational ratings of sensitivity to EtOH and to further investigate the relationship between central serotonin activity and behavioral response to EtOH. Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were obtained from 4 cohorts of alcohol-naïve, adolescent rhesus macaques (N=82, 45 females, 37 males). One to 3months after the CSF sample, subjects were administered a standardized intravenous EtOH bolus (males: 2.1g/kg body weight, females: 2.0g/kg body weight), placed into an open-top, clear plexiglass chamber suspended from the ceiling, and their latency to escape was recorded as a measure of the degree of intoxication. Thereafter, subjects were rated using a Likert scale for the degree of intoxication during a 30-minute observation period. Our results indicate that latency to escape from the chamber was associated with intoxication ratings (p=0.0009) following the standardized intravenous administration of EtOH. Low CSF 5-HIAA concentrations predicted short escape latency (p=0.007) and were associated with low intoxication ratings (p=0.02), indicating that low central nervous system (CNS) serotonin functioning is related to relative insensitivity to the intoxicating effects of alcohol. Our study shows that, in monkeys exposed to alcohol for the first time, objective measures of intoxication are associated with subjective ratings for intoxication, and both were associated with CSF 5-HIAA concentrations. Our data confirm and extend the finding that low CNS serotonin functioning is predictive of intrinsic low sensitivity to the intoxicating effects of EtOH.

ШЛЯХ БІОСИНТЕЗУ СЕРОТОНІНУ В ГОЛОВНОМУ МОЗКУ ЩУРІВ ЗА УМОВ ЕКСПЕРИМЕНТАЛЬНОГО ОЖИРІННЯ, ВИКЛИКАНОГО ДОВГОТРИВАЛИМ УВЕДЕННЯМ ПРОГЕСТЕРОНУ

Obesity is one of the most common complex health problem. The pathway of serotonin synthesis takes part in neuroendocrine regulation, as well as in the regulation of a number of behavioral functions of the body and fat deposition. Serotonin is a mediator of the amine nature, which functions as a neurotransmitter and tissue hormone. The greatest amount of serotonin is synthesized in the brain and 12 duodenum. As a neurotransmitter, serotonin affects both directly and indirectly on the function of most brain cells. Female hormone progesterone influence on serotonin functions. One of the effect of progesterone is increasing of amount of fat tissue during the pregnancy. Long-term using of progesterone in hormone substitution therapy or as part of contraception also lead to fat accumulation effect. The levels of activity of serotonergic system enzymes, tryptophan hydroxylase, tryptophan decarboxylase and monoamine oxidase (MAO), and tryptophan, 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid concentrations in the rat brain under obesity conditions caused by prolonged administration of progesterone were determined in this study. Studies have shown that the content of tryptophan, 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in the brain of rats under obesity caused by prolonged administration of progesterone increased in comparison with the rats of the control group. The levels of tryptophan hydroxylase and MAO activity decreased, and tryptophan decarboxylase activity levels increased in the rat brain under obesity conditions caused by prolonged administration of progesterone. Thus, as a result of our studies, we found an imbalance in the system of serotonin metabolism in the brain of rats with the development of hormonal obesity induced by prolonged administration of progesterone, which may indicate the involvement of the serotonergic neurotransmitter system in the mechanisms of the development of obesity and concomitant diseases.

The effects of prenatal hyperhomocysteinemia on the formation of memory and the contents of biogenic amines in the rat hippocampus

We evaluated the long-term neurophysiological effects of prenatal hyperhomocysteinemia (HHC) in mature female rats whose mothers received an oral methionine load daily from the fourth day of pregnancy to delivery. We have shown that after the experimentally induced prenatal HHC in mature female rats, shortterm and long-term memory were disrupted. These changes were observed in the absence of exogenous methionine intake and after recovery of normal values of homocysteine in the serum of rats in comparison with the level detected immediately after birth. A significant reduction in the concentration of noradrenaline, serotonin, and 5-hydroxyindoleacetic acid in the hippocampus of mature female rats subjected to prenatal HHC was also found, which may be one of the causes of their cognitive impairment.

The effect of oxytocin on the level and monoamines turnover in the brain of isolated mice of highand low-aggressive lines

Objective. In the course of the study, the effect of oxytocin on the behavior and level of monoamines of the brain in aggressive male isolates of the initially low-aggressive C57Bl/6 line with similar indices of highly aggressive white outbred mice was compared. Methods. In experiments on isolated male mice of the low-aggressive C57Bl/6 line and highly aggressive white outbred mice, the effects of oxytocin on the aggressive behavior and the activity of monoaminergic systems of the left and right cerebral hemispheres was investigated. After prolonged social isolation, the male mice, who attacked in the resident-intruder test, were selected for further research. Oxytocin (5 IU/ml, 20μl) was admitrated intranasally. Control animals was treated with saline. With the HPLC-method, in the cerebral cortex, hippocampus, olfactory tubercle and striatum of the left and right sides of the brain the concentrations of dopamine, norepinephrine, serotonin and their metabolites of dioxyphenylacetic, homovaniline and 5-hydroxyindoleacetic acids were measured. Results. Among the male isolates of the C57Bl/6 line, the proportion of aggressive individuals was 56.5%, and among white outbred mice 87.5%. The investigated lines also differed in the attack latency time: aggressive C57Bl/6 mice attacked an average on the 113.1±23.5 second, while in white outbred mice the attack followed on the 35.3±14.7 second (p &lt; 0.01). In the aggressive male isolates of the C57Bl/6 line, which received intranasally saline solution, the content of serotonin and 5-hydroxyindoleacetic acid in the hippocampus was significantly higher on the right. In C57Bl/6, oxytocin reduced the manifestation of aggression caused by prolonged social isolation (p &lt; 0.05), but had no absolute ability to stop this type of behavior. Under its influence, the level of dopamine in the left cortex (p = 0.054), as well as serotonin content in the right hippocampus (p &lt; 0.05) and in the left striatum (p &lt; 0.05) decreased. In addition, the use of oxytocin in C57Bl/6 neutralized the asymmetry of serotonin and 5-hydroxyindoleacetic acid levels in the hippocampus. At the same time there was an asymmetry in the content of dopamine in the cerebral cortex with the predominance of this mediator in the right hemisphere (p &lt; 0.05). In male isolates of highly aggressive white outbred mice, the effect of oxytocin on behavior was not found. However, in these animals oxytocin caused certain changes in monoaminergic systems of the brain. Under the action of oxytocin, the inicial right-sided asymmetry of the level of dopamine metabolites in the striatum and left-sided asymmetry in the level of serotonin in the cortex disappeared. Oxytocin caused an increase in the content of 5-hydroxyacetic acid in the right striatum (p &lt; 0.05) and norepinephrine in the left hippocampus (p &lt; 0.05). In addition, white outbred mice under the influence of oxytocin developed asymmetry with the predominance of norepinephrine in the right olfactory tubercle (p &lt; 0.05). Conclusions. It can be assumed that relatively weak changes in the state of serotonergic and dopaminergic systems against the background of high reactivity of the noradrenergic system are a feature of the reaction of the brain of highly aggressive animals to oxytocin. The data obtained are discussed in terms of the lateralization of neurotransmitter systems responsible for intraspecific aggression caused by prolonged social isolation. (For citation: Karpova IV, Bychkov ER, Marysheva VV, et al. The effect of oxytocin on the level and monoamines turnover in the brain of isolated mice of high- and low-aggressive lines. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(2):23-30. doi: 10.17816/RCF15223-30).

Neuroendocrine neoplasms of the small intestine and appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.

Sex and intrauterine growth restriction modify brain neurotransmitters profile of newborn piglets

The current study aimed to determine, using a swine model of intrauterine growth restriction (IUGR), whether short- and long-term neurological deficiencies and interactive dysfunctions of Low Birth-Weight (LBW) offspring might be related to altered pattern of neurotransmitters. Hence, we compared the quantities of different neurotransmitters (catecholamines and indoleamines), which were determined by HPLC, at brain structures related to the limbic system (hippocampus and amygdala) in 14 LBW and 10 Normal Body-Weight (NBW) newborn piglets. The results showed, firstly, significant effects of sex on the NBW newborns, with females having higher dopamine (DA) concentrations than males. The IUGR processes affected DA metabolism, with LBW piglets having lower concentrations of noradrenaline at the hippocampus and higher concentrations of the DA metabolites, homovanillic acid (HVA), at both the hippocampus and the amygdala than NBW neonates. The effects of IUGR were modulated by sex; there were no significant differences between LBW and NBW females, but LBW males had higher HVA concentration at the amygdala and higher concentration of 5-hydroxyindoleacetic acid, the serotonin metabolite, at the hippocampus than NBW males. In conclusion, the present study shows that IUGR is mainly related to changes, modulated by sex, in the concentrations of catecholamine neurotransmitters, which are related to adaptation to physical activity and to essential cognitive functions such as learning, memory, reward-motivated behavior and stress.

Determination of 5-Hydroxyindole Acetic Acid by Electrochemical Methods with an Oxidized Glassy Carbon Electrode

The concentration of 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, might be the diagnosis basis for some cranial nerve pathology. An oxidized glassy carbon electrode (named OGCE) was employed to detect 5-HIAA with electrochemical methods. Multi-peaks appeared from the second cycle in range of 0.10–0.55V (vs. AgCl/Ag) were assigned to the oxidative intermediates and products of 5-HIAA after the electrochemically driven oxidation at over 0.6V in the first cycle. Kinetics studies show that all of these electrode reactions are adsorption-controlled processes, which are contributed to the strong hydrogen-bond interaction of these intermediates with the negatively charged hydroxyl and carboxyl groups on the surface of OGCE. Based on the square wave voltammetry (SWV) method, the linear relationship was shown between the peak current at 0.7V and the concentration of 5-HIAA in range of 1.56–58.6μmol/L, so 5-HIAA could be determined with limit of 0.917μmol/L (S/N=3) even certain interference were co-existed.

Concentrations of various tryptophan metabolites are higher in patients with diabetes mellitus than in healthy aged male adults.

Tryptophan metabolites in plasma samples from 20 male subjects with type 2 diabetes mellitus (T2DM) and 20 nondiabetic reference males were analyzed by ultra high performance liquid chromatography. Tryptophan levels in the diabetic subjects were significantly lower than those in nondiabetic subjects. The concentrations of 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid were found to be higher in the diabetic patients. When the diabetic patients were divided into higher- and lower-tryptophan groups, the concentrations of 5-hydroxytryptophan, indole-3-acetic acid, kynurenine, 5-hydroxykynurenine, and kynurenic acid were found to be higher in the diabetic patients with higher tryptophan levels. However, diabetic patients with lower plasma tryptophan levels had higher levels of 5-hydroxyindoleacetic acid than the patients with higher tryptophan levels. These results suggest that tryptophan was metabolized more in T2DM patients than in nondiabetic subjects. In the kynurenine pathway, the degradation of tryptophan seems to be accelerated in patients with higher plasma levels of tryptophan than in patients with lower levels of tryptophan. In the serotonin pathway, when the level of tryptophan is low, the conversion of serotonin to 5-hydroxyindoleacetic acid appears to be accelerated. In conclusion, our results suggest that T2DM patients may be exposed to stress constantly.

Influence of a HTR2B Stop Codon on Glucagon Homeostasis and Glucose Excursion in Non-Diabetic Men.

Limited data are available about the role of the serotonin 2B (5-HT2B) receptor in the function of human islets. This study aimed to test whether the 5-HT2B receptor contributes to glucose, insulin, and glucagon homeostasis in humans, utilizing a hereditary loss-of-function gene mutation in the receptor, which causes a 50% reduction in the production of the receptor protein in heterozygotes. This clinical study enrolled participants recruited by newspaper advertisements and from mental status examinations. A cohort of participants from a young Finnish founder population composed of 68 non-diabetic males with a mean age of 30 was divided into groups for comparison based on being a 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*) heterozygote carrier (n=11) or not (n=57). Serum levels of glucose, insulin, and glucagon were measured in a 5 h oral glucose tolerance test using a 75 g glucose challenge. Insulin resistance, insulin sensitivity, and beta cell activity were calculated using the homeostasis model assessment (HOMA2) and whole body insulin sensitivity index (WBISI), as well as the ratio of glucagon to insulin was noted. The areas under the curves (AUCs) were also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF). Covariate adjusted mean score comparisons were applied. Lower glucagon secretion and decreased glucose excursion were observed among HTR2B Q20* carriers as compared with individuals who were homozygotes for the wild-type Q20 allele (controls). No differences in insulin secretion, beta cell activity, insulin resistance, or insulin sensitivity were observed. The glucagon to insulin ratio differed between the HTR2B Q20* carriers and controls. CSF levels of 5-HIAA were similar between groups. Our findings indicate that the 5-HT2B receptor may contribute to the regulation of human glucagon and glucose homeostasis and the interplay between glucagon and insulin secretion.

The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males

Herein, we examined insulin resistance (IR), insulin sensitivity (IS), beta cell activity, and glucose metabolism in subjects with antisocial personality disorder (ASPD), and whether the serotonin 2B (5-HT2B) receptor and testosterone have a role in energy metabolism. A cohort of subjects belonging to a founder population that included 98 ASPD males, aged 25–30, was divided into groups based on the presence of a heterozygous 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*; n = 9) or not (n = 89). Serum glucose and insulin levels were measured in a 5 h oral glucose tolerance test (75 g) and indices describing IR, IS, and beta cell activity were calculated. Body mass index (BMI) was also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were measured in cerebrospinal fluid, and testosterone levels from serum. An IR-like state comprising high IR, low IS, and high beta cell activity indices was observed among ASPD subjects without the HTR2B Q20* allele. By contrast, being an ASPD HTR2B Q20* carrier appeared to be preventive of these pathophysiologies. The HTR2B Q20* allele and testosterone predicted lower BMI independently, but an interaction between HTR2B Q20* and testosterone lead to increased insulin sensitivity among HTR2B Q20* carriers with low testosterone levels. The HTR2B Q20* allele also predicted reduced beta cell activity and enhanced glucose metabolism. Reduced 5-HT2B receptor function at low or normal testosterone levels may be protective of obesity. Results were observed among Finnish males having an antisocial personality disorder, which limits the generality.

Oxytocin-Induced Changes in Monoamine Level in Symmetric Brain Structures of Isolated Aggressive C57Bl/6 Mice.

Changes in activity of monoaminergic systems of the left and right brain hemispheres after administration of saline and oxytocin were studied in male C57Bl/6 mice subjected to social isolation. The concentrations of dopamine, norepinephrine, serotonin, and their metabolites dihydroxyphenylacetic, homovanillic, and 5-hydroxyindoleacetic acids were measured in the cerebral cortex, hippocampus, olfactory tubercle, and striatum of the left and right brain hemispheres by HPLC. In isolated aggressive males treated intranasally with saline, the content of serotonin and 5-hydroxyindoleacetic acid was significantly higher in the right hippocampus. Oxytocin reduces aggression caused by long-term social isolation, but has no absolute ability to suppress this type of behavior. Oxytocin reduced dopamine content in the left cortex and serotonin content in the right hippocampus and left striatum. Furthermore, oxytocin evened the revealed asymmetry in serotonin and 5-hydroxyindoleacetic acid concentrations in the hippocampus. At the same time, asymmetry in dopamine concentration appeared in the cortex with predominance of this transmitter in the right hemisphere. The data are discussed in the context of lateralization of neurotransmitter systems responsible for intraspecific aggression caused by long-term social isolation.

Lotus Leaf Alkaloid Extract Displays Sedative-Hypnotic and Anxiolytic Effects through GABAA Receptor.

Lotus leaves have been used traditionally as both food and herbal medicine in Asia. Open-field, sodium pentobarbital-induced sleeping and light/dark box tests were used to evaluate sedative-hypnotic and anxiolytic effects of the total alkaloids (TA) extracted from the herb, and the neurotransmitter levels in the brain were determined by ultrafast liquid chromatography-tandem mass spectrometry. The effects of picrotoxin, flumazenil, and bicuculline on the hypnotic activity of TA, as well as the influence of TA on Cl(-) influx in cerebellar granule cells, were also investigated. TA showed a sedative-hypnotic effect by increasing the brain level of γ-aminobutyric acid (GABA), and the hypnotic effect could be blocked by picrotoxin and bicuculline, but could not be antagonized by flumazenil. Additionally, TA could increase Cl(-) influx in cerebellar granule cells. TA at 20 mg/kg induced anxiolytic-like effects and significantly increased the concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and dopamine (DA). These data demonstrated that TA exerts sedative-hypnotic and anxiolytic effects via binding to the GABAA receptor and activating the monoaminergic system.

Disruption of glucocorticoid receptors in the noradrenergic system leads to BDNF up-regulation and altered serotonergic transmission associated with a depressive-like phenotype in female GRDBHCre mice

Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the noradrenergic system, may evoke depressive-like behavior in female but not male mutant mice (GRDBHCre mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the noradrenergic system influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic system. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GRDBHCre mice on both the mRNA and protein levels. The possible impact of the mutation on brain noradrenergic and serotonergic systems was addressed by investigating the tissue neurotransmitter levels under basal conditions and after acute restraint stress. The findings indicated a stress-provoked differential response in tissue noradrenaline content in the GRDBHCre female but not male mutant mice. An analogous gender-specific effect was identified in the diminished content of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the prefrontal cortex, which suggests down-regulation of this monoamine system in female GRDBHCre mice. The lack of GR also resulted in an up-regulation of alpha2-adrenergic receptor (α2-AR) density in the female but not male mutants in the locus coeruleus. We have also confirmed the utility of the investigated model in pharmacological studies, which demonstrates that the depressive-like phenotype of GRDBHCre female mice can be reversed by antidepressant treatment with desipramine or fluoxetine, with the latter drug evoking more pronounced effects. Overall, our study validates the use of female GRDBHCre mice as an interesting and novel genetic tool for the investigation of the cross-connected mechanisms of depression that is not only based on behavioral phenotypes.

Preliminary Evidence That High-Dose Vitamin C has a Vascular Disrupting Action in Mice.

High intravenous doses of vitamin C (ascorbic acid) have been reported to benefit cancer patients, but the data are controversial and there is incomplete knowledge of what physiological mechanisms might be involved in any response. Vitamin C is taken up efficiently by cells expressing SVCT2 transporters and since vascular endothelial cells express SVCT2, we explored the hypothesis that administration of high-dose vitamin C (up to 5 g/kg) to mice might affect vascular endothelial function. A single administration of vitamin C to mice induced time- and dose-dependent increases in plasma concentrations of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), a marker for vascular disrupting effects. Responses were comparable to those for the tumor vascular disrupting agents, vadimezan and fosbretabulin. High-dose vitamin C administration decreased tumor serotonin concentrations, consistent with the release of serotonin from platelets and its metabolism to 5-HIAA. High-dose vitamin C also significantly increased the degree of hemorrhagic necrosis in tumors removed after 24 h, and significantly decreased tumor volume after 2 days. However, the effect on tumor growth was temporary. The results support the concept that vitamin C at high dose increases endothelial permeability, allowing platelets to escape and release serotonin. Plasma 5-HIAA concentrations could provide a pharmacodynamic biomarker for vitamin C effects in clinical studies.

Effects of a dietary sweetener on growth performance and health of stressed beef calves and on diet digestibility and plasma and urinary metabolite concentrations of healthy calves1

Two experiments were conducted to explore the effects of a sodium saccharin-based dietary sweetener (Sucram) on growth performance, health, and physiological responses of feedlot steers. In Exp. 1, 173 newly-received male calves purchased from auction barns were fed 0, 100, 200, or 300 g of Sucram/t of DM over 56 d. Overall, ADG and G:F (P > 0.10) were not different among treatments, but steers receiving 200 g Sucram/t displayed numerically greater ADG (23%). In addition, DMI was 17% greater for steers receiving 200 g of Sucram/t compared to steers fed the control diet (cubic effect, P = 0.09). The morbidity rate for respiratory disease did not differ (P > 0.50) among treatments. In Exp. 2, 15 steers (initial BW = 261 ± 28 kg) were used to evaluate the effects of Sucram on apparent total tract digestibility, plasma metabolite concentrations, and urine monoamine metabolite concentrations. Treatments consisted of ad libitum access to a 60% concentrate diet (Control), ad libitum access to Control + 200 g of Sucram/t of DM (Adlib), and Control + 200 g of Sucram/t of DM with feed intake paired to the Control (Paired). By design, steer DMI during the metabolism period did not differ (P = 0.34) between Paired and Control, but DMI tended (P = 0.14) to be 8.2% greater for Adlib than for Control. Treatments did not alter (P > 0.17) apparent total tract nutrient digestibility. Postprandial plasma citrulline concentration was lower (P = 0.03) for Adlib than for Control and tended to be lower (P = 0.13) for Paired than for Control. Plasma homocysteine concentration was reduced (P < 0.03) by feeding Sucram. Urinary concentrations of ethylmalonic acid, vanillymandelic acid, and 5-hydroxyindolacetic acid were greater (P < 0.06) for Adlib than for Control; Paired steers had a greater (P = 0.02) urine vanillymandelic acid concentration than Control steers and tended (P < 0.12) to have a greater urinary concentration of ethylmalonic and 5-hydroxyindolacetic acid than Control steers. Serum insulin was greater for Adlib than for Control steers (P = 0.04) and tended to be greater for Paired than for Control steers (P = 0.14), but serum prolactin area did not differ (P > 0.22) among treatments. Supplementation with Sucram may increase feed intake by newly-received, stressed feedlot calves. Saccharin supplementation reduced plasma homocysteine and increased urinary excretion of vanillymandelic acid, suggesting an improved activity of the dopamine reward system.