Decreased Serotonin Levels Research Articles

Alcohol and substance use are associated with altered metabolome in the first trimester serum samples of pregnant mothers

BackgroundAlthough the effects of alcohol on metabolic processes in the body have been studied widely, there do not appear to be any previous reports clarifying how substance abuse changes metabolic profiles of pregnant women during the first trimester of pregnancy. ObjectiveOur aim was to evaluate the effect of substance abuse, especially alcohol use, on the metabolic profile of pregnant women during the first trimester. Study designWe applied mass spectrometry based non-targeted metabolite profiling of serum collected during routine visit to the hospital between gestational weeks 9 + 0 to 11 + 6 from controls (n = 55), alcohol users (n = 19), drug users (n = 24) and tobacco smokers (n = 40). ResultsWe observed statistically significantly differences among the study groups in serum levels of glutamate, glutamine, and serotonin (p-values ≤ 0.0001). The serum levels of glutamate were increased in alcohol and drug using mothers when compared to the controls, whereas levels of glutamine were decreased in alcohol and drug using mothers. In addition, serum levels of serotonin were decreased in alcohol using mothers when compared to the controls. ConclusionThe present study shows that alcohol and drug use were associated with increased glutamate, and decreased glutamine levels, and alcohol use is associated with decreased serotonin levels. This study serves as a proof-of-concept that the metabolite profile of human first trimester serum samples could be used to detect alcohol exposure during pregnancy.

Multiple metal exposures and their correlation with monoamine neurotransmitter metabolism in Chinese electroplating workers

Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases.

Anxiety-depressive disorders in children: Neurobiological and neurohormonal aspects

ObjectiveThe need for diagnosis and correct classification of depression among children is dictated by its burdeness with age, high risk of recurrence at further stages of child development and propensity to suicidal behavior.Materials and methodsOne hundred and sixty adolescents with ADD were included in our study. The study design comprised: clinicopsychopathological, somatoneurological, psychological and neurohormonal methods.ResultsClustering symptom of anxiety and depression have shown that for children in early puberty is typical more formation of somatic (35.2%), behavioral (21.6%), phobic (21.6%) variants of depression, less-anxiety (13.5%), asthenia (8.1%). For children in puberty – apathetic (30.1%), anxiety (28.9%), dismorfofobic (27.7%), behavioral (13.3%) variants. The proportion of suicidal behavior of depression increases in proportion to age, mainly due to suicidal thoughts, sayings, auto-aggressive behavior. Analysis of the formation conditions of anxiety and depression in children showed a significant correlation of genetic, biological and socio-environmental components.Symptoms of the minimal brain dysfunction (MBD) at an early ontogeny (prognostic value = +4.8), loaded natal period (PV = +4.2), frequent colds in the medical history (PV = 3.7), signs of cerebro-organic failure (PV = +3.8) and obesity as an endocrine disorder (PV = +2.1), sex and age of the manifestation of the first depressive episode in the early stages ontogenesis in boys aged 7 years (PS = +5.3), in girls aged 9 years (PS = +3.9) have been registered among biological risk factors for the ADD formation. Prognostic significance of neurohormonal parameters as regards the risk for ADD formation in adolescents is based on a decreased serotonin level in patients with depressive anxiety (PV = +2.8) and a reduced melatonin level, irrespective of the variant of clinical depression (PV = +2.4).ConclusionDetermination of neurobiological and neurohormonal risk markers for the development of the ADD makes it possible to carry out psychoprophylactic measures.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Serotonin depletion induces pessimistic-like behavior in a cognitive bias paradigm in pigs

Cognitive and affective processes are highly interrelated. This has implications for neuropsychiatric disorders such as major depressive disorder in humans but also for the welfare of non-human animals. The brain serotonergic system might play a key role in mediating the relationship between cognitive functions and affective regulation. The aim of our study was to examine the influence of serotonin depletion on the affective state and cognitive processing in pigs, an important farm animal species but also a potential model species for biomedical research in humans. For this purpose, we modified a serotonin depletion model using para-chlorophenylalanine (pCPA) to decrease serotonin levels in brain areas involved in cognitive and affective processing (part 1). The consequences of serotonin depletion were then measured in two behavioral tests (part 2): the spatial judgement task (SJT), providing information about the effects of the affective state on cognitive processing, and the open field/novel object (OFNO) test, which measures behavioral reactions to novelty that are assumed to reflect affective state. In part 1, 40 pigs were treated with either pCPA or saline for six consecutive days. Serotonin levels were assessed in seven different brain regions 4, 5, 6, 11 and 13days after the first injection. Serotonin was significantly depleted in all analyzed brain regions up to 13days after the first application. In part 2, the pCPA model was applied to 48 animals in behavioral testing. Behavioral tests, the OFNO test and the SJT, were conducted both before and after pCPA/saline injections. While results from the OFNO tests were inconclusive, an effect of treatment as well as an effect of the phase (before and after treatment) was observed in the SJT. Animals treated with pCPA showed more pessimistic-like behavior, suggesting a more negative affective state due to serotonin depletion. Thus, our results confirm that the serotonergic system is a key player in cognitive-emotional processing. Hence, the serotonin depletion model and the spatial judgement task can increase our understanding of the basic mechanisms underlying both human neuropsychiatric disorders and animal welfare.

Interrelation between Anxiety Level and Aggressiveness

High anxiety is the base not only for depression development but also to impulsive aggression manifestation. In the previous study we revealed the differences in neurohumoral status in animals with submissive and dominant behavioral types. Hypothalamic pituitary adrenal axis hyperactivity, the increase in noradrenaline and the decrease in serotonin levels in limbicocortical regions were observed in submissive male rats (high anxiety). Due to these results, we studied the interrelation between anxiety level and aggressiveness index and its components. The research involved 138 participants: 121 young men aged 18 to 22 years and 17 male adolescents within the age range 15-16 years. They were asked to answer Buss-Durkee Hostility Inventory, Spielberger State-Trait Anxiety Inventory and Eysenck Personality Inventory. The anxiety level was assessed in points. The aggressiveness index, physical, verbal and indirect aggressions were estimated in a percentage of the maximum level. No correlation between the anxiety level and the aggressiveness index was found in whole group of young men. Whole group was separated into three subgroups depending on anxiety level: with high, moderate and low anxiety levels. Strong positive correlation between anxiety level and aggression index in men with high anxiety level and negative correlation between these two parameters in men with low anxiety level were revealed. In last subgroup the correlation was statistically insignificant. In men with moderate anxiety level no correlation between anxiety level and aggression index was observed. This interrelation may be taken into account in anxiety treatment and in the prevention of impulsive aggression manifestation. In whole group of male adolescents no correlation between anxiety and aggressiveness index was found. Obtained data indicate the necessity of participants division depending on anxiety level and using the closed age groups to study the mechanisms of aggression development.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice.

5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models. LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined. The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain. Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Estradiol Valerate and Remifemin ameliorate ovariectomy-induced decrease in a serotonin dorsal raphe–preoptic hypothalamus pathway in rats

Perimenopausal syndromes begin as ovarian function ceases and the most common symptoms are hot flushes. Data indicate that the projections of serotonin to hypothalamus may be involved in the mechanism of hot flushes. Therefore, the aim of this study is to investigate the potential role of the serotonin dorsal raphe–preoptic hypothalamus pathway for hot flushes in an animal model of menopause. We determined the changes in serotonin expression in the dorsal raphe (DR) and preoptic anterior hypothalamus (POAH) in ovariectomized rats. We also explored the therapeutical effects of estradiol valerate and Remifemin in this model. Eighty female Sprague-Dawley rats were randomly assigned to sham-operated (SHAM) group, ovariectomy (OVX) group with vehicle, ovariectomy with estradiol valerate treatment (OVX+E) group and ovariectomy with Remifemin (OVX+ICR) group. Serotonin expression was evaluated in the DR and POAH using immunofluorescence and quantified in the DR using an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed in the DR by TUNEL assay. The number of serotonin immunoreactive neurons and the level of serotonin expression in the DR decreased significantly following OVX compared to the SHAM group. No TUNEL-positive cells were detected in the DR in any group. In addition, following OVX, the number of serotonin-positive fibers decreased significantly in the ventromedial preoptic nucleus (VMPO), especially in the ventrolateral preoptic nucleus (VLPO). Treatment with either estradiol or Remifemin for 4 weeks countered the OVX-induced decreases in serotonin levels in both the DR and the hypothalamus, with levels in the treated rats similar to those in the SHAM group. A fluorescently labeled retrograde tracer was injected into the VLPO at the 4-week time point. A significantly lower percentage of serotonin with CTB double-labeled neurons in CTB-labeled neurons was demonstrated after ovariectomy, and both estradiol and Remifemin countered this OVX-induced decrease. We conclude that serotonin pathway is changed after ovariectomy, including the serotonin synthesis in DR and serotonin fibers in PO/AH, both E and Remifemin have an equivalent therapeutic effect on it.

The reverse role of the hypothalamic paraventricular (PVN) and arcuate (ARC) nuclei in the central serotonergic regulation of the liver cytochrome P450 isoform CYP2C11

Our recent work showed that the brain serotonergic system negatively regulated liver cytochrome P450. The aim of our present research was to study the effect of damage to the serotonergic innervation of the paraventricular (PVN) or arcuate nuclei (ARC) of the hypothalamus on the neuroendocrine regulation of cytochrome P450 (CYP). Male rats received bilateral injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the PVN or ARC. One week after the injection brain neurotransmitters, serum hormones (growth hormone, testosterone, corticosterone, thyroid hormones), pituitary somatostatin and liver cytochrome P450 expression and activity were measured. Lesion of the serotonergic innervation of the PVN decreased serotonin level in the hypothalamic area containing the PVN, causing an increase in growth hormone and testosterone concentrations in the blood and, subsequently, an increase in the expression (mRNA and protein level) and activity of isoform CYP2C11 in the liver. In contrast, damage to the serotonergic innervation of the ARC, which caused a decrease in serotonin level in the hypothalamic area containing the ARC, reduced the concentration of growth hormone and the expression and activity of CYP2C11. In conclusion, the obtained results show a reverse effect of the serotonergic innervation of the hypothalamic paraventricular (a negative effect) and arcuate nuclei (a positive effect) on growth hormone secretion and growth hormone-dependent CYP2C11 expression. They also suggest that CYP2C11 expression may be changed by drugs acting via the serotonergic system, their effect depending on their mechanism of action, route of administration (intracerebral, peripheral) and distribution pattern within the hypothalamus.

Quinolone antibiotics and suicidal behavior: analysis of the World Health Organization's adverse drug reactions database and discussion of potential mechanisms.

Several case-reports suggest that the use of quinolones may increase the risk of psychiatric adverse reactions such as suicidal behaviors. The aim of this study is to investigate whether there is a safety signal for quinolone-related suicidal behaviors in a global adverse drug reactions database. All antibiotic-related adverse reactions were extracted from VigiBase, the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. Disproportionality analyses were performed to investigate the association between reports of suicidal behavior and exposure to quinolones, in comparison with other antibiotics. From December 1970 through January 2015, we identified 992,097 antibiotic-related adverse reactions. Among them, 608 were quinolone-related suicidal behaviors including 97 cases of completed suicides. There was increased reporting of suicidal behavior (adjusted reporting odds ratios [ROR] 2.78, 95% CI 2.51-3.08) with quinolones as compared to other antibiotics. Candidate mechanisms for quinolone-induced suicidal behaviors include GABAA antagonism, activation of NMDA receptors, decreased serotonin levels, oxidative stress, and altered microRNA expressions. We found a strong safety signal suggesting an increased risk of suicidal behaviors associated with quinolone use. Plausible psychopharmacological mechanisms could underlie this association. Further investigations are urgent to confirm and better understand these findings.

Effects of maternal stress and perinatal fluoxetine exposure on behavioral outcomes of adult male offspring

Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. METHODS: C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. Results: Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive abilities, memory, sensorimotor information processing, or risk assessment behaviors. These results demonstrate that maternal exposure to stress and Flx have a number of sustained effects on the male offspring.

A Serotonin Circuit Acts as an Environmental Sensor to Mediate Midline Axon Crossing through EphrinB2.

We show here that serotonin has a novel role in regulating connectivity in response to the developmental environment. We demonstrate that serotonergic projections from raphe neurons regulate pathfinding of crossing axons. The neurons modulate their serotonin levels, and thus alter crossing, in response to the developmental environment including hypoxia. The findings suggest that modification of the serotonergic system by early exposures may contribute to permanent CNS connectivity alterations. This has important ramifications because of the association between premature birth and accompanying hypoxia, and increased risk of autism and evidence associating in utero exposure to some antidepressants and neurodevelopmental disorders. Finally, this work demonstrates that the vertebrate CNS can modulate its connectivity in response to the external environment.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol.The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.

Decreased Serotonin Levels and Serotonin-Mediated Osteoblastic Inhibitory Signaling in Patients With Ankylosing Spondylitis.

Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFα blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean ± SEM ng/mL 122.9 ± 11.6 versus 177.4 ± 24.58, p = 0.038) and patients with RA (mean ± SEM ng/mL 244.8 ± 37.5, p = 0.0004). Patients with AS receiving TNFα blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean ± SEM ng/mL 95.8 ± 14.9 versus 149.2 ± 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFα treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS.

Cognitive enhancing, anti-acetylcholinesterase, and antioxidant properties of Tagetes patula on scopolamine-induced amnesia in mice

Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by a gradual decline in memory associated with shrinkage of brain tissue and loss of neurons with a diminished level of the central cholinergic neurotransmitter acetylcholine. Objective: The present study was performed to examine the effect of ethanolic extract of Tagetes patula (EETP) on cognitive impairment induced by scopolamine, a muscarinic antagonist, in mice. Materials and Methods: Rats were treated with EETP and donepezil for 15 successive days followed by treatment with scopolamine (1 mg/kg) for 3 days. The changes in behavioral, biochemical, and neurotransmitters were assessed in rats. Cognitive functions were assessed using step‐through latency on a passive avoidance apparatus and Morris water maze test. Antioxidants parametes such as superoxide dismutase (SOD), glutathione reductase (GR), lipid peroxidation (LPO), and nitrates were assessed. Neurotransmitters including acetylcholinesterase (AChE), dopamine (DA), and serotonin were also assessed, and neuronal damage was also analyzed. Results: Scopolamine‐treated rats showed impaired learning and memory, increased activity of AChE, LPO and decreased levels of SOD, reduced glutathione, nitrates, serotonin, and DA. The EETP significantly reversed the scopolamine‐induced cognitive impairment in mice was measured by the passive avoidance test. In addition, EETP decreased escape latency in the Morris water maze. In probe trail session, EETP increased the latency time in the target quadrant. Ex vivo EETP inhibited AChE activity in the mice brain. EETP treated mice significantly increased the SOD, GR, nitrates, DA, and serotonin levels, and decreased the level of LPO when compared with scopolamine‐treated mice. Conclusion: These results indicate that EETP may exert anti‐amnesic effect through both by anti‐AChE and antioxidant mechanisms. Key words: Cognition, Morris water maze, passive avoidance, scopolamine, Tagetes patula, transfer latency

MONITORING OF NEUROTRANSMITTER SEROTONIN IN IXODID TICK BORRELIOSIS

The study presents the results of measurement of platelet serotonin level and estimation of emotional status and degree of asthenia in 45 patients in acute period of Ixodid tick borreliosis (27 patients with local and 18 with disseminated forms). Twenty (20) healthy subjects consisted control group. Serotonin level was measured using enzyme-linked immunosorbent assay (ELISA). Significant decrease of serotonin level at the height of disease was seen in patient group compared to the control group. During the early recovery stage the platelet serotonin level in the group of patients with borreliosis only had the trend to increase, but still remained lower than in control group. We revealed negative correlation between platelet serotonin level and reactive anxiety assessed with Spielberger-Hanin questionnaire. The assessment of platelet serotonin level in patients with Ixodid tick borreliosis can suggest the severity of potential nervous tissue damage and involvement of serotonin in genesis of anxiety and depressive symptoms. This question should be investigated further.

Infralimbic cortex activation and motivated arousal induce histamine release.

Appetitive behaviours occur in a state of behavioural and physiological activation that allows the optimal performance of these goal-directed behaviours. Here, we tested the hypothesis that histamine neurons under the command of the infralimbic cortex are important to provide behavioural activation. Extracellular histamine and serotonin were measured by microdialysis of the medial prefrontal cortex in behaving rats in parallel with a picrotoxin microinjection into the infralimbic cortex. The injection aroused the rats behaviourally, increased histamine release and decreased serotonin levels. Inhibition of the infralimbic cortex with muscimol produced the opposite effects on neurotransmitter release. The behavioural activation induced by motivating hungry rats with caged food was paralleled by an immediate histamine release, whereas awakening induced by tapping their microdialysis bowl increased serotonin, but not histamine levels. In conclusion, picrotoxin injection into the infralimbic cortex produces behavioural activation together with histamine release; in a similar manner, induction of an appetitive state produced histamine release, likely related to increased behavioural activation characteristic of an appetitive behaviour.

Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels.

Structural Changes in the Subnuclei of the Parabrachial Complex in Rats with Serotoninergic System Deficiency during Prenatal Development

Experiments were performed on the offspring of female Wistar rats (n = 8) given parachlorophenylalanine on day 16 of pregnancy to decrease endogenous serotonin levels in the offspring. Histological, immunocytochemical, and morphometric methods were used in rat pups on days 10 and 14 of postnatal development (5–6 individuals at each time point) for studies of the dorsal and ventral subnuclei of the lateral part of the parabrachial complex. The results showed that serotonin deficiency led to changes in the structure of these subnuclei. The population of large, multipolar neurons in the ventral subnucleus was found to be more sensitive to decreased serotonin levels. Experimental animals showed decreases in the body sizes of these neurons by a factor of 1.6 compared with controls, with virtually no change in the number of cells in this population. The morphological characteristics of small neurons corresponded to those in controls, though there was a reduction in the number of cells, which may explain the rarefaction of neurons in this nucleus. In the dorsal subnucleus of experimental animals, neurons of both of the populations in this structure underwent more marked changes. The sizes of both large and smaller neuron cell bodies decreased significantly, by factors of 2.0 and 1.8 respectively; the cytoplasmic volumes of these cells decreased compared with controls; the numbers of cells in both populations remained largely unaltered. Reactions detecting glial fibrillary acidic protein showed increases in the numbers of the astrocyte glial population in the early postnatal period in the experimental animals.

Widespread Monoaminergic Dysregulation of Both Motor and Non-Motor Circuits in Parkinsonism and Dyskinesia

Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4-dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution.

Colon preneoplasia after carcinogen exposure is enhanced and colonic serotonergic system is suppressed by food deprivation

Calorie restriction regimens usually promote health and extend life-span in mammals. This is partially related to their preventive effects against malignancies. However, certain types of nutritional restriction failed to induce beneficial effects. The American Institute of Nutrition defines calorie restriction as diets which have only 40% fewer calories, but provide normal amounts of necessary food components such as protein, vitamins and minerals; whereas, food restriction means 40% less of all dietary ingredients plus 40% less calories. Our study aimed to test the hypothesis that the latter type of food deprivation (40% less food than consumed by standard fed rats) might increase cancer risk instead of reducing it, as is generally assumed for all dietary restrictive regimens. Since the endogenous modulation of the colon serotonergic system has been observed to play a role during the early steps of carcinogenesis we also investigated whether the serotoninergic system could be involved in the food intake modulation of cancer risk. For this, rats were exposed to a carcinogen and subjected to food deprivation for 56 days. Triglyceride levels and visceral adipose tissue were reduced while hepatic and colonic lipid peroxidation was increased. This dietary restriction also decreased serotonin levels in colon, and gene expression of its intestinal transporter and receptors. Finally, the numbers of preneoplastic lesions in the colon tissue of carcinogen-exposed rats were increased. Our data suggest that food deprivation enhances formation of early tumorigenic lesions by suppressing serotonergic activity in colon tissue.