Brain Serotonin Concentrations Research Articles

Constitutive Ret Activity in Knock-In Multiple Endocrine Neoplasia Type B Mice Induces Profound Elevation of Brain Dopamine Concentration via Enhanced Synthesis and Increases the Number of TH-Positive Cells in the Substantia Nigra

Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT). This study investigates whether sex differences in the acute and long-term effects of MDMA exist. Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment. Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later. MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females.

Calcitriol Protects against the Dopamine‐ and Serotonin‐Depleting Effects of Neurotoxic Doses of Methamphetamine

Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

The effects of fluoxetine and its complexes with glycerrhizic acid on behavior in rats and brain monoamine levels

The effects of the serotonin reuptake inhibitor fluoxetine (FL) and its complexes with glycyrrhizic acid (GA) in molar ratios of 1:1 (FLG-1) and 4:1 (FLG-4) on the behavior of adult rats were studied in an elevated cross maze, with measurement of brain monoamine and monamine metabolite levels. Agents were given via the intragastric route using a cannula at a dose of 25 mg/kg 1 h before testing. FL increased anxiety in the rats and decreased their movement activity; FLG-1 and FLG-4 had no effect on behavior. None of the agents affected brain serotonin content, though all decreased the levels of its metabolite 5-hydroxyindoleacetic acid in the hypothalamus, FLG-4 also decreasing this in the cortex. Noradrenaline levels in the hypothalamus were increased after FLG-1 and FLG-4. In the striatum, FL increased the levels of dopamine and its metabolite dihydroxyphenylacetic acid but had no effect on the level of transmitter catabolism. Unlike FL, FLG-1 activated dopamine metabolism in the striatum. Overall, use of FL complexed with GA significantly modified its behavioral effects, which appears to be associated with the effects of FL and its complexes on the function of the monoaminergic systems involved in controlling behavior.

Effects of supplementing pig diets with tryptophan and acidifier on protein digestion and deposition, and on brain serotonin concentration in young pigs

The objective of the study was to find out whether feeding acidifying preparation with diets containing crystalline tryptophan (Trp) affects availability of this amino acid for protein and serotonin (5-HT) synthesis in young pigs. Two experiments were performed. Supplementation of Trp-deficient diet with 3 g/kg of acidifier (A) (mixture of phosphoric, citric and fumaric acids) did not affect the coefficients of ileal apparent digestibility (CIAD) of protein and protein-bound amino acids except CIAD of Trp which was increased from about 0.65 to 0.73. In pigs of initial body weight 16 kg, the increase of digestible dietary Trp level from 0.77 to 1.39 and 1.85 g/kg improved growth performance, nitrogen retention and utilization of nitrogen absorbed, while the increase from 0.77 to 1.39 g/kg enhanced 5-HT concentration in all six analyzed brain structures. Supplementation with A did not affect blood Trp level in animals fed on Trp-deficient diet while it decreased it considerably on diet supplemented with Trp to 1.85 g/kg. Feeding A affected 5-HT metabolism: decreased its level in five of six brain structures in pigs fed on Trp-deficient diet, changed 5-HT metabolite 5-hydroxy-indolo-3-acetic acid (5-HIAA) and 5-HIAA/5-HT ratio, and modified response of 5-HT to Trp supplementation. It is concluded that feeding A both with Trp-deficient and Trp-supplemented diets has positive net effect on growth and protein deposition in pigs while it seems to affect negatively 5-HT synthesis and, probably, accelerates its turnover. The mechanism of this action is not known, and it was not proved that it is related to destructive effect of acids on crystalline Trp.

Cerebral formation in situ of S-carboxymethylcysteine after ifosfamide administration to mice: A further clue to the mechanism of ifosfamide encephalopathy

The clinical use of the alkylating oxazaphosphorine ifosfamide is hampered by a potentially severe encephalopathy. S-carboxymethylcysteine (SCMC), a metabolite of ifosfamide (IF), activates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor, causes neuronal acidification, and could thus be responsible for the encephalopathy. Since the presence of SCMC in brain has not been documented following administration of IF, SCMC was measured in the brain of mice following both the individual i.p. administration of IF and SCMC. SCMC was found in a concentration of 108.2 ± 29.7 nmol/g following IF, but was detectable at much lower levels following the administration of SCMC (21.1 ± 21.2 nmol/g). Together with the observation that the concentration of SCMC was 10-fold higher in liver than in brain 1 h after administration of SCMC, these findings suggest that the SCMC found after IF was formed in the brain in situ. The concentration of glutamic acid was similar in IF and SCMC treated animals. Methylene blue, which is used clinically to treat and to prevent IF encephalopathy, did not decrease the formation of SCMC in brain. By inhibiting monoamine oxidase activity it did, however, markedly increase the concentration of serotonin in brain which could modulate the effects of SCMC on AMPA/kainate receptors. Thus, SCMC is present in brain following the administration of IF and could contribute to the IF-associated encephalopathy by activation of AMPA/kainate receptors.

The effects of a diet enriched with α-lactalbumin on mood and cortisol response in unmedicated recovered depressed subjects and controls

Alpha-lactalbumin is a tryptophan-rich protein fraction. A diet enriched with alpha-lactalbumin increases the ratio of tryptophan to the other large neutral amino acids, which may in turn increase brain serotonin content. In stress-vulnerable individuals, alpha-lactalbumin improved mood and attenuated the cortisol response after experimental stress. The aim of the present study was to investigate the effects of an alpha-lactalbumin-enriched diet on mood and stress response in recovered depressed subjects and healthy controls. Forty-three subjects (twenty-three recovered depressed and twenty healthy subjects) received alpha-lactalbumin and casein (placebo) on separate days, in a double-blind randomised crossover design. On both occasions, subjects underwent a stress test (an unsolvable mental arithmetic task with loud noise). The stress test affected mood in both conditions. Although the alpha-lactalbumin diet led to the expected rises in tryptophan and tryptophan:large neutral amino acids ratio, only minimal effects were found on mood and cortisol response to experimental stress. The results were the same for recovered depressed patients and controls. A 1 d diet enriched with alpha-lactalbumin is not sufficient to prevent a stress-induced mood deterioration or a cortisol response in unmedicated, recovered depressed subjects. Future studies may investigate the effects of longer-term diets or may investigate different samples (e.g. medicated patients).

Insulin resistance and depressive symptoms in middle aged men: findings from the Caerphilly prospective cohort study

Insulin resistance may protect against depression, possibly through an effect on circulating free fatty acid concentrations and brain serotonin concentration,1 2 although a recent study contradicted these findings.3 Studies to...

Loss of brain‐derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.

Increased cerebrospinal fluid corticotropin-releasing factor concentrations during tryptophan depletion in healthy adults

Brain serotonin neurotransmission and hypothalamic-pituitary-adrenal axis function are implicated in the pathophysiology of depression, and these systems interact in a reciprocal modulatory fashion. This study examined the effect of tryptophan depletion, which acutely reduces brain serotonin concentrations, on serial cerebrospinal fluid concentrations of corticotropin-releasing factor in healthy humans. Five subjects completed a standard tryptophan depletion protocol, and four subjects participated in a comparison condition. Subjects underwent continuous sampling of cerebrospinal fluid via lumbar peristaltic pump. Concentrations of cerebrospinal fluid corticotropin-releasing factor were measured by radioimmunoassay. No mood changes were observed in either group. Tryptophan-depleted subjects exhibited significantly greater increases in corticotropin-releasing factor concentrations over time than subjects in the comparison condition. These findings highlight the potential importance of corticotropin-releasing factor and serotonin interactions and suggest that activation of corticotropin-releasing-factor-containing neurons could play a role in the emergence of mood symptoms following tryptophan depletion in vulnerable individuals.

Endorphin excess at weaning durably influences sexual activity, uterine estrogen receptor's binding capacity and brain serotonin level of female rats.

Perinatally, the first encounter between the maturing receptor and its target hormone results in hormonal imprinting, which adjusts the binding capacity of the receptor for life. In the presence of an excess of the target hormone or foreign molecules than can be bound by the receptor, faulty imprinting carries life-long consequences. In cytogenic organs, imprinting could also be provoked in other periods of life (late imprinting). Imprinting also durably influences the production of the imprinter and related hormones. In the present study, single beta-endorphin doses was given to three-week old female rats at 3 microg/animal, and the serotonin in five brain regions (frontal cortex, striatum, hippocampus, hypothalamus and brain stem) and uterine estrogen receptor content were determined, thymic glucocorticoid receptor binding capacity was measured, and sexual behavior was tested at five months of age. Brain serotonin levels highly significantly decreased, while sexual activity (Meyerson index and lordosis quotient) increased. At the same time, uterine estrogen receptor affinity decreased. There was no change in receptor binding capacity in the thymus. We will go on to discuss interrelations between the results. The experiments demonstrate that a non-perinatal treatment with a molecule acting at receptor level (late imprinting) can also lastingly influence various indexes in non-cytogenic organs. The results call attention to the possible long-lasting influence of an endorphin surge (caused, for example, by pain) on brain serotonin content and sexual behavior.

Single neonatal treatment with β-endorphin (hormonal imprinting) extremely enhances nocistatin level of cerebrospinal fluid in adult rats

In earlier experiments endorphin treatment of newborn rats caused the decrease of brain serotonin content, increasing aggressivity, enhanced sexual activity of females and changes in the binding capacity of uterine estrogen receptors at adult age, however nociceptin content of the cerebrospinal fluid was not changed. In the present experiment neonatal treatment of male and female rats was done with a single dose of 3 μg β-endorphin and in five months old rats the level of nociceptin antagonist nocistatin was determined by radioimmunoassay in the cerebrospinal fluid. In both genders the amount of nocistatin was one magnitude higher in the endorphin treated groups. There was also a significant difference between the male and female nocistatin level in the treated and non-treated groups alike, with the adventage of females. The results call attention to the possibility of influencing pain-tolerance for life, by the pain-provoked endorphin levels during delivery.

Association of insulin resistance with depression: cross sectional findings from the British women's heart and health study

A large cohort study of nearly 15 000 individuals found that indicators of insulin sensitivity were associated with increased risk of suicide.1 The authors assumed that insulin resistance was the...

Photoperiod affects the development of central neurotransmitter systems of tilapia, Oreochromis mossambicus

The effects of photoperiod on the development of central neurotransmitters were investigated with tilapia, Oreochromis mossambicus. Zero-day-old (the hatching day) tilapia were raised in three different photoperiods (light/dark cycle): 12/1, 24/0, and 0/24 h, respectively. On the 5th day, brain serotonin (5-HT), norepinephrine (NE), γ-aminobutyric acid (GABA), and glutamate (Glu) contents were quantified by a high-performance liquid chromatograph with electrochemical detection. Similar experiments were performed on the 5-, 10-, 15-, 20-, and 25-day-olds. These results showed that the photoperiod influenced both brain NE and GABA contents during its respective restricted period, before days 10 posthatching. Brain 5-HT content was influenced, either facilitated or suppressed according to the developing stage, whereas, brain Glu content was not altered by the different photoperiod exposure throughout the present studies.

Impact of single neonatal serotonin treatment (hormonal imprinting) on the brain serotonin content and sexual behavior of adult rats

Hormonal imprinting takes place perinatally at the first encounter between the developing receptor and its target hormone. As a consequence of imprinting the receptor accomplishes its maturation and reaches the binding capacity characteristic to the adult age. In the excess of target hormone or presence of molecules similar to the target hormone, which are able to bind to the unmatured receptors, faulty imprinting develops with life-long consequences. At present, serotonin was given to neonatal rats and their sexual activity, brain serotonin level and steroid receptor's binding capacity was measured in adult age. Brain serotonin level was significantly reduced in male's striatum and parallel with this, male's sexual activity significantly increased. In other regions of the male brain (prefrontal cortex, hypothalamus, hippocampus) there was a statistically non-significant tendency for a decrease in serotonin level. No significant differences were detected in female brain values, and there was only slight change in female's sexual activity. There was also no change in the binding capacity of thymic glucocorticoid and uterine estrogen receptors. The experiments call attention to the possibility of perinatal imprinting by a neurotransmitter causing changes in brain neurotransmitter level for life, which is manifested in altered sexual activity.

Effect of neonatal β-endorphin imprinting on sexual behavior and brain serotonin level in adult rats

A single dose (3 μg) β-endorphin was administered to newborn female and male rats (hormonal imprinting). In adult age (at 5 months) sexual behavior, steroid hormone binding capacity and brain serotonin content was studied. Females' sexual activity (lordosis quotient) significantly decreased and more animals protested against mounting (ratio of kicking and crying 21/24 vs. 8/24; p < 0.001). Males' sexual activity did not change, however more males were aggressive (4/10 vs. 1/10). Uterine estrogen receptor density significantly increased and affinity decreased. There was no change in the binding capacity of thymic glucocorticoid receptors. In the brain, five regions were studied for serotonin content. There was a gender difference in serotonin level and the intragroup differences were also high. In the endorphin treated males the serotonin level was significantly lower than in the controls. In the endorphin treated females the intragroup scattering has been significantly reduced. Nociceptin content of the cerebrospinal fluid was not changed. The experiments call attention to the possibility of adjustment of sexual and behavioral sphere by the individually different endorphin surge during labor.

Exercise, fatigue, neurotransmission and the influence of the neuroendocrine axis.

Fatigue during prolonged exercise has traditionally been attributed to the occurrence of a "metabolic end point", where muscle glycogen concentrations are depleted, plasma glucose concentrations are reduced, and plasma free fatty acid levels are elevated. But there exists also a "central fatigue hypothesis" which is based on the increase in the concentration of brain serotonin (5-Hydroxytryptamine or 5-HT) during exercise. However, the physiological mechanisms for central fatigue are largely unexplored, therefore we designed several experiments where central serotonergic activity was manipulated. These animal and human experiments showed that although brain neurotransmission had significantly increased, the supplementation with L-TRP did not lead to premature fatigue. In human studies we used several reuptake inhibitors in order to modify brain activity during exercise. These results clearly showed that time trial performance could not be influenced, but that during prolonged exercise the brain activity can be influenced, as measured by the peripheral hormones.

Feeding Condition and Strain Difference Influence Sleeping Behavior in Newborn Chicks.

To clarify sleeping behavior of neonatal chicks, two experiments were conducted. In Experiment 1, the contribution of feeding on sleeping behavior was investigated over a 24 h period. Newly hatched layer-type chicks were kept under continuous lighting, and were maintained at 28°C for one day without any food or water. Thereafter, one group was provided food and water, and another group was given only water for 23 h. The chicks were then video recorded over the next 24 h in order to quantify the following behaviors : (1) active wakefulness or sitting with eyes open, and (2) sitting or standing motionless with their eyes closed and head dropping on the ground (sleeping posture). Thereafter, the chicks were sacrificed and brain serotonin levels determined. The time fasted chicks spent in a sleeping posture was longer than in fed chicks. The serotonin content tended to be higher in fasted than in fed chicks. No significant difference in the concentration of ketone bodies was detected between fed, fast and control chicks. In Experiment 2, the differences of sleeping activity between ad libitum fed layers and broilers were examined. Broiler chicks spent more time in a sleeping posture than layer chicks, but brain serotonin content was higher in layer chicks. In conclusion, sleep in the neonatal stage was largely influence by feeding conditions, and was modified by genetic selection.

Calcium disodium edetate enhances type A monoamine oxidase activity in monkey brain.

The effects of metal chelators on monoamine oxidase (MAO) isozymes, MAO-A and MAO-B, in monkey brain mitochondria were investigated in vitro. MAO-A activity increased to about 40% with 0.1 microM calcium disodium edetate (CaNa2EDTA) using serotonin as a substrate, and this activation was proportional to the concentration of CaNa2EDTA. On the other hand, MAO-A activities were decreased gradually with an increasing concentration of o-phenanthroline and diethyldithiocarbamic acid, but these metal chelators had no effect on MAO-B activity in monkey brain. The activation of MAO-A activity by CaNa2EDTA was reversible. CaNa2EDTA did not activate both MAO-A and MAO-B activities in rat brain mitochondria. Zn and Fe ions were found in the mitochondria of monkey brain. Zn ions potently inhibited MAO-A activity, but Fe ions did not inhibit either MAO-A or MAO-B activity in monkey brain mitochondria. These results indicate that the activating action of CaNa2EDTA on MAO-A was the result of the chelating of Zn ions contained in mitochondria by CaNa2EDTA. These results also indicate the possibility that Zn ions may regulate physiologically the level of serotonin and norepinephrine content in brain by inhibiting a MAO-A activity.

Environmental chemical compounds could induce sensitization to drugs of abuse.

Chemical environment should be considered as an additional factor that influences drugs of abuse. Besides, maternal exposure to environmental chemicals has increased, and fetuses as well as neonates may be at greater risk than adults. Studies from our laboratory have described a permanent effect of the worldwide use of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) on serotonin and dopamine content in total brain and specific brain areas of adult rats born of mothers treated during lactation and fed with 2,4-D-treated diet after weaning. These animals show a modified neurotransmitter-related behavioral pattern in their developmental young and in adult age. Drugs that could be used to challenge the dopaminergic or serotoninergic systems include amphetamine or haloperidol, a postsynaptic dopamine receptor blocker. 2,4-D-exposed animals showed exacerbated response to challenges. Postnatal alterations in central dopaminergic and serotoninergic systems due to environmental chemical exposure may contribute to the enhanced/reduced behavioral sensitization to drugs of abuse.