Changes In Serotonin Content Research Articles

ECCO Grant Serotonin gets into your genes: the role of histone serotonylation in inflammatory response and visceral hypersensitivity in Crohn’s Disease

Abstract Background and Aims More than 70% of CD patients experience visceral hypersensitivity (VH) despite reaching remission. VH treatment is difficult because the mechanism of its complication is unknown. Serotonin is mainly produced in the gut and regulates several physiological processes, such as intestinal immunity and pain. Disturbances in serotonin levels are associated with CD severity and VH. Intriguingly, we have recently observed that serotonin can covalently bind to glutamine at position 5 on histone H3 tail, leading to histone serotonylation (H3Q5ser) in peripheral blood mononuclear cells (PBMCs). Another study has demonstrated that H3Q5ser can also occur in cultured neuronal cells. Our objective is to investigate the role of this newly discovered epigenetic signature (H3Q5ser) in immune cells and enteric neurons in CD and its potential impact on the transcriptional programs of the inflammatory response and VH. Methods To accomplish this goal, we will first determine the concentrations of serotonin in the mucosa and serum of active CD patients compared to healthy controls and establish how these levels relate to the enhancement of H3Q5ser in immune cells and enteric neurons. To study the functional role of H3Q5ser in cell activation, we will use site-directed or oligonucleotide- mediated mutagenesis to induce a point mutation in cultured enteric neuron cell lines and PBMCs to remove the binding site for serotonin on histone. Both wild-type and mutant cells will be incubated with or without serotonin and subjected to chromatin immunoprecipitation sequencing and RNA sequencing profiling to investigate the effect of H3Q5ser on the transcriptional programs associated with inflammation and VH. Anticipated Impact This project will provide a comprehensive understanding of the impact of the changes in serotonin concentrations on H3Q5ser-related gene expression in CD- associated VH and the inflammatory response. Our anticipated impact is subsequent studies that monitor H3Q5ser in VH in CD patients during treatment.

SEROTONIN INFLUENCE ON THE CLINICAL COURSE OF PREGNANCY IN THE FIRST TREMESTER

Changes of melatonin and serotonin levels in the plasma can be associated with thedevelopment of the threatened abortion. Hormones of the pineal gland stimulate thesecretion of progesterone, which reduces the contractile activity of the uterus and preventsthe immunological rejection of the trophoblast. The real observations motivated us tostudy serotonin plasma concentrations in cases of the threatened abortion.The aim of the study – to study changes in serotonin levels in pregnant women withclinical manifestations of the threatened abortion before 12 weeks of gestation comparedto women with normal pregnancies.Research material and methods. Two groups were formed: the 1st main group –40 pregnant women with signs of threatened abortion, the 2nd control group – 44 healthypregnant women. An obstetric study, enzyme immunoassay to determine serotonin, andultrasound were carried out. Statistical analysis was conducted according to the generallyaccepted methods of variational statistics.The approval of the scientific work was obtained from the Bioethical Commission of theBukovinian State Medical University (Ukraine).Research results. Results of serotonin levels in venous blood showed their extremeincrease in women with threatened abortion 739.89±111.27 ng/ml compared to normalpregnancy 511.05±140.36 ng/ml (p˂ 0.003). In the pregnant women of the main group,consisting of 40 women, almost all of them had an increased serotonin, except 4 women(10%). This can be explained by hypoprogesteronemia in women with a threat of abortion.Therefore, we consider the change in serotonin concentration as a secondary process thatdoes not require specific treatment. Attention is also drawn to the fact of a reduced levelof serotonin in the control group in cases of further complicated course. Conclusions. Serotonin levels were higher in patients with threatened abortion comparedto uncomplicated pregnancies. Changes in serotonin plasma in cases of threatenedabortion are a consequence, not a cause of abortion, therefore pregnant women needtreatment of obstetric pathology, namely the prescription of progesterone.

Effect of different serotonin concentrations on the inotropic function and morphometric parameters of the heart of infant rats

In recent years, studies of serotonin in physiological and pathological processes of the body have widely discussed its role as a link in the pathogenesis of atherosclerosis, arterial hypertension, and coronary heart disease. In the embryonic period, serotonin acts as a growth factor and plays an important regulatory role in the decisive period of embryo development, particularly, in the development of the heart. This research aims to study the influence of serotonin on the temporal parameters of contraction of the myocardium of the right ventricle in the newborn pups with a blockade of serotonin synthesis and membrane transporter in the embryonic period of ontogenesis. Thus, these studies have shown that the response of cardiomyocytes to serotonin is statistically higher in the group with excess serotonin and lower in the group with serotonin deficiency compared to the control group. The article also presents data indicating the change in serotonin concentration, which was created by the blockade of serotonin synthesis and the membrane transporter of serotonin in the embryonic period of ontogenesis, which results in morphological changes in the myocardium in early postnatal ontogenesi.

The Role of Gut Microbiota in Hypertension Pathogenesis and the Efficacy of Antihypertensive Drugs.

To review the relationship between intestinal microbes and hypertension and its impact on the efficacy of antihypertensive drugs, and help to address some of these knowledge gaps. Hypertension is associated with cardiovascular diseases and is the most important modifiable risk factor for all-cause morbidity and mortality worldwide. The pathogenesis of hypertension is complex, including factors such as dietary, environmental and genetics. Recently, the studies have shown that the gut microbiota influences the occurrence and development of hypertension through a variety of ways, including affecting the production of short-chain fatty acids, dysfunction of the brain-gut axis, and changes in serotonin content that cause the imbalance of vagus and sympathetic nerve output associated with hypertension. However, patients with hypertension typically take antihypertensive drugs orally on a long-term basis, and most antihypertensive drugs are absorbed by the gastrointestinal tract. Studies have shown that the pharmacokinetics and metabolism of antihypertensive drugs may be influenced by microbiota, or antihypertensive drugs act directly on the intestinal flora to exert efficacy, including regulation of intestinal microbial metabolism, intestinal inflammation, and intestinal sympathetic nervous system disorders. The intestinal flora can affect the pharmacokinetics and metabolism of antihypertensive drugs in the rats, and intestinal microbiota also can be the target "organ" by antihypertensive drugs.

Serotonin and cyclic sleep organization in healthy full-term newborns

Relevance: The growth of neuropsychiatric diseases caused by perinatal pathology indicates the need to study the biochemical markers of brain damage in the newborn for the timely prevention of adverse consequences. Serotonin in early ontogenesis provides intensive development of neuronal structures and cortical networks involved in the mechanisms of formation of cyclic sleep organization a fine criterion of morphofunctional development of the brain.
 aim: The aim of the work is to study the content of serotonin in healthy full-term newborns in comparison with the quantitative and qualitative characteristics of the electropoligraphic sleep pattern.
 Material and methods: 84 healthy newborns were examined, which, depending on the gestational age, were divided into 3 groups: I 37 weeks (20 people), II 38 weeks (24 people), III 39-40 weeks (40 people). The content of serotonin in platelet-rich plasma of blood from the umbilical cord vein and in platelet suspension prepared from venous blood taken from mothers and children on the first day of life and again on day 5 was determined by high-performance liquid chromatography with electrochemical detection. A quantitative and qualitative analysis of the sleep electropoligram was performed 7-12 hours after birth.
 Results: The content of serotonin in platelet-rich plasma in umbilical cord blood in children does not depend on the method of birth, is 2 times lower than in the venous blood of mothers (0.379 0.116 microns/l, versus 0.756 0.200 microns/l, but there is a high correlation between the indicators (r = 0.8, p 0.05). At the gestational age of 39-40 weeks, the level of serotonin in platelet-rich plasma and in venous blood platelets is significantly higher than in those born at 37 weeks. In the latter, the increase in the content of serotonin in platelets continues after birth (at day 1, 0.539 0.149 nM/109 Tr, and on day 5 0.846 0.094 nM/109 Tr; p 0.05), whereas the indicators for those born at 39-40 weeks of pregnancy. They do not change (0.797 0.190 nM/109 Tr and 0.749 0.142 nM/109 Tr, respectively). A significant increase in the content of serotonin in the platelet-rich plasma and in the platelets of the child in the period from 37 to 39 weeks, both during intrauterine development and in the first days of life, correlates with an increase in the representation of the orthodox phase in the sleep cycle.
 Conclusion: The general pattern of changes in serotonin content and cyclic sleep organization in the early neonatal period in healthy newborns, depending on gestational age, indicates the possibility of using the obtained standard values of serotonin as a biochemical marker of functional brain development.

Physiologic changes in serotonin concentrations in breast milk during lactation.

Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in milk volume homeostasis in the mammary glands during lactation, and 5-HT in milk also may affect infant development. The aim of this study was to investigate changes in 5-HT concentration in breast milk according to the duration of lactation and evaluate whether the 5-HT concentration varied before and after nursing. Healthy nursing Japanese women who had a natural delivery or underwent a cesarean delivery at Iwate Medical University Hospital were included in this study. The mean 5-HT concentration in milk was obtained from multiparous mothers 6 to 7 d after delivery (colostrum) and was significantly higher compared with primiparous mothers (24.3 ± 2.63 versus 18.5 ± 2.60 ng/mL). Additionally, mean 5-HT concentration increased with increasing lactation duration in primiparous women (colostrum: 18.5 ± 2.60; 1 mo postdelivery: 19.8 ± 2.46; 3 mo postdelivery: 22.7 ± 2.55 ng/mL); in particular, the mean 5-HT concentration in breast milk 3 mo after delivery was significantly higher than in colostrum. The mean 5-HT concentrations in breast milk in primiparous mothers immediately before nursing, 1 to 2 h after nursing, and immediately before the next nursing event were 23.6 ± 1.48, 22.82 ± 1.65, and 21.84 ± 1.31 ng/mL, respectively; mean 5-HT concentrations in multiparous women were 25.4 ± 1.65, 23.6 ± 2.20, or 22.4 ± 2.09 ng/mL, respectively. There was no significant difference in 5-HT concentrations at each time point between the groups. This information may be useful in determining the role of 5-HT in breast milk on infant development and growth.

Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurotransmitters in the Frontal Cortex and Striatum of C57BL/6 Mice.

Electronic (E)-cigarettes are the latest form of nicotine delivery device and are highly popular in the general population. It is currently unknown whether vaping E-cigarettes (E-CIGs) leads to nicotine addiction. Alterations in the levels of the neurotransmitters in the mesocorticolimbic areas have been reported to mediate the initiation and development of nicotine addiction. Therefore, to determine whether E-CIGs activate the same addiction pathways as conventional cigarettes, we investigated for the effects of daily inhalation of nicotine (24 mg/ml)-containing E-CIG vapor for 6 months on the concentrations of these neurotransmitters in the frontal cortex (FC) and striatum (STR) of male C57BL/6 mice as compared to control group that was exposed to air only. We reported here that 6-month E-CIG vapor containing nicotine inhalation decreased dopamine concentration only in the STR. There were no changes in serotonin concentrations in the FC or STR. Chronic E-CIG exposure also increased glutamate concentration in the STR alone, while glutamine concentrations were increased in both the FC and STR. We found that E-CIG exposure also decreased GABA concentration only in the FC. These data suggest that chronic E-CIG use alters homeostasis of several neurotransmitters in the mesocorticolimbic areas, which may result in the development of nicotine dependence in E-CIG users.

Association of the SLC6A4 gene 5HTTLPR polymorphism and ADHD with epilepsy, gestational diabetes, and parental substance abuse in Mexican mestizo children

Introduction. Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric conditions in childhood and a multifactorial condition attributable to genetic and/or environmental influence. Allelic variants in the serotonin transporter gene (SLC6A4) have been associated to lower transcriptional efficiency, changes in serotonin concentration in several brain regions, and ADHD development. Objective. To identify the association between the SLC6A4 alleles and ADHD diagnosis and risk factor phenotypes in children from a Mexican mestizo population. Method. In this study, 134 unrelated children were included and evaluated for ADHD, genotypification for the 5HTTLPR polymorphism, and identification of multiple phenotypes from their clinical records and family background for association analysis. Results. The following distribution of genotypes was observed: 23% SS, 49% SL, and 28% LL. From the phenotypes evaluated in the present study, gestational diabetes mellitus (p = .045), history of epilepsy (p = .047), and parental substance abuse (p = .033) showed an association with ADHD development in regression analysis along with the S variant. Discussion and conclusion. Results suggest that interaction of the S allele and some of the phenotypes analyzed may play a relevant role in the development of ADHD in the studied population.

Subsecond Sensory Modulation of Serotonin Levels in a Primary Sensory Area and Its Relation to Ongoing Communication Behavior in a Weakly Electric Fish.

Serotonergic neurons of the raphe nuclei of vertebrates project to most regions of the brain and are known to significantly affect sensory processing. The subsecond dynamics of sensory modulation of serotonin levels and its relation to behavior, however, remain unknown. We used fast-scan cyclic voltammetry to measure serotonin release in the electrosensory system of weakly electric fish, Apteronotus leptorhynchus. These fish use an electric organ to generate a quasi-sinusoidal electric field for communicating with conspecifics. In response to conspecific signals, they frequently produce signal modulations called chirps. We measured changes in serotonin concentration in the hindbrain electrosensory lobe (ELL) with a resolution of 0.1 s concurrently with chirping behavior evoked by mimics of conspecific electric signals. We show that serotonin release can occur phase locked to stimulus onset as well as spontaneously in the ELL region responsible for processing these signals. Intense auditory stimuli, on the other hand, do not modulate serotonin levels in this region, suggesting modality specificity. We found no significant correlation between serotonin release and chirp production on a trial-by-trial basis. However, on average, in the trials where the fish chirped, there was a reduction in serotonin release in response to stimuli mimicking similar-sized same-sex conspecifics. We hypothesize that the serotonergic system is part of an intricate sensory–motor loop: serotonin release in a sensory area is triggered by sensory input, giving rise to motor output, which can in turn affect serotonin release at the timescale of the ongoing sensory experience and in a context-dependent manner.

Influence of social isolation on serotonergic fiber density in the auditory midbrain

Animal communication involves both a “sender”, which emits a signal, and a “receiver”, which processes the signal. Signal processing can be shaped by past social experience. In the auditory midbrain, serotonin is a potential mechanism for linking social experience with auditory processing for three reasons: 1) the serotonergic system is sensitive to social experience in other brain regions; 2) changes in serotonin concentration reflect contextual features of social encounters; and 3) serotonin influences single auditory neurons’ response to sounds, such as conspecific vocalizations. Laboratory mice (Mus musculus) provide an excellent model for addressing this potential mechanism, because mice demonstrate sensitivity to social experience via a simple manipulation of social housing conditions, and because laboratory mice are being increasingly studied as a model of auditory communication. In this study, we investigated how social isolation affects serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain region that demonstrates selectivity for species‐specific vocalizations. Male CBA/J laboratory mice were given different social experiences by housing mice for four weeks either individually or in a social group of three mice. Subsequently, immunohistochemistry with florescence was used to label the serotonin transporter (SERT) as a marker for serotonergic fibers. Coronal sections of brain tissue were imaged, and ImageJ was used to quantify fiber density as the percent area of the IC covered by fibers. Mice from both social treatments demonstrated dense coverage (around 30%) of the IC by serotonergic fibers, corroborating with previous studies that demonstrate innervation of the IC by the serotonergic system. Individually housed mice had qualitatively lower percent coverage of the IC by serotonergic fibers than socially housed mice, particularly in sections of the IC that were more caudal; however, there were no statistically significant differences between social versus isolated treatment groups. Whether the smaller qualitative differences over the entire IC could be driven by disparities in the effects of social isolation among subregions of the IC has not yet been explored. These preliminary results suggest that social experience does not affect serotonergic fiber density in the IC. However, this does not rule out influences of social experience on other aspects of serotonergic signaling in the auditory midbrain, including socially induced serotonin release and profiles of serotonin receptors.Support or Funding InformationNSF grants: IOS 1456298 and DBI 1460949

The influence of electrical stimulation on dorsal raphe nucleus with different current intensities on morphine-induced conditioned place preference in male rats.

The dorsal raphe nucleus (DRN) influences a wide range of behavioral and physiological processes. The purpose of the present study was to test the effects of electrical stimulation of the DRN with different current intensities on morphine-induced conditioned place preference (CPP). Male Wistar rats were divided for experimental groups (n=7). Stimulating electrodes were stereotaxically implanted into the DRN in anesthetized rats. We investigated the influences of electrical stimulation of the DRN with different current intensities with ineffective and effective dose of morphine (0.5 and 2.5mg/kg, respectively) on morphine-induced CPP. Subcutaneous administration of morphine 2.5mg/kg produced significant CPP in comparison with saline group. The stimulation of the DRN with different current intensities (10, 25, 50 and 100μA) in combination with an effective dose of morphine did not show significant differences on acquisition phases, whereas there were significant decreases on expression phases versus to the morphine group on CPP only in current intensity 100μA. The stimulation of the DRN with different current intensities in combination with an ineffective dose of morphine showed significant increases in current intensities (50 and 100μA) on acquisition phases of CPP, but did not show significant differences on expression phases versus to the morphine group on CPP. It is possible that electrical stimulation of the DRN with changes in concentration of serotonin or involving other transmitters such as glutamate and GABA would be involved with these changes of CPP.

Effect of chronic l-DOPA treatment on 5-HT1A receptors in parkinsonian monkey brain

After chronic use of l-3,4-dihydroxyphenylalanine (l-DOPA), most Parkinson’s disease (PD) patients suffer from its side effects, especially motor complications called l-DOPA-induced dyskinesia (LID). 5-HT1A agonists were tested to treat LID but many were reported to worsen parkinsonism. In this study, we evaluated changes in concentration of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and of 5-HT1A receptors in control monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, dyskinetic MPTP monkeys treated chronically with l-DOPA, low dyskinetic MPTP monkeys treated with l-DOPA and drugs of various pharmacological activities: Ro 61-8048 (an inhibitor of kynurenine hydroxylase) or docosahexaenoic acid (DHA) and dyskinetic MPTP monkeys treated with l-DOPA+naltrexone (an opioid receptor antagonist). Striatal serotonin concentrations were reduced in MPTP monkeys compared to controls. Higher striatal 5-HIAA/serotonin concentration ratios in l-DOPA-treated monkeys compared to untreated monkeys suggest an intense activity of serotonin axon terminals but this value was similar in dyskinetic and nondyskinetic animals treated with or without adjunct treatment with l-DOPA. As measured by autoradiography with [3H]8-hydroxy-2-(di-n-propyl) aminotetralin (8-OH-DPAT), a decrease of 5-HT1A receptor specific binding was observed in the posterior/dorsal region of the anterior cingulate gyrus and posterior/ventral area of the superior frontal gyrus of MPTP monkeys compared to controls. An increase of 5-HT1A receptor specific binding was observed in the hippocampus of MPTP monkeys treated with l-DOPA regardless to their adjunct treatment. Cortical 5-HT1A receptor specific binding was increased in the l-DOPA-treated MPTP monkeys alone or with DHA or naltrexone and this increase was prevented in low dyskinetic MPTP monkeys treated with l-DOPA and Ro 61-8048. These results highlight the importance of 5-HT1A receptor alterations in treatment of PD with l-DOPA.

Noradrenergic projections to the ventromedial hypothalamus regulate fat metabolism during endurance exercise

The regulation of energy metabolism by the central nervous system during endurance exercise was examined. We conducted respiratory gas analysis by functionally paralyzing the ventromedial hypothalamus (VMH), the lateral hypothalamic area, and the paraventricular nucleus of the hypothalamus with local anaesthetic (lidocaine) during treadmill running at a velocity that allowed for efficient fatty acid oxidation. Our results showed that only the lidocaine treatment of the VMH attenuated fatty acid oxidation during endurance exercise. The monoaminergic neural activities at these nuclei during in vivo microdialysis in rats under the same conditions indicated a significant increase in the extracellular concentration of noradrenaline in all nuclei. Similarly, a significant increase in dopamine occurred at some points during exercise, but no change in serotonin concentration occurred regardless of exercise. Disruption of noradrenergic projections to the VMH by 6-hydroxydopamine attenuated the enhancement of fat oxidation during running. Blocker treatments clarified that noradrenergic inputs to the VMH are mediated by β-adrenoceptors. These data indicate that information about peripheral tissues status is transmitted via noradrenergic projections originating in the medulla oblongata, which may be an important contribution by the VMH and its downstream mechanisms to enhanced fatty acid oxidation during exercise.

Topiramate effects on plasma serotonin levels in children with epilepsy

Topiramate (TPM) is a new, effective and safe antiepileptic drug. TPM is also effective in treating a wide spectrum of conditions such as eating disorders and related anomalies, bulimia nervosa and other conditions in which serotonin (5-hydroxytryptamine, 5-HT) is involved pathogenetically. Plasma serotonin mainly derives from blood platelets, which represent a valid model of serotoninergic neurons. We measured plasma 5-HT levels in 12 children affected by epilepsy who underwent TPM therapy. Inclusion criteria were (i) age range 2-12 years, (ii) weight greater than 12 kg, (iii) no more than one antiepileptic drug used when TPM therapy was instituted, and (iv) a minimum study period of 3 months. After a mean period of 3 months of TPM treatment, a significant increase in mean plasma serotonin levels was observed with respect to the basal levels and those of a control group. There were no significant correlations between the changes in serotonin concentrations and the antiepileptic efficacy or doses of TPM used. TPM may influence serotonin metabolism in children affected by epilepsy. Further studies are needed to establish whether these serotonin plasma changes represent an epiphenomenon or indicate direct effects of TPM on the serotoninergic system.

Progressive Loss of Dopaminergic Neurons in the Ventral Midbrain of Adult Mice Heterozygote forEngrailed1

Engrailed1 and Engrailed2 (En1 and En2) are two developmental genes of the homeogene family expressed in the developing midbrain. En1 and, to a lesser degree, En2 also are expressed in the adult substantia nigra (SN) and ventral tegmental area (VTA), two dopaminergic (DA) nuclei of the ventral midbrain. In an effort to study En1/2 adult functions, we have analyzed the phenotype of mice lacking one En1 allele in an En2 wild-type context. We show that in this mutant the number of DA neurons decreases slowly between 8 and 24 weeks after birth to reach a stable 38 and 23% reduction in the SN and VTA, respectively, and that neuronal loss can be antagonized by En2 recombinant protein infusions in the midbrain. These loss and gain of function experiments firmly establish that En1/2 is a true survival factor for DA neurons in vivo. Neuronal death in the mutant is paralleled by a 37% decrease in striatal DA, with no change in serotonin content. Using established protocols, we show that, compared with their wild-type littermates, En1+/- mice have impaired motor skills, an anhedonic-like behavior, and an enhanced resignation phenotype; they perform poorly in social interactions. However, these mice do not differ from their wild-type littermates in anxiety-measuring tests. Together, these results demonstrate that En1/2 genes have important adult physiological functions. They also suggest that mice lacking only one En1 allele could provide a novel model for the study of diseases associated with progressive DA cell death.

Neurochemical effects of the endocannabinoid uptake inhibitor UCM707 in various rat brain regions

To date, UCM707, (5 Z,8 Z,11 Z,14 Z)- N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro and in vivo as inhibitor of the endocannabinoid uptake. Its biochemical, pharmacological and therapeutic properties have been intensely studied recently, but the information on its capability to modify neurotransmitter activity, which obviously underlies the above properties, is still limited. In the present study, we conducted a time-course experiment in rats aimed at examining the neurochemical effects of UCM707 in several brain regions following a subchronic administration (5 injections during 2.5 days) of this inhibitor in a dose of 5 mg/kg weight. In the hypothalamus, the administration of UCM707 did not modify GABA contents but reduced norepinephrine levels at 5 h after administration, followed by an increase at 12 h. Similar trends were observed for dopamine, whereas serotonin content remained elevated at 1 and, in particular, 5 and 12 h after administration. In the case of the basal ganglia, UCM707 reduced GABA content in the substantia nigra but only at longer (5 or 12 h) times after administration. There were no changes in serotonin content, but a marked reduction in its metabolite 5HIAA was recorded in the substantia nigra. The same pattern was found for dopamine, contents of which were not altered by UCM707 in the caudate–putamen, but its major metabolite DOPAC exhibited a marked decrease at 5 h. In the cerebellum, UCM707 reduced GABA, serotonin and norepinephrine content, but only the reduction found for norepinephrine at 5 h reached statistical significance. The administration of UCM707 did not modify the contents of these neurotransmitters in the hippocampus and the frontal cortex. Lastly, in the case of limbic structures, the administration of UCM707 markedly reduced dopamine content in the nucleus accumbens at 5 h, whereas GABA content remained unchanged in this structure and also in the ventral–tegmental area and the amygdala. By contrast, norepinephrine and serotonin content increased at 5 h in the nucleus accumbens, but not in the other two limbic structures. In summary, UCM707 administered subchronically modified the contents of serotonin, GABA, dopamine and/or norepinephrine with a pattern strongly different in each brain region. So, changes in GABA transmission (decrease) were restricted to the substantia nigra, but did not appear in other regions, whereas dopamine transmission was also altered in the caudate–putamen and the nucleus accumbens. By contrast, norepinephrine and serotonin were altered by UCM707 in the hypothalamus, cerebellum (only norepinephrine), and nucleus accumbens, exhibiting biphasic effects in some cases.

Changes in the endorphin and serotonin content of rat immune cells during adulthood following maternal exposure to ethanol during pregnancy and lactation

Lactating and lactating/pregnant rat dams consumed either 3% (vol/vol) ethanol (as the sole source of fluid) between the 1st and 21st days after delivery or 15% (vol/vol) ethanol for 24 h on the 3rd day after delivery. Offspring of ethanol-consuming dams were compared with offspring of untreated control dams. In other groups, offspring of mothers given 3% ethanol during pregnancy were also compared to untreated controls. When the offspring were 2 months of age, endorphin and serotonin contents of immune cells (lymphocytes, granulocytes and monocytes, mast cells of the peritoneal fluid, and lymphocytes of the thymus) were determined by hormone-specific antibodies and flow cytometric as well as confocal microscopic analysis. In rats exposed to ethanol through breast-feeding, endorphin content significantly decreased in thymic cells independent of the alcohol concentration (and duration) during treatment. Each type of peritoneal cell contained significantly more serotonin after 3% alcohol treatment. For the prenatally exposed offspring, serotonin content significantly decreased for both ethanol treatment conditions during pregnancy. Remarkably, one day of exposure to 15% ethanol on the third day of pregnancy was sufficient to induce this enduring change in serotonin content of immune cells of offspring. Considering that endorphin and serotonin are important immunomodulators, these alcohol-induced changes could produce enduring influences on immune function.

Circulating serotonin in vertebrates.

The role of circulating serotonin is unclear and whether or not serotonin is present in the blood of non-mammalian species is not known. This study provides the first evidence for the presence of serotonin in thrombocytes of birds and three reptilian species, the endothermic leatherback sea turtle, the green sea turtle and the partially endothermic American alligator. Thrombocytes from a fresh water turtle, American bullfrog, Yellowfin tuna, and Chinook salmon did not contain serotonin. Serotonin is a vasoactive substance that regulates skin blood flow, a major mechanism for endothermic body temperature regulation, which could explain why circulating serotonin is present in warm-blooded species. The temperature sensitivity of human blood platelets with concomitant changes in serotonin content further supports a link between circulating serotonin and thermoregulation. Phylogenetic comparison of the presence of circulating serotonin indicated an evolutionary divergence within reptilian species that might coincide with the emergence of endothermy.

The nNOS inhibitor, AR-R17477AR, prevents the loss of NF68 immunoreactivity induced by methamphetamine in the mouse striatum.

The present study examined the time-course and regionally-selective changes in the levels of the neurofilament protein NF68 in the mouse brain induced by methamphetamine (METH). The ability of low ambient temperature, or of the specific neuronal nitric oxide synthase (nNOS) inhibitor AR-R17477AR, to protect against both long-term striatal NF68 and dopamine loss induced by METH (3 mg/kg, i.p.) was also studied. Seven days after METH administration (3, 6 and 9 mg/kg, i.p., three times at 3 h intervals), mice showed a reduction of about 40% in immunoreactivity for NF68 in the striatum. This effect was not produced in cortex after METH administration at the dose of 3 mg/kg. No difference from controls was observed when measurements were carried out 1 h and 24 h after the last METH injection at the dose of 3 mg/kg. The loss of NF68 immunoreactivity seems to be associated with the long-term dopamine depletion induced by METH, since no change in serotonin concentration is observed in either the striatum or cortex 7 days after dosing. Animals kept at a room temperature of 4 degrees C showed a loss of NF68 similar to those treated at 22 degrees C but an attenuation of dopamine depletion in the striatum. Pre-treatment with AR-R17477AR (5 mg/kg, s.c.) 30 min before each of the three METH (3 mg/kg, i.p.) injections provided complete protection against METH-induced loss of NF68 immunoreactivity and attenuated the decrease in striatal dopamine and HVA concentrations by about 50%. These data indicate that both the reduction of NF68 immunoreactivity and the loss of dopamine concentration are due to an oxidative stress process mediated by reactive nitrogen species, and are not due to changes in body temperature.

Chronic daily headache: a scientist's perspective.

Certain features of chronic daily headache, namely, increased headache frequency, expansion of headache area, and cutaneous allodynia, may imply sensitization of central nociceptive neurons in the trigeminal pathway. Repetitive activation of the trigeminal nerve can lead to a biologic and functional change in trigeminal nucleus caudalis neurons, characterized by a decrease in nociceptive threshold and receptive field expansion. Suppression of the endogenous pain control system can facilitate the process of central sensitization. Evidence of such suppression in patients with chronic daily headache includes decreased platelet serotonin, up-regulation of 5-HT2A receptors, increased platelet nitric oxide production, and increased levels of substance P and nerve growth factor in the cerebrospinal fluid. Results from a number of animal experiments have indicated that chronic analgesic exposure leads to changes in serotonin content and density of 5-HT2A receptors in the central nervous system. This plasticity of the serotonin-dependent pain control system may accelerate the process of sensitization; a biologic outcome that is expressed clinically by the development of chronic daily headache associated with analgesic overuse.