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Sample records for brain serotonin 2a

  1. Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, A.; da Cunha-Bang, S.; McMahon, Barry P.

    2014-01-01

    [C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely...... than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT receptors with [C]Cimbi-36 PET. The two-tissue compartment model using arterial input...... significantly decreased [C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [C]Cimbi-36 binding is selective for 5-HT receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT receptors in the human brain...

  2. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use

    DEFF Research Database (Denmark)

    Erritzoe, D.; Frokjaer, V. G.; Haugbol, S.

    2009-01-01

    Manipulations of the serotonin levels in the brain can affect impulsive behavior and influence our reactivity to conditioned reinforcers. Eating, tobacco smoking, and alcohol consumption are reinforcers that are influenced by serotonergic neurotransmission; serotonergic hypofunction leads to incr...

  3. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

    Science.gov (United States)

    Gresch, P J; Strickland, L V; Sanders-Bush, E

    2002-01-01

    Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations. Copyright 2002 IBRO

  4. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, Anders; Svarer, Claus; McMahon, Brenda

    2016-01-01

    BPNDs measured with [(11)C]Cimbi-36 and [(18)F]altanserin (mean Pearson's r: 0.95 ± 0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [(11)C]Cimbi-36 as compared to [(18)F]altanserin was found in the choroid plexus and hippocampus in the human brain......INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C...... test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures...

  5. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

    Science.gov (United States)

    Bernasconi, Fosco; Schmidt, André; Pokorny, Thomas; Kometer, Michael; Seifritz, Erich; Vollenweider, Franz X

    2014-12-01

    Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims.

    Science.gov (United States)

    Pandey, Ghanshyam N; Dwivedi, Yogesh; Rizavi, Hooriyah S; Ren, Xinguo; Pandey, Subhash C; Pesold, Christine; Roberts, Rosalinda C; Conley, Robert R; Tamminga, Carol A

    2002-03-01

    Abnormalities of serotonin (5-HT) receptor subtypes have been observed in the postmortem brains of adult suicide victims; however, their role in teenage suicide is unexplored. The authors examined whether 5-HT(2A) receptor subtypes are altered in the postmortem brains of teenage suicide victims. Levels of 5-HT(2A) receptors were determined through examination of [(125)I] LSD binding, protein expression (by use of Western blotting with a specific 5-HT(2A) receptor antibody), and mRNA (by means of quantitative reverse transcription polymerase chain reaction) in the prefrontal cortex, hippocampus, and nucleus accumbens of 15 teenage suicide victims and 15 normal matched teenage subjects. The cellular localization of the 5-HT(2A) receptors was determined by means of gold immunolabeling. The authors observed significantly higher [(125)I]LSD binding in the prefrontal cortex and greater protein expression and mRNA levels in the prefrontal cortex and hippocampus but not in the nucleus accumbens of suicide victims, compared with normal subjects. Greater protein expression was localized on pyramidal cells in cortical layer V but not in other cortical layers or in the surrounding neuropil of the prefrontal cortex of teenage suicide victims. The evidence indicates higher levels of 5-HT(2A) receptor, protein, and mRNA expression in the prefrontal cortex and hippocampus, which have been implicated in emotion, stress, and cognition. There was no higher level in the nucleus accumbens, which has been implicated in drug dependence and craving. Our findings suggest that a higher level of 5-HT(2A) receptors may be one of the neurobiological abnormalities associated with teenage suicide.

  7. Temperament, character and serotonin activity in the human brain

    DEFF Research Database (Denmark)

    Tuominen, L; Salo, J; Hirvonen, J

    2013-01-01

    The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT...

  8. Neuro-imaging the serotonin 2A receptor as a valid biomarker for canine behavioural disorders

    NARCIS (Netherlands)

    Vermeire, S.; Audenaert, K.; Vandermeulen, E.; Waelbers, T.; De Meester, R.; Eersels, J.L.H.; Dobbeleir, A.; Peremans, K.

    2011-01-01

    The serotonergic system is disturbed in different mood and affective disorders, with especially the serotonin (5-HT) 2A receptor involved in impulsive aggressiveness and anxiety. The aim of the study was to evaluate the involvement of the brain 5-HT 2A receptor in dogs with different behavioural

  9. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    : Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...

  10. Serotonin 2a Receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice

    Directory of Open Access Journals (Sweden)

    Juan Facundo Morici

    2015-12-01

    Full Text Available Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a -/- with wild type (htr2a+/+ littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

  11. Serotonin and brain function: a tale of two receptors

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    Carhart-Harris, RL; Nutt, DJ

    2017-01-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID:28858536

  12. Serotonin syndrome

    Science.gov (United States)

    Hyperserotonemia; Serotonergic syndrome; Serotonin toxicity; SSRI - serotonin syndrome; MAO - serotonin syndrome ... brain area. For example, you can develop this syndrome if you take migraine medicines called triptans together ...

  13. Serotonin 5-HT2A Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Charles D. Nichols

    2009-01-01

    Full Text Available There are high levels of comorbidity between neuropsychiatric and cardiovascular disorders. A key molecule central to both cognitive and cardiovascular function is the molecule serotonin. In the brain, serotonin modulates neuronal activity and is actively involved in mediating many cognitive functions and behaviors. In the periphery, serotonin is involved in vasoconstriction, inflammation, and cell growth, among other processes. It is hypothesized that one component of the serotonin system, the 5-HT2A receptor, is a common and contributing factor underlying aspects of the comorbidity between neuropsychiatric and cardiovascular disorders. Within the brain this receptor participates in processes such as cognition and working memory, been implicated in effective disorders such as schizophrenia, and mediate the primary effects of hallucinogenic drugs. In the periphery, 5-HT2A receptors have been linked to vasoconstriction and hypertension, and to inflammatory processes that can lead to atherosclerosis.

  14. Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Mortensen, Erik L.; Nielsen, Finn Årup

    2008-01-01

    Background: Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain...... regions of relevance for affective disorders. Methods: Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [F-18]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding....... The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. Results: Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [r(79) = .24, p = .028]. Post hoc...

  15. High brain serotonin levels in migraine between attacks

    DEFF Research Database (Denmark)

    Deen, Marie; Hansen, Hanne D.; Hougaard, Anders

    2017-01-01

    Objectives To investigate brain 5-HT4-receptor binding with positron emission tomography (PET) as a proxy of serotonin (5-hydroxytryptamine, 5-HT) levels in migraine patients between attacks. Methods Brain 5-HT4-receptor binding, assessed with PET imaging of the specific 5-HT4-receptor radioligand...... episodically high brain 5-HT-level. Our finding is in apparent contrast with the longstanding hypothesis of migraine being a syndrome of chronic low brain 5-HT-levels. We were unable to demonstrate any associations with attack frequency or years with migraine. This suggests that high brain 5-HT-levels may...

  16. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

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    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  17. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.

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    O'Mahony, S M; Clarke, G; Borre, Y E; Dinan, T G; Cryan, J F

    2015-01-15

    The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate.

    Science.gov (United States)

    Lefevre, Arthur; Richard, Nathalie; Jazayeri, Mina; Beuriat, Pierre-Aurélien; Fieux, Sylvain; Zimmer, Luc; Duhamel, Jean-René; Sirigu, Angela

    2017-07-12

    Oxytocin (OT) is increasingly studied for its therapeutic potential in psychiatric disorders, which are associated with the deregulation of several neurotransmission systems. Studies in rodents demonstrated that the interaction between OT and serotonin (5-HT) is critical for several aspects of social behavior. Using PET scan in humans, we have recently found that 5-HT 1A receptor (5-HT 1A R) function is modified after intranasal oxytocin intake. However, the underlying mechanism between OT and 5-HT remains unclear. To understand this interaction, we tested 3 male macaque monkeys using both [ 11 C]DASB and [ 18 F]MPPF, two PET radiotracers, marking the serotonin transporter and the 5-HT 1A R, respectively. Oxytocin (1 IU in 20 μl of ACSF) or placebo was injected into the brain lateral ventricle 45 min before scans. Additionally, we performed postmortem autoradiography. Compared with placebo, OT significantly reduced [ 11 C]DASB binding potential in right amygdala, insula, and hippocampus, whereas [ 18 F]MPPF binding potential increased in right amygdala and insula. Autoradiography revealed that [ 11 C]DASB was sensitive to physiological levels of 5-HT modification, and that OT does not act directly on the 5-HT 1A R. Our results show that oxytocin administration in nonhuman primates influences serotoninergic neurotransmission via at least two ways: (1) by provoking a release of serotonin in key limbic regions; and (2) by increasing the availability of 5-HT 1A R receptors in the same limbic areas. Because these two molecules are important for social behavior, our study sheds light on the specific nature of their interaction, therefore helping to develop new mechanisms-based therapies for psychiatric disorders. SIGNIFICANCE STATEMENT Social behavior is largely controlled by brain neuromodulators, such as oxytocin and serotonin. While these are currently targeted in the context of psychiatric disorders such as autism and schizophrenia, a new promising pharmaceutical

  19. Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex.

    Science.gov (United States)

    Basura, Gregory J; Abbas, Atheir I; O'Donohue, Heather; Lauder, Jean M; Roth, Bryan L; Walker, Paul D; Manis, Paul B

    2008-10-01

    Maturation of the mammalian cerebral cortex is, in part, dependent upon multiple coordinated afferent neurotransmitter systems and receptor-mediated cellular linkages during early postnatal development. Given that serotonin (5-HT) is one such system, the present study was designed to specifically evaluate 5-HT tissue content as well as 5-HT(2A) receptor protein levels within the developing auditory cortex (AC). Using high performance liquid chromatography (HPLC), 5-HT and the metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was measured in isolated AC, which demonstrated a developmental dynamic, reaching young adult levels early during the second week of postnatal development. Radioligand binding of 5-HT(2A) receptors with the 5-HT(2A/2C) receptor agonist, (125)I-DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; in the presence of SB206553, a selective 5-HT(2C) receptor antagonist, also demonstrated a developmental trend, whereby receptor protein levels reached young adult levels at the end of the first postnatal week (P8), significantly increased at P10 and at P17, and decreased back to levels not significantly different from P8 thereafter. Immunocytochemical labeling of 5-HT(2A) receptors and confocal microscopy revealed that 5-HT(2A) receptors are largely localized on layer II/III pyramidal cell bodies and apical dendrites within AC. When considered together, the results of the present study suggest that 5-HT, likely through 5-HT(2A) receptors, may play an important role in early postnatal AC development.

  20. Sleep deprivation increases cerebral serotonin 2A receptor binding in humans.

    Science.gov (United States)

    Elmenhorst, David; Kroll, Tina; Matusch, Andreas; Bauer, Andreas

    2012-12-01

    Serotonin and its cerebral receptors play an important role in sleep-wake regulation. The aim of the current study is to investigate the effect of 24-h total sleep deprivation on the apparent serotonin 2A receptor (5-HT(2A)R) binding capacity in the human brain to test the hypothesis that sleep deprivation induces global molecular alterations in the cortical serotonergic receptor system. Volunteers were tested twice with the subtype-selective radiotracer [(18)F]altanserin and positron emission tomography (PET) for imaging of 5-HT(2A)Rs at baseline and after 24 h of sleep deprivation. [(18)F]Altanserin binding potentials were analyzed in 13 neocortical regions of interest. The efficacy of sleep deprivation was assessed by questionnaires, waking electroencephalography, and cognitive performance measurements. Sleep laboratory and neuroimaging center. Eighteen healthy volunteers. Sleep deprivation. A total of 24 hours of sleep deprivation led to a 9.6% increase of [(18)F]altanserin binding on neocortical 5-HT(2A) receptors. Significant region-specific increases were found in the medial inferior frontal gyrus, insula, and anterior cingulate, parietal, sensomotoric, and ventrolateral prefrontal cortices. This study demonstrates that a single night of total sleep deprivation causes significant increases of 5-HT(2A)R binding potentials in a variety of cortical regions although the increase declines as sleep deprivation continued. It provides in vivo evidence that total sleep deprivation induces adaptive processes in the serotonergic system of the human brain.

  1. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.

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    Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H; Fernstrom, John D

    2013-11-01

    Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.

  2. Neuro-imaging the serotonin 2A receptor as a valid biomarker for canine behavioural disorders.

    Science.gov (United States)

    Vermeire, Simon; Audenaert, Kurt; De Meester, Rudy; Vandermeulen, Eva; Waelbers, Tim; De Spiegeleer, Bart; Eersels, Jos; Dobbeleir, André; Peremans, Kathelijne

    2011-12-01

    The serotonergic system is disturbed in different mood and affective disorders, with especially the serotonin (5-HT) 2A receptor involved in impulsive aggressiveness and anxiety. The aim of the study was to evaluate the involvement of the brain 5-HT 2A receptor in dogs with different behavioural disorders. Three groups of drug naive dogs were studied: 22 dogs showing impulsive aggressive behaviour, 22 showing normal behaviour, and 22 showing anxious behaviour. The serotonin 2A receptor was evaluated with Single Photon Emission Computed Tomography (SPECT) and the serotonin 2A receptor-selective radiopharmaceutical (123)I-R91150. A serotonin 2A receptor binding index (BI), proportional to the cortical receptor density, was calculated. A receiver operating characteristic (ROC) analysis was performed to determine cut-off values at which optimal sensitivity and specificity are achieved and to evaluate the general performance of the BI in reflecting the state of the dog, i.e., impulsive aggressive, normal or anxious. Significantly (Pdogs behaving abnormally, with consistently increased BI in impulsive aggressive dogs and decreased BI in anxious dogs. These results provide clear evidence for a disturbed serotonergic balance in canine impulsive aggression and anxiety disorders. A right frontal cut-off value of ≥1.92 with 86.4% sensitivity and 2.3% (1-specificity) was obtained for the impulsive aggressive dogs. Differentiating the anxious dogs from the rest of the population was possible with a cut-off value of ≤1.73 with 86.4% sensitivity and 18.2% (1-specificity). We conclude that SPECT imaging with the radioligand (123)I-R91150 can be a helpful tool in evaluating the involvement of the serotonin 2A receptor in the complex mechanisms of impulsive aggressive and anxious behaviour. The 5HT-2A binding index of the right frontal cortex appears to be a valid biomarker in differentiating the studied canine behavioural disorders. Copyright © 2010 Elsevier Ltd. All rights

  3. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Frøkjær, Vibe; Kalbitzer, Jan

    2012-01-01

    In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor...

  4. In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frøkjær, Vibe; Holst, Klaus K

    2011-01-01

    Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.......Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin....

  5. ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers.

    Science.gov (United States)

    Davis, Robert E; Vanover, Kimberly E; Zhou, Yun; Brašić, James R; Guevara, Maria; Bisuna, Blanca; Ye, Weiguo; Raymont, Vanessa; Willis, William; Kumar, Anil; Gapasin, Lorena; Goldwater, D Ronald; Mates, Sharon; Wong, Dean F

    2015-08-01

    Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

  6. Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding.

    Science.gov (United States)

    Wihlbäck, Anna-Carin; Sundström Poromaa, Inger; Bixo, Marie; Allard, Per; Mjörndal, Tom; Spigset, Olav

    2004-07-01

    Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (pLSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (pLSD binding were found (p<0.05, respectively).

  7. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.

    Science.gov (United States)

    Chugani, D C; Muzik, O; Behen, M; Rothermel, R; Janisse, J J; Lee, J; Chugani, H T

    1999-03-01

    Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using alpha[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.

  8. Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia.

    Science.gov (United States)

    Navarro, Silvia Victoria; Gutiérrez-Ferre, Valeria; Flores, Pilar; Moreno, Margarita

    2015-02-01

    Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. We investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT2A/C) receptors in compulsive SIP behaviour. Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT2C receptor antagonist SB242084, serotonin 5-HT2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP. Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

  9. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

    Science.gov (United States)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

    2017-01-04

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein synthesis

  10. [Investigation of association of the brain-derived neurotrophic factor (BDNF) and a serotonin receptor 2A (5-HTR2A) genes with voluntary and involuntary attention in schizophrenia].

    Science.gov (United States)

    Alfimova, M V; Lezheĭko, T V; Golimbet, V E; Korovaĭtseva, G I; Lavrushkina, O M; Kolesina, N Iu; Frolova, L P; Muratova, A A; Abramova, L I; Kaleda, V G

    2008-01-01

    To investigate the effect of Val66Met BDNF and 5-HTR2A T102C polymorphisms on the characteristics of voluntary and involuntary visual attention, 89 patients with schizophrenia, 91 their well relatives and 163 controls have been studied. Attention was assessed using a modified version of the Munsterberg test. The significant interaction effect of the BDNF, 5-HTR2A and diagnosis on attention characteristics was found (p=0,04). Carriers of the Val/Val genotype demonstrated higher scores of both voluntary and involuntary attention and those with the A1 (T) allele needed more time for the performance of the test. The combination of the A1 allele with a Met BDNF allele was associated with lower scores of voluntary attention and higher scores of involuntary attention. The study confirmed the impairment of selective attention in patients with schizophrenia and their relatives while any pathological changes in involuntary attention were not observed. The effect of genotypes was presented irrespective of diagnostic group studied. The data obtained suggest that carriers of the Val/Val genotype are able to allocate more attentional resources to process external stimuli. At the same time, the possibility that this polymorphism is likely associated with specific visual-spatial abilities than with attention as such or general cognitive resources can not be excluded.

  11. Serotonin transporter and dopamine transporter imaging in the canine brain

    Energy Technology Data Exchange (ETDEWEB)

    Peremans, Kathelijne [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Goethals, Ingeborg [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); De Vos, Filip [Laboratory of Radiopharmacy, Pharmaceutical Sciences, Ghent University, B-9000 Ghent (Belgium); Dobbeleir, A. [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Ham, Hamphrey [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); Van Bree, Henri [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Heeringen, Cees van [Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium); Audenaert, Kurt [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium) and Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium)]. E-mail: kurt.audenaert@ugent.be

    2006-10-15

    The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [{sup 123}I]-{beta}-CIT and [{sup 123}I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models.

  12. The role of brain serotonin. A neurophysiologic perspective.

    Science.gov (United States)

    Jacobs, B L; Wilkinson, L O; Fornal, C A

    1990-01-01

    In behaving animals, the activity of brain serotonergic neurons is closely tied to the sleep-wake-arousal cycle: highest firing rate during active waking or arousal; intermediate level of discharge during quiescent states and slow wave sleep; and virtual silence during rapid-eye-movement sleep. Environmental stressors, such as exposure to white noise or physical restraint, and physiologic stressors, such as induction of a febrile response or hypoglycemia, do not activate these cells above the baseline level observed during active waking. Continuing this line of investigation, we have utilized in vivo brain microdialysis in order to determine whether there could be a dissociation between level of serotonergic neuronal activity and release of serotonin at the nerve terminal. Our data indicate that under a variety of the above conditions, neuronal activity and release are not dissociated. We have recently discovered a group of serotonergic neurons whose activity is strongly linked to various oral-buccal activities, such as feeding, grooming, etc. In general, we propose that the brain serotonergic system exerts a modulatory influence over its target structures so as to coordinate their activity with the organism's sleep-wake-arousal state (level of behavioral arousal).

  13. Brain Serotonin Transporter Binding In a Minipig Model of Parkinson's Disease

    DEFF Research Database (Denmark)

    Lillethorup, Thea Pinholt; Glud, Andreas Nørgaard; Sørensen, Jens Christian Hedemann

    Objectives: Some of the debilitating non-motor aspects of Parkinson’s disease (PD) are related to the serotonin system1. To investigate the involvement of the brain serotonergic system in a PD animal model, we measured the in vivo binding of [11C]-DASB to the serotonin transporter (SERT...

  14. Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

    Science.gov (United States)

    Fujimoto, Yohei; Funao, Tomoharu; Suehiro, Koichi; Takahashi, Ryota; Mori, Takashi; Nishikawa, Kiyonobu

    2015-01-01

    Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P seizure threshold (P seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

  15. Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals' perspective taking ability and autistic-like traits.

    Science.gov (United States)

    Gong, Pingyuan; Liu, Jinting; Blue, Philip R; Li, She; Zhou, Xiaolin

    2015-01-01

    Previous studies have indicated that empathic traits, such as perspective taking, are associated with the levels of serotonin in the brain and with autism spectrum conditions. Inspired by the finding that the serotonin receptor 2A gene (HTR2A) modulates the availability of serotonin, this study investigated to what extent HTR2A modulates individuals' perspective taking ability and autistic-like traits. To examine the associations of the functional HTR2A polymorphism T102C (rs6313) with individuals' perspective taking abilities and autistic-like traits, we differentiated individuals according to this polymorphism and measured empathic and autistic-like traits with Interpersonal Reactivity Index (IRI) and Autism-Spectrum Quotient (AQ) scale in 523 Chinese people. The results indicated that this polymorphism was significantly associated with the scores on Perspective Taking and Personal Distress subscales of IRI, and Communication subscale of AQ. Individuals with a greater number of the C alleles were less likely to spontaneously adopt the point of view of others, more likely to be anxious when observing the pain endured by others, and more likely to have communication problems. Moreover, the genotype effect on communication problems was mediated by individuals' perspective taking ability. These findings provide evidence that the HTR2A T102C polymorphism is a predictor of individual differences in empathic and autistic-like traits and highlight the role of the gene in the connection between perspective taking and autistic-like traits.

  16. Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits

    Science.gov (United States)

    Gong, Pingyuan; Liu, Jinting; Blue, Philip R.; Li, She; Zhou, Xiaolin

    2015-01-01

    Previous studies have indicated that empathic traits, such as perspective taking, are associated with the levels of serotonin in the brain and with autism spectrum conditions. Inspired by the finding that the serotonin receptor 2A gene (HTR2A) modulates the availability of serotonin, this study investigated to what extent HTR2A modulates individuals’ perspective taking ability and autistic-like traits. To examine the associations of the functional HTR2A polymorphism T102C (rs6313) with individuals’ perspective taking abilities and autistic-like traits, we differentiated individuals according to this polymorphism and measured empathic and autistic-like traits with Interpersonal Reactivity Index (IRI) and Autism-Spectrum Quotient (AQ) scale in 523 Chinese people. The results indicated that this polymorphism was significantly associated with the scores on Perspective Taking and Personal Distress subscales of IRI, and Communication subscale of AQ. Individuals with a greater number of the C alleles were less likely to spontaneously adopt the point of view of others, more likely to be anxious when observing the pain endured by others, and more likely to have communication problems. Moreover, the genotype effect on communication problems was mediated by individuals’ perspective taking ability. These findings provide evidence that the HTR2A T102C polymorphism is a predictor of individual differences in empathic and autistic-like traits and highlight the role of the gene in the connection between perspective taking and autistic-like traits. PMID:26557070

  17. Serotonin receptor gene (HTR2A T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits

    Directory of Open Access Journals (Sweden)

    Pingyuan eGong

    2015-10-01

    Full Text Available Previous studies have indicated that empathic traits, such as perspective taking, are associated with the levels of serotonin in the brain and with autism spectrum conditions. Inspired by the finding that the serotonin receptor 2A gene (HTR2A modulates the availability of serotonin, this study investigated to what extent HTR2A modulates individuals’ perspective taking ability and autistic-like traits. To examine the associations of the functional HTR2A polymorphism T102C (rs6313 with individuals’ perspective taking ability and autistic-like traits, we differentiated individuals according to this polymorphism and measured empathic and autistic-like traits with Interpersonal Reactivity Index (IRI and Autism-Spectrum Quotient (AQ scale in 523 Chinese people. The results indicated that this polymorphism was significantly associated with the scores on Perspective Taking and Personal Distress subscales of IRI, and Communication subscale of AQ. Individuals with a greater number of the C alleles were less likely to spontaneously adopt the point of view of others, more likely to be anxious when observing the pain endured by others, and more likely to have communication problems. Moreover, the genotype effect on communication problems was mediated by individuals’ perspective taking ability. These findings provide evidence that the HTR2A T102C polymorphism is a predictor of individual differences in empathic and autistic-like traits and highlight the role of the gene in the connection between perspective taking and autistic-like traits.

  18. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

    DEFF Research Database (Denmark)

    Santini, Martin A; Ratner, Cecilia Friis; Aznar, Susana

    2013-01-01

    Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia...

  19. Solubilization of serotonin-1a and serotonin-1b binding sites from bovine brain

    Energy Technology Data Exchange (ETDEWEB)

    Asarch, K.B.; Shih, J.C.

    1987-05-01

    Serotonin1 (5-hydroxytryptamine1, 5-HT1) binding sites have been solubilized from bovine brain cortex using a mixture of 0.1% Nonidet P-40 and 0.3% digitonin in a low-salt buffer containing 0.1% ascorbic acid. The affinity of (/sup 3/H)5-HT for the soluble cortical binding sites (2.1 nM) is identical to its affinity at membrane-bound binding sites (2.1 nM). (/sup 3/H)8-Hydroxy-2-(di-n-propylamino)tetralin ((/sup 3/H)DPAT), a selective 5-HT1a radioligand, also binds to soluble cortical binding sites with high affinity (1.8 nM) comparable with its affinity in the crude membranes (1.7 nM). A significant correlation exists in the rank order potency of serotonergic agents for (/sup 3/H)5-HT binding and for (/sup 3/H)DPAT binding to crude and soluble membranes. The density of (/sup 3/H)DPAT binding sites relative to the (/sup 3/H)5-HT sites in the solubilized cortical membranes (35%) corresponds well with the proportion of 5-HT1a sites in the crude membranes determined by spiperone displacement (33%), suggesting that both the 5-HT1a and 5-HT1b binding sites have been cosolubilized. (/sup 3/H)5-HT binding in the soluble preparations was inhibited by GTP, suggesting that a receptor complex may have been solubilized. (/sup 3/H)Spiperone-specific binding was not detectable in this preparation, suggesting that 5-HT2 sites were not cosolubilized.

  20. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2...

  1. Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder.

    Science.gov (United States)

    Vermeire, Simon; Audenaert, Kurt; De Meester, Rudy; Vandermeulen, Eva; Waelbers, Tim; De Spiegeleer, Bart; Eersels, Jos; Dobbeleir, André; Peremans, Kathelijne

    2012-01-30

    Neuro-imaging studies have shown altered, yet often inconsistent, serotonergic and dopaminergic neurotransmission in patients with obsessive-compulsive disorder (OCD). We investigated both serotonergic and dopaminergic neurotransmission in 9 drug-naïve dogs with compulsive behaviour, as a potential model for human OCD. Single photon emission computed tomography was used with (123)I-R91150 and (123)I-FP-CIT, in combination with (99m)Tc-ECD brain perfusion co-registration, to measure the serotonin (5-HT) 2A receptor, dopamine transporter (DAT) and serotonin transporter (SERT) availability. Fifteen normally behaving dogs were used as reference group. Significantly lower 5-HT2A receptor radioligand availability in frontal and temporal cortices (bilateral) was observed. Further, in 78% of the compulsive dogs abnormal DAT ratios in left and right striatum were demonstrated. Interestingly, both increased and decreased DAT ratios were observed. Finally, significantly lower subcortical perfusion and (hypo)thalamic SERT availability were observed in the compulsive dogs. This study provides evidence for imbalanced serotonergic and dopaminergic pathways in the pathophysiology of compulsions in dogs. The similarities with the altered neurotransmission in human OCD provide construct validity for this non-induced, natural canine model, suggesting its usefulness for future investigations of the pathophysiology of human OCD as well as the effectiveness of psychopharmacological interventions. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia.

    Science.gov (United States)

    Santini, Martin A; Ratner, Cecilia; Aznar, Susana; Klein, Anders B; Knudsen, Gitte M; Mikkelsen, Jens D

    2013-05-01

    Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

  3. Dopamine Modulates Serotonin Innervation in the Drosophila Brain

    Directory of Open Access Journals (Sweden)

    Janna Niens

    2017-10-01

    Full Text Available Parkinson’s disease (PD results from a progressive degeneration of the dopaminergic nigrostriatal system leading to a decline in movement control, with resting tremor, rigidity and postural instability. Several aspects of PD can be modeled in the fruit fly, Drosophila melanogaster, including α-synuclein-induced degeneration of dopaminergic neurons, or dopamine (DA loss by genetic elimination of neural DA synthesis. Defective behaviors in this latter model can be ameliorated by feeding the DA precursor L-DOPA, analogous to the treatment paradigm for PD. Secondary complication from L-DOPA treatment in PD patients are associated with ectopic synthesis of DA in serotonin (5-HT-releasing neurons, leading to DA/5-HT imbalance. Here we examined the neuro-anatomical adaptations resulting from imbalanced DA/5-HT signaling in Drosophila mutants lacking neural DA. We find that, similar to rodent models of PD, lack of DA leads to increased 5-HT levels and arborizations in specific brain regions. Conversely, increased DA levels by L-DOPA feeding leads to reduced connectivity of 5-HT neurons to their target neurons in the mushroom body (MB. The observed alterations of 5-HT neuron plasticity indicate that loss of DA signaling is not solely responsible for the behavioral disorders observed in Drosophila models of PD, but rather a combination of the latter with alterations of 5-HT circuitry.

  4. Lipid Fluidity Markedly Modulates the Binding of Serotonin to Mouse Brain Membranes

    Science.gov (United States)

    Heron, David S.; Shinitzky, Meir; Hershkowitz, Moshe; Samuel, David

    1980-12-01

    The binding of [3H]serotonin to mouse brain crude membrane and synaptosomal membrane preparations was investigated as a function of membrane fluidity changes by lipids. The microviscosity ({eta}) of the synaptic membranes was increased by in vitro incubation with either cholesteryl hemisuccinate or stearic acid, resulting in an up to 5-fold increase in the specific binding of [3H]serotonin. Serotonin binding increased progressively until it reached a maximum at 1.75 relative {eta} units; then it declined. Fluidization of membrane lipids, by treatment with lecithin or linoleic acid, caused a small but significant decrease in serotonin binding. These observations are compatible with the concept of vertical displacement of membrane proteins, indicating that in the untreated brain tissue the accessibility (Bmax) of serotonin receptor binding sites constitutes only a fraction (about 20%) of the potential binding capacity stored in the membrane. Scatchard plots of [3H]serotonin binding, at different {eta} values, indicate a continuous change in the binding affinity (Kd) of serotonin to its receptor, concomitant with changes in its accessibility. These results may have important implications for physiological processes in the central nervous system, which are associated with modulation of membrane lipids, such as aging. In addition, the regional heterogeneity and plasticity of receptors may be accounted for by differences in membrane lipid fluidity. It was found here that various brain regions differ markedly in their membrane lipid viscosity.

  5. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

    Science.gov (United States)

    Mc Mahon, Brenda; Andersen, Sofie B; Madsen, Martin K; Hjordt, Liv V; Hageman, Ida; Dam, Henrik; Svarer, Claus; da Cunha-Bang, Sofi; Baaré, William; Madsen, Jacob; Hasholt, Lis; Holst, Klaus; Frokjaer, Vibe G; Knudsen, Gitte M

    2016-05-01

    Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions

  6. Effects of diets containing unripe plantain diet on brain serotonin in ...

    African Journals Online (AJOL)

    In this study, the effect of plantain-containing mouse diet on brain serotonin mice was investigated in mice. Thirty adult Swiss mice were divided into three groups of ten each and fed normal rodent chow containing 0%, 50% and 100% unripe plantain. After thirty days, the brain levels of 5-HT and 5-HTP were measured using ...

  7. Changes in markers of brain serotonin activity in response to chronic exercise in senior men.

    Science.gov (United States)

    Melancon, Michel O; Lorrain, Dominique; Dionne, Isabelle J

    2014-11-01

    Aging is associated with noticeable impairments in brain serotonin transmission, which might contribute to increased vulnerability to developing depression in later life. Animal and human studies have shown that aerobic exercise can stimulate brain serotonin activity and trigger parallel elevations in tryptophan (TRP, the serotonin precursor) availability in blood plasma. However, the influence of chronic exercise on serotonergic activity in older adults is not yet known. Sixteen men aged 64 ± 3 years exercised for 1 h (67%-70% peak oxygen consumption) at baseline and following 16 weeks of aerobic training. The main outcome measures were cardiorespiratory fitness, body composition, branched-chain amino acids (BCAA), TRP, prolactin, lactate, and free fatty acids (FFA). Changes in plasma free-TRP/BCAA and prolactin served as surrogates for TRP availability and serotonin activity, respectively. Chronic exercise decreased body mass (P brain at rest, both pre- and post-training exercise challenges markedly increased TRP availability (P exercise that was lower following training (P exercise elicits consistent transient elevations in plasma TRP availability to the brain in older men; the elevations were independent from physical training, although less pronounced following training. The data support the contention that repeated elevations in brain serotonin activity might be involved in the antidepressant effect of exercise training in older adults.

  8. The 5-HT2A receptor and serotonin transporter in Asperger’s Disorder: a PET study with [11C]MDL 100907 and [11C]DASB

    OpenAIRE

    Girgis, Ragy R.; Slifstein, Mark; Xu, Xiaoyan; Frankle, W Gordon; Anagnostou, Evdokia; Wasserman, Stacey; Pepa, Lauren; Kolevzon, Alexander; Abi-Dargham, Anissa; Laruelle, Marc; Hollander, Eric

    2011-01-01

    Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [11C]MDL 100907 and [11C]DASB to characterize the 5-HT2A receptor and serotonin transporter in Asperger’s Disorder. 17 individuals with Asperger’s Disorder (age = 34.3 ± 11.1 yr) and 17 healthy controls (age = 33.0 ± 9.6 yr) were scanned with [11C]MDL 100907. Of the 17 patients, eight (a...

  9. BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Holst, Klaus K; Adamsen, Dea

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address t...

  10. Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Hornboll, Bettina; Elliott, Rebecca

    2013-01-01

    and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated...... tryptophan depletion. Moreover, with the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT(2A) receptor binding. Specifically, acute tryptophan depletion (ATD) produced a relatively larger NoGo response in the right IFG...

  11. Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves

    Directory of Open Access Journals (Sweden)

    PA. Polo

    Full Text Available This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 µg.kg-1, sc elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg.kg-1, sc reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg.kg-1, sc did not affect any of the responses evoked by the serotonin. Quipazine (5 mg.kg-1, sc a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.

  12. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  13. The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)]. E-mail: zhizhen_zeng@merck.com; Chen, T.-B. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Miller, Patricia J. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Dean, Dennis [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Tang, Y.S. [Labeled Compound Synthesis Group, Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900 (United States); Sur, Cyrille [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States); Williams, David L. [Imaging Department, Merck Research Laboratories, West Point, PA 19486 (United States)

    2006-05-15

    We have characterized the interaction of the serotonin transporter ligand [{sup 3}H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [{sup 3}H]-DASB, a tritiated version of the widely used [{sup 11}C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K {sub d}=0.20{+-}0.04 nM). The serotonin transporter density (B {sub max}) obtained for rhesus frontal cortex was found to be 66{+-}8 fmol/mg protein using [{sup 3}H]-DASB, similar to the B {sub max} value obtained using the reference radioligand [{sup 3}H]-citalopram, a well-characterized and highly selective serotonin reuptake inhibitor (83{+-}22 fmol/mg protein). Specific binding sites of both [{sup 3}H]-DASB and [{sup 3}H]-citalopram were similarly and nonuniformly distributed throughout the rhesus central nervous system, in a pattern consistent with serotonin transporter localization reported for human brain. Regional serotonin transporter densities, estimated from optical densities of the autoradiographic images, were well correlated between the two radioligands. Finally, DASB and fluoxetine showed dose-dependent full inhibition of [{sup 3}H]-citalopram binding in a competition autoradiographic study, with K {sub i} values in close agreement with those obtained from rhesus brain homogenates. This side-by-side comparison of [{sup 3}H]-DASB and [{sup 3}H]-citalopram binding sites in rhesus tissue homogenates and in adjacent rhesus brain slices provides additional support for the use of [{sup 11}C]-DASB to assess the availability and distribution of serotonin transporters in nonhuman primates.

  14. The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Arfan, Haroon; Haugbol, Steven

    2007-01-01

    With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human...... brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between...

  15. Tryptophan as an evolutionarily conserved signal to brain serotonin : Molecular evidence and psychiatric implications

    NARCIS (Netherlands)

    Russo, Sascha; Kema, Ido P.; Bosker, Fokko; Haavik, Jan; Korf, Jakob

    2009-01-01

    The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is

  16. Autoradiographic localization of /sup 3/H-paroxetine-labeled serotonin uptake sites in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    De Souza, E.B.; Kuyatt, B.L.

    1987-01-01

    Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.

  17. Reduction in brain serotonin synthesis rate following chronic methamphetamine administration in rats.

    Science.gov (United States)

    Trulson, M E; Trulson, V M

    1982-09-10

    Chronic administration of methamphetamine (20 mg/kg i.p., every 12 h for 6 days) produced significant decreased in brain 5-hydroxytryptophan accumulation following decarboxylase inhibition and 5-hydroxyindoleacetic acid accumulation following probenecid treatment in rats. Administration of fluoxetine prior to each methamphetamine injection prevented these neurochemical changes. Acute methamphetamine treatment produced no changes in these neurochemical measures. These data demonstrate that chronic, but not acute, methamphetamine treatment reduces brain serotonin synthesis rate.

  18. Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin

    Science.gov (United States)

    Angoa-Pérez, Mariana; Kuhn, Donald M.

    2016-01-01

    Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960’s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior while an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that upon activation, certain receptor subtypes facilitate while some others suppress sexual behavior as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be differential in males versus females. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin as well as animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female and male

  19. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Madsen, Karine

    2010-01-01

    Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy...... is expected to increase competition from endogenous serotonin. Given radiotracer administration at a range of specific activities, we were able to use the individual BP(ND) measurements for population-based estimation of the saturation binding parameters; B(max) ranged from 0.3 to 1.6 nM. B...

  20. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Ganz-Benjaminsen, Melanie; Feng, Ling

    2017-01-01

    ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...... autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique...

  1. Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine

    DEFF Research Database (Denmark)

    Rasmussen, Hans; Ebdrup, Bjorn H; Erritzoe, David

    2011-01-01

    -episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment. Moreover, we investigated possible relationships between clinical efficacy, oral dose, and plasma levels of quetiapine RESULTS: Significant nonlinear relationships were found between serotonin2A receptor occupancy...... whereas no additional serotonin2A receptor associated treatment effect was obtained above a receptor occupancy of 70%. CONCLUSIONS: Taken together, the data point to a therapeutic role of the serotonin2A receptor in the treatment of subgroups of patients with schizophrenia. Specifically, the study...... indicates a serotonin2A receptor associated therapeutic window on positive symptoms in responding patients in the range between 60% and 70% occupancy in antipsychotic-naïve first-episode schizophrenia. We speculate that non-responding patients need higher dopamine D(2) receptor blockade. Future studies...

  2. Glucosylsphingosine Activates Serotonin Receptor 2a and 2b: Implication of a Novel Itch Signaling Pathway

    OpenAIRE

    Afzal, Ramsha; Shim, Won-Sik

    2017-01-01

    Recent reports claimed that glucosylsphingosine (GS) is highly accumulated and specifically evoking itch-scratch responses in the skins of atopic dermatitis (AD) patients. However, it was unclear how GS can trigger itch-scratch responses, since there were no known molecular singling pathways revealed yet. In the present study, it was verified for the first time that GS can activate mouse serotonin receptor 2a (mHtr2a) and 2b (mHtr2b), but not 2c (mHtr2c) that are expressed in HEK293T cells. S...

  3. Serotonin 2A receptors contribute to the regulation of risk-averse decisions

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina

    2013-01-01

    Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors...... in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were...

  4. A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans

    DEFF Research Database (Denmark)

    Erritzoe, David; Holst, Klaus; Frokjaer, Vibe G.

    2010-01-01

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT2A) receptor and the presynaptic serotonin transporter (SERT) are sensitive...

  5. Novel biochemical manipulation of brain serotonin reveals a role of serotonin in the circadian rhythm of sleep-wake cycles.

    Science.gov (United States)

    Nakamaru-Ogiso, Eiko; Miyamoto, Hiroyuki; Hamada, Kozo; Tsukada, Koji; Takai, Katsuji

    2012-06-01

    Serotonin (5-HT) neurons have been implicated in the modulation of many physiological functions, including mood regulation, feeding, and sleep. Impaired or altered 5-HT neurotransmission appears to be involved in depression and anxiety symptoms, as well as in sleep disorders. To investigate brain 5-HT functions in sleep, we induced 5-HT deficiency through acute tryptophan depletion in rats by intraperitoneally injecting a tryptophan-degrading enzyme called tryptophan side chain oxidase I (TSOI). After the administration of TSOI (20 units), plasma tryptophan levels selectively decreased to 1-2% of those of controls within 2 h, remained under 1% for 12-24 h, and then recovered between 72 and 96 h. Following plasma tryptophan levels, brain 5-HT levels decreased to ∼30% of the control level after 6 h, remained at this low level for 20-30 h, and returned to normal after 72 h. In contrast, brain norepinephreine and dopamine levels remained unchanged. After TSOI injection, the circadian rhythms of the sleep-wake cycle and locomotive activity were lost and broken into minute(s) ultradian alternations. The hourly slow-wave sleep (SWS) time significantly increased at night, but decreased during the day, whereas rapid eye movement sleep was significantly reduced during the day. However, daily total (cumulative) SWS time was retained at the normal level. As brain 5-HT levels gradually recovered 48 h after TSOI injection, the circadian rhythms of sleep-wake cycles and locomotive activity returned to normal. Our results suggest that 5-HT with a rapid turnover rate plays an important role in the circadian rhythm of sleep-wake cycles. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  6. Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

    Science.gov (United States)

    Barrett, Frederick S; Preller, Katrin H; Herdener, Marcus; Janata, Petr; Vollenweider, Franz X

    2017-09-28

    Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks

    DEFF Research Database (Denmark)

    Grady, Cheryl Lynn; Siebner, Hartwig R; Hornboll, Bettina

    2013-01-01

    distributed brain responses identified two brain networks with modulations of activity related to face emotion and serotonin level. The first network included the left amygdala, bilateral striatum, and fusiform gyri. During the Control session this network responded only to fearful faces; increasing serotonin...... decreased this response to fear, whereas reducing serotonin enhanced the response of this network to angry faces. The second network involved bilateral amygdala and ventrolateral prefrontal cortex, and these regions also showed increased activity to fear during the Control session. Both drug challenges...

  8. Acute melatonin and para-chloroamphetamine interactions on pineal, brain and serum serotonin levels as well as stress hormone levels.

    Science.gov (United States)

    Manzana, E J; Chen, W J; Champney, T H

    2001-08-03

    para-Chloroamphetamine, an amphetamine analog, alters serotonergic neurochemistry. In previous reports, melatonin (MEL), when administered with other amphetamine analogs, altered the decline in serotonin content produced by these analogs. The present studies assessed the effects of various doses of melatonin and p-chloroamphetamine on serotonin levels in numerous brain regions in male rats. Melatonin (10, 25 or 50 mg/kg, s.c.) and p-chloroamphetamine (3 or 5 mg/kg, s.c.) were administered and, 3 h later, brain samples and serum were collected. Serotonin levels in the serum and various regions of the brain were assayed using high-performance liquid chromatography. Melatonin in combination with a high dose of p-chloroamphetamine (5 mg/kg) produced cumulative deficits in serotonin levels in the serum. However, serotonin levels in the pineal, cortex or brain stem in all combined melatonin and p-chloroamphetamine groups were not significantly different from groups that received p-chloroamphetamine alone. Serum adrenocorticotropin (ACTH) and corticosterone levels were significantly elevated in the melatonin and p-chloroamphetamine combined groups, suggesting that animals receiving both treatments were more stressed than control animals or animals receiving melatonin or p-chloroamphetamine alone. These results indicate that melatonin does not alter p-chloroamphetamine-induced deficits in central serotonin levels. The increased serum adrenocorticotropic hormone, corticosterone and serotonin levels observed following melatonin and p-chloroamphetamine treatment suggest that this combination may have adverse peripheral effects.

  9. 5-Hydroxytryptamine (serotonin 2A receptor gene polymorphism is associated with schizophrenia

    Directory of Open Access Journals (Sweden)

    Subash Padmajeya Sujitha

    2014-01-01

    Full Text Available Background & objectives: Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. w0 e therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs at the serotonin receptor gene (5HT2A and the occurrence of the disease. Methods: Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing. The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. Results: The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311 and CC genotypes (32%, rs6313, were higher in patients (P<0.05 than in controls. The study also showed presence of G and C alleles in patients. s0 ignificant levels of linkage disequilibrium (LD were found to exist between the genotype frequencies of rs6311 and rs6313. Interpretation & conclusions: This study indicated an association between the SNPs (rs6311 and rs6313 of the serotonin receptor 5HT2A and schizophrenia. HapMap analysis revealed that in its genotype distribution, the Tamil speaking population was different from several other populations across the world, signifying the importance of such ethnicity-based studies to improve our understanding of this complex disease.

  10. Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.

    Science.gov (United States)

    Baumann, Michael H; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A; Partilla, John S; Ali, Syed F; Stockner, Thomas; Rothman, Richard B; Sandtner, Walter; Sitte, Harald H

    2014-05-01

    Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.

  11. Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks.

    Science.gov (United States)

    Grady, Cheryl L; Siebner, Hartwig R; Hornboll, Bettina; Macoveanu, Julian; Paulson, Olaf B; Knudsen, Gitte M

    2013-05-01

    Pharmacological manipulation of serotonin availability can alter the processing of facial expressions of emotion. Using a within-subject design, we measured the effect of serotonin on the brain's response to aversive face emotions with functional MRI while 20 participants judged the gender of neutral, fearful and angry faces. In three separate and counterbalanced sessions, participants received citalopram (CIT) to raise serotonin levels, underwent acute tryptophan depletion (ATD) to lower serotonin, or were studied without pharmacological challenge (Control). An analysis designed to identify distributed brain responses identified two brain networks with modulations of activity related to face emotion and serotonin level. The first network included the left amygdala, bilateral striatum, and fusiform gyri. During the Control session this network responded only to fearful faces; increasing serotonin decreased this response to fear, whereas reducing serotonin enhanced the response of this network to angry faces. The second network involved bilateral amygdala and ventrolateral prefrontal cortex, and these regions also showed increased activity to fear during the Control session. Both drug challenges enhanced the neural response of this set of regions to angry faces, relative to Control, and CIT also enhanced activity for neutral faces. The net effect of these changes in both networks was to abolish the selective response to fearful expressions. These results suggest that a normal level of serotonin is critical for maintaining a differentiated brain response to threatening face emotions. Lower serotonin leads to a broadening of a normally fear-specific response to anger, and higher levels reduce the differentiated brain response to aversive face emotions. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  12. Effects of the serotonin 1A, 2A, 2C, 3A, and 3B and serotonin transporter gene polymorphisms on the occurrence of paroxetine discontinuation syndrome.

    Science.gov (United States)

    Murata, Yusuke; Kobayashi, Daisuke; Imuta, Nanae; Haraguchi, Koichi; Ieiri, Ichiro; Nishimura, Ryoji; Koyama, Susumu; Mine, Kazunori

    2010-02-01

    Paroxetine discontinuation symptoms can at times be severe enough to reduce the quality of life. However, it is currently not possible to predict the occurrence of discontinuation syndrome before the initiation or discontinuation of paroxetine treatment. In this study, we investigated the effects of genetic polymorphisms in the serotonin 1A, 2A, 2C, 3A, and 3B receptor, the serotonin transporter, and the cytochrome P450 2D6 (CYP2D6) genes on the occurrence of paroxetine discontinuation syndrome. A consecutive series of 56 Japanese patients who had a diagnosis of major depressive or anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were treated with paroxetine. Paroxetine discontinuation syndrome was found in 35.7% of the patients by direct interview. Patients who stopped taking paroxetine abruptly experienced paroxetine discontinuation syndrome significantly more often than patients who had a tapering off of the dosage of medication. Patients who had the -1019C allele experienced paroxetine discontinuation syndrome more frequently than patients who had the -1019G homozygote (nominal P = 0.0423) of the serotonin 1A receptor gene. However, this result did not remain significant after the Bonferroni correction for multiple comparisons. The findings suggest that the abrupt stoppage of medication is a major risk factor for the occurrence of paroxetine discontinuation syndrome and that C(-1019)G polymorphism of the serotonin 1A receptor gene may be related to the occurrence of the syndrome.

  13. Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

    DEFF Research Database (Denmark)

    Yang, Kai-Chun; Stepanov, Vladimir; Martinsson, Stefan

    2017-01-01

    Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the c......Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands....... In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain...... binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high...

  14. Glucosylsphingosine Activates Serotonin Receptor 2a and 2b: Implication of a Novel Itch Signaling Pathway.

    Science.gov (United States)

    Afzal, Ramsha; Shim, Won-Sik

    2017-09-01

    Recent reports claimed that glucosylsphingosine (GS) is highly accumulated and specifically evoking itch-scratch responses in the skins of atopic dermatitis (AD) patients. However, it was unclear how GS can trigger itch-scratch responses, since there were no known molecular singling pathways revealed yet. In the present study, it was verified for the first time that GS can activate mouse serotonin receptor 2a (mHtr2a) and 2b (mHtr2b), but not 2c (mHtr2c) that are expressed in HEK293T cells. Specifically, effects of GS on all mouse serotonin receptor 2 subfamily were evaluated by calcium imaging techniques. The GS-induced intracellular calcium increase was dose-dependent, and antagonists such as ketanserin (Htr2a antagonist) and RS-127445 (Htr2b antagonist) significantly blocked the GS-induced responses. Moreover, the proposed GS-induced responses appear to be mediated by phospholipase C (PLC), since pretreatment of a PLC inhibitor U-73122 abolished the GS-induced responses. Additionally, the GS-induced calcium influx is probably mediated by endogenous TRPC ion channels in HEK293T cells, since pretreatment of SKF-96365, an inhibitor for TRPC, significantly suppressed GS-induced response. In conclusion, the present study revealed for the first time that GS can stimulate mHtr2a and mHtr2b to induce calcium influx, by utilizing PLC-dependent pathway afterwards. Considering that GS is regarded as a pruritogen in AD, the present study implicates a novel GS-induced itch signaling pathway.

  15. Narcotic drugs: effects on the serotonin biosynthetic systems of the brain.

    Science.gov (United States)

    Knapp, S; Mandell, A J

    1972-09-29

    The effects of short- and long-term administration of morphine on the activity of two measurable forms of rat brain tryptophan hydroxylase were studied. Morphine administration produced an immediate decrease and a longterm increase in the nerve ending (particulate) enzyme activity but did not change the cell body (soluble) enzyme activity. Cocaine administration demnonstrated a short-term decrcease in measurable nerve eniding enzyme activity that was due to the inhibition of the high affinity uptake (the Michaelis constant, K(m) is 10-(5) molar) of trytophan, the serotonin precursor. Cocaine did not aflect the low affinity uptake K(m) = 10-(5) molar) of tryptophan. Both the uptake of the precursor and the enizymiie activity appeared to be drug-sensitive regullatory processes in the biosynthlesis of serotonin.

  16. Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats

    Directory of Open Access Journals (Sweden)

    Gianluca Lavanco

    2018-02-01

    Full Text Available Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.

  17. The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers.

    Science.gov (United States)

    Tseng, P Y; Lee, I H; Chen, K C; Chen, P S; Chiu, N T; Yao, W J; Chu, C L; Yeh, T L; Yang, Y K

    2015-02-01

    This study was performed to investigate the association between the mid-brain serotonin transporter (SERT) availability and intelligence quotient (IQ). One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [(123)I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects' IQ using the WAIS-R. We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. This result implied that the higher the SERT binding in the mid-brain, the better the IQ in healthy participants. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  18. Serotonin & Depression

    OpenAIRE

    Axholm, Ida; Haxgart, Nina; Ranum, Kasper; Svendsen, Astrid Helmer

    2014-01-01

    350.000.000 people worldwide have a depression and 150.000 Danes are affected every year. Depresion is defined by WHO from it’s syptoms. The diagnose is given from a point system for the patient’s symptoms, for instance HAM-D scale and MADRS scale Serotonin in the brain is synthesized from L-tryptophan in the presynaptic parts of the neuron and is released into the synapse as a transmitter drug. According to the serotonin theory, the concentration of serotonin in the brain is low in depressio...

  19. Tardive dyskinesia and polymorphism of dopamine D3, serotonin 2A and 2C receptors in Russian psychiatric inpatients

    NARCIS (Netherlands)

    Al Hadithy, A. F. Y.; Ivanova, S. A.; Pechlivanoglou, P.; Semke, A.; Fedorenko, O.; Kornetova, E.; Ryadovaya, L.; Brouwers, J. R. B. J.; Bruggeman, R.; Loonen, A. J. M.

    Tardive dyskinesia (TD) is a potentially irreversible motor sideeffect occurring in about 30% of patients chronically exposed to neuroleptics. Genetic polymorphisms of dopamine D3 (DRD3), serotonin 2A (HTR2A) and 2C (HTR2C) receptors have been associated with TD. Currently, there are no

  20. Serotonin-2A homodimers are needed for signalling via both phospholipase A2 and phospholipase C in transfected CHO cells.

    Science.gov (United States)

    Iglesias, Alba; Cimadevila, Marta; Cadavid, María Isabel; Loza, María Isabel; Brea, José

    2017-04-05

    Different ligands differentially activate phospholipase A2 (PLA2) and phospholipase C (PLC) signalling pathways that are coupled to the serotonin 2A (5-HT2A) receptor, a class-A G-protein coupled receptor (GPCR). The serotonin 5-HT2A receptor has been shown to be expressed as a homodimer displaying some ligands negative cooperativity between protomers in the PLA2 signalling pathway. We hypothesized that the homodimeric complex is the minimum functional unit required for activation of the PLA2 and PLC pathways by the serotonin 5-HT2A receptor. To investigate this hypothesis, we partially blocked the serotonin 5-HT2A receptors with ritanserin and measured PLA2 and PLC activity simultaneously. We subsequently added the competitive antagonist spiperone to release the inactivator through a crosstalk mechanism and thus allow the dimer to return to a reactive state. Partial inactivation of the homodimer by ritanserin binding decreased the activity of the receptor by 59±13% and 70±4% in the PLA2 and PLC pathways respectively (Pserotonin (5-HT) was observed. The subsequent binding of spiperone released ritanserin due to the crosstalk between protomers and recovery of the receptor activity to 74±7% and 72±4%. Negative cooperativity between protomers in the dimer was maintained during arachidonic acid (AA) release after blocking ritanserin, as indicated by the biphasic inhibition curves for clozapine over 1μM serotonin (5-HT) in these conditions. These findings provide evidence that serotonin 5-HT2A receptors must be expressed as homodimers in order to activate both the PLA2 and PLC signalling pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Central serotonin depletion affects rat brain areas differently: a qualitative and quantitative comparison between different treatment schemes

    DEFF Research Database (Denmark)

    Kornum, Birgitte Rahbek; Licht, Cecilie Löe; Weikop, Pia

    2006-01-01

    Depletion of rat brain serotonin (5-hydroxytryptamin, 5-HT) has been widely used to study effects of serotonin and its interaction with other transmitter systems. Various treatment regimes for serotonin depletion have been applied, but the efficacy of these seems to vary considerably. So far...... and tyrosine hydroxylase immunocytochemistry. The schemes included repeated administration of fenfluramine (FEN) and/or p-chlorophenylalanine (pCPA). The most efficient treatment for rat brain 5-HT depletion was the combined treatment with one daily pCPA (200 mg/kg) injection for 3 days followed by one...... injection of d,l-FEN (20 mg/kg) on the fourth day, causing a 94.9% brain 5-HT depletion. Immunostaining revealed a distinct brain distribution of the remaining 5-HT, with an almost complete depletion of 5-HT in the cerebral cortex, hippocampus and thalamus, while a substantial amount of 5-HT still was left...

  2. Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.

    Science.gov (United States)

    Csaba, G; Knippel, Barbara; Karabélyos, Cs; Inczefi-Gonda, Agnes; Hantos, Mónika; Tóthfalusi, L; Tekes, Kornélia

    2004-07-09

    Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

  3. Effects of sugar rich diet on brain serotonin, hyperphagia and anxiety in animal model of both genders.

    Science.gov (United States)

    Inam, Qurrat-ul-Aen; Ikram, Huma; Shireen, Erum; Haleem, Darakhshan Jabeen

    2016-05-01

    Lower levels of 5-hydroxytryptamine (5-HT; serotonin) in the brain elicit sugar craving, while ingestion of sugar rich diet improves mood and alleviates anxiety. Gender differences occur not only in brain serotonin metabolism but also in a serotonin mediated functional responses. The present study was therefore designed to investigate gender related differences on the effects of long term consumption of sugar rich diet on the metabolism of serotonin in the hypothalamus and whole brain which may be relevant with the hyperphagic and anxiety reducing effects of sugar rich diet. Male and female rats were fed freely on a sugar rich diet for five weeks. Hyperphagic effects were monitored by measuring total food intake and body weights changes during the intervention. Anxiolytic effects of sugar rich diet was monitored in light-dark transition test. The results show that ingestion of sugar rich diet decreased serotonin metabolism more in female than male rats. Anxiolytic effects were elicited only in male rats. Hyperphagia was comparable in both male and female rats. Finings would help in understanding the role of sugar rich diet-induced greater decreases of serotonin in sweet craving in women during stress.

  4. Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.

    Science.gov (United States)

    Gresch, Paul J; Smith, Randy L; Barrett, Robert J; Sanders-Bush, Elaine

    2005-09-01

    Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance

  5. Brain Serotonin Receptors and Transporters: Initiation vs. Termination of Escalated Aggression

    Science.gov (United States)

    Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

    2013-01-01

    Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment. PMID:20938650

  6. Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin.

    Directory of Open Access Journals (Sweden)

    Barbara Pelosi

    Full Text Available Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84-178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2null/null mice

  7. Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin

    Science.gov (United States)

    Migliarini, Sara; Pacini, Giulia; Pasqualetti, Massimo

    2015-01-01

    Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84–178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2null/null mice. Finally, we set up

  8. Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation.

    Science.gov (United States)

    Kraehenmann, Rainer; Pokorny, Dan; Vollenweider, Leonie; Preller, Katrin H; Pokorny, Thomas; Seifritz, Erich; Vollenweider, Franz X

    2017-07-01

    Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. LSD, compared with placebo, significantly increased cognitive bizarreness (p LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.

  9. New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.

    Directory of Open Access Journals (Sweden)

    Ibrahim M Shokry

    Full Text Available In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP, intracerebroventricular (ICV and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible

  10. Neocortical serotonin2A receptor binding predicts quetiapine associated weight gain in antipsychotic-naive first-episode schizophrenia patients

    DEFF Research Database (Denmark)

    Rasmussen, Hans; Ebdrup, Bjørn H; Oranje, B

    2014-01-01

    binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean...

  11. [Determination of serotonin in rat brain microdialysate after i. p. administration of fluoxetine hydrochloride by high performance liquid chromatography].

    Science.gov (United States)

    Guo, Yunzhen; Yu, Li; Ma, Zheng; Guo, Xingjie

    2007-03-01

    The concentration of serotonin (5-HT) in rat brain microdialysate before and after i. p. administration of fluoxetine hydrochloride was determined through precolumn derivatization by reversed-phase high performance liquid chromatography (RP-HPLC). A baseline separation of serotonin was achieved on a Hypersil C18 column (250 mm x 2. 0 mm, 5 microm) with acetonitrile-20 mmol/L sodium acetic solution (pH 5. 0) (45: 55, v/v) containing 20 mmol/L of sodium octanesulfonate as the mobile phase. Fluorescence detection with the excitation wavelength at 330 nm and emission wavelength at 455 nm was used for serotonin. There was good linear relationship between the peak area and concentration in the range of 0. 25 - 5. 0 nmol/L( r =0. 999 1). The limit of quantitation was 0. 25 nmol/L. The method is simple, accurate and can be applied to the determination of serotonin in biological specimen.

  12. LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

    Directory of Open Access Journals (Sweden)

    Rainer Kraehenmann

    2017-11-01

    Full Text Available Rationale: Stimulation of serotonin 2A (5-HT2A receptors by lysergic acid diethylamide (LSD and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects.Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally. The main outcome variable in this study was primary index (PI, a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC rating scale.Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected. The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected, and blissful state (p < 0.05, Bonferroni-corrected on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin.Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and

  13. LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation.

    Science.gov (United States)

    Kraehenmann, Rainer; Pokorny, Dan; Aicher, Helena; Preller, Katrin H; Pokorny, Thomas; Bosch, Oliver G; Seifritz, Erich; Vollenweider, Franz X

    2017-01-01

    Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking - an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale. Results: LSD, compared with placebo, significantly increased primary index (p primary index was positively correlated with LSD-induced disembodiment (p primary index and changes in state of consciousness were fully blocked by ketanserin. Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.

  14. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis

    Directory of Open Access Journals (Sweden)

    Trisha A. Jenkins

    2016-01-01

    Full Text Available The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis.

  15. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis.

    Science.gov (United States)

    Jenkins, Trisha A; Nguyen, Jason C D; Polglaze, Kate E; Bertrand, Paul P

    2016-01-20

    The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis.

  16. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis

    Science.gov (United States)

    Jenkins, Trisha A.; Nguyen, Jason C. D.; Polglaze, Kate E.; Bertrand, Paul P.

    2016-01-01

    The serotonergic system forms a diffuse network within the central nervous system and plays a significant role in the regulation of mood and cognition. Manipulation of tryptophan levels, acutely or chronically, by depletion or supplementation, is an experimental procedure for modifying peripheral and central serotonin levels. These studies have allowed us to establish the role of serotonin in higher order brain function in both preclinical and clinical situations and have precipitated the finding that low brain serotonin levels are associated with poor memory and depressed mood. The gut-brain axis is a bi-directional system between the brain and gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral functioning of the digestive tract. An influence of gut microbiota on behaviour is becoming increasingly evident, as is the extension to tryptophan and serotonin, producing a possibility that alterations in the gut may be important in the pathophysiology of human central nervous system disorders. In this review we will discuss the effect of manipulating tryptophan on mood and cognition, and discuss a possible influence of the gut-brain axis. PMID:26805875

  17. Spatial cluster analysis of nanoscopically mapped serotonin receptors for classification of fixed brain tissue

    Science.gov (United States)

    Sams, Michael; Silye, Rene; Göhring, Janett; Muresan, Leila; Schilcher, Kurt; Jacak, Jaroslaw

    2014-01-01

    We present a cluster spatial analysis method using nanoscopic dSTORM images to determine changes in protein cluster distributions within brain tissue. Such methods are suitable to investigate human brain tissue and will help to achieve a deeper understanding of brain disease along with aiding drug development. Human brain tissue samples are usually treated postmortem via standard fixation protocols, which are established in clinical laboratories. Therefore, our localization microscopy-based method was adapted to characterize protein density and protein cluster localization in samples fixed using different protocols followed by common fluorescent immunohistochemistry techniques. The localization microscopy allows nanoscopic mapping of serotonin 5-HT1A receptor groups within a two-dimensional image of a brain tissue slice. These nanoscopically mapped proteins can be confined to clusters by applying the proposed statistical spatial analysis. Selected features of such clusters were subsequently used to characterize and classify the tissue. Samples were obtained from different types of patients, fixed with different preparation methods, and finally stored in a human tissue bank. To verify the proposed method, samples of a cryopreserved healthy brain have been compared with epitope-retrieved and paraffin-fixed tissues. Furthermore, samples of healthy brain tissues were compared with data obtained from patients suffering from mental illnesses (e.g., major depressive disorder). Our work demonstrates the applicability of localization microscopy and image analysis methods for comparison and classification of human brain tissues at a nanoscopic level. Furthermore, the presented workflow marks a unique technological advance in the characterization of protein distributions in brain tissue sections.

  18. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

    Directory of Open Access Journals (Sweden)

    Janušonis Skirmantas

    2005-07-01

    Full Text Available Abstract Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin in blood platelets (platelet hyperserotonemia. The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene based on currently available clinical and

  19. The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease.

    Science.gov (United States)

    Pawlak, Dariusz; Domaniewski, Tomasz; Znorko, Beata; Oksztulska-Kolanek, Ewa; Lipowicz, Paweł; Doroszko, Michał; Karbowska, Malgorzata; Pawlak, Krystyna

    2017-12-01

    Chronic kidney disease (CKD) results in decreased bone strength. Serotonin (5-HT) is one of the critical regulators of bone health, fulfilling distinct functions depending on its synthesis site: brain-derived serotonin (BDS) favors osteoblast proliferation, whereas gut-derived serotonin (GDS) inhibits it. We assessed the role of BDS and peripheral leptin in the regulation of bone metabolism and strength in young rats with 5/6 nephrectomy. BDS synthesis was accelerated during CKD progression. Decreased peripheral leptin in CKD rats was inversely related to BDS content in the hypothalamus, brainstem and frontal cortex. Serotonin in these brain regions affected bone strength and metabolism in the studied animals. The direct effect of circulating leptin on bone was not shown in uremia. At the molecular level, there was an inverse association between elevated GDS and the expression of cAMP responsive element-binding protein (Creb) gene in bone of CKD animals. In contrast, increased expression of activating transcription factor 4 (Atf4) was shown, which was associated with GDS-dependent transcription factor 1 (Foxo1), clock gene - Cry-1, cell cycle genes: c-Myc, cyclins, and osteoblast differentiation genes. These results identified a previously unknown molecular pathway, by which elevated GDS can shift in Foxo1 target genes from Creb to Atf4-dependent response, disrupting the leptin-BDS - dependent gene pathway in the bone of uremic rats. Thus, in the condition of CKD the effect of BDS and GDS on bone metabolism and strength can't be distinguished. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing.

    Science.gov (United States)

    Preller, Katrin H; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X

    2016-05-03

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

  1. Polymorphism in the serotonin receptor 2a (HTR2A) gene as possible predisposal factor for aggressive traits.

    Science.gov (United States)

    Banlaki, Zsofia; Elek, Zsuzsanna; Nanasi, Tibor; Szekely, Anna; Nemoda, Zsofia; Sasvari-Szekely, Maria; Ronai, Zsolt

    2015-01-01

    Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP) were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ). Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007) both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits.

  2. Polymorphism in the serotonin receptor 2a (HTR2A gene as possible predisposal factor for aggressive traits.

    Directory of Open Access Journals (Sweden)

    Zsofia Banlaki

    Full Text Available Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ. Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007 both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits.

  3. Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

    Directory of Open Access Journals (Sweden)

    Lise Gutknecht

    Full Text Available Brain serotonin (5-HT is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2. Tph2 inactivation (Tph2-/- resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT(1A and 5-HT(1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.

  4. SIMULTANEOUS MEASUREMENT OF EXTRACELLULAR MORPHINE AND SEROTONIN IN BRAIN-TISSUE AND CSF BY MICRODIALYSIS IN AWAKE RATS

    NARCIS (Netherlands)

    MATOS, FF; ROLLEMA, H; BASBAUM, AI

    In this report, we describe an HPLC with electrochemical detection assay for the simultaneous measurement of levels of morphine, serotonin, 5-hydroxyindole-3-acetic acid, and homovanillic acid in dialysates of various brain areas and CSF in the awake rat. Morphine could be detected in the dialysates

  5. Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

    Science.gov (United States)

    Rao, Hengyi; Gillihan, Seth J; Wang, Jiongjiong; Korczykowski, Marc; Sankoorikal, Geena Mary V; Kaercher, Kristin A; Brodkin, Edward S; Detre, John A; Farah, Martha J

    2007-09-15

    Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.

  6. [Association between dopamine (DRD2) and serotonin (5HTR2A) gene polymorphisms with the indicators of adolescent behavior adaptiveness].

    Science.gov (United States)

    Barskiĭ, V I; Aksenova, M G; Kozlova, O B; Kirillov, A V; Demin, A A; Il'inykh, L M

    2010-01-01

    The paper gives the results of a study of the impact of dopamine (DRD2) and serotonin (5HTR2A) genes on the development of personality characteristics in adolescents, by applying the Cattell (16PF) questionnaire. The study was performed in a group of 360 Moscow teenagers (185 girls and 175 boys) aged 14-17 years. The boys carrying the A1 allelle of the DRD2 gene were found to have a lower self-control, indiscipline, and impulsiveness. An association between the indicators of unconscientiousness, social introversion, and group independence was established in the girls with the G/G genotype of the 5HTR2A gene. Thus, gender differences have been revealed from the impact of dopamine and serotonin gene polymorphisms on the teenagers' personality characteristics that characterize the forms of disadaptive behavior, such as unconscientiousness, indiscipline, low self-control, and impulsiveness.

  7. Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder.

    Science.gov (United States)

    Soloff, Paul H; Chiappetta, Laurel; Mason, Neale Scott; Becker, Carl; Price, Julie C

    2014-06-30

    Impulsivity and aggressiveness are personality traits associated with a vulnerability to suicidal behavior. Behavioral expression of these traits differs by gender and has been related to central serotonergic function. We assessed the relationships between serotonin-2A receptor function, gender, and personality traits in borderline personality disorder (BPD), a disorder characterized by impulsive-aggression and recurrent suicidal behavior. Participants, who included 33 BPD patients and 27 healthy controls (HC), were assessed for Axis I and II disorders with the Structured Clinical Interview for DSM-IV and the International Personality Disorders Examination, and with the Diagnostic Interview for Borderline Patients-Revised for BPD. Depressed mood, impulsivity, aggression, and temperament were assessed with standardized measures. Positron emission tomography with [(18)F]altanserin as ligand and arterial blood sampling was used to determine the binding potentials (BPND) of serotonin-2A receptors in 11 regions of interest. Data were analyzed using Logan graphical analysis, controlling for age and non-specific binding. Among BPD subjects, aggression, Cluster B co-morbidity, antisocial PD, and childhood abuse were each related to altanserin binding. BPND values predicted impulsivity and aggression in BPD females (but not BPD males), and in HC males (but not HC females.) Altanserin binding was greater in BPD females than males in every contrast, but it did not discriminate suicide attempters from non-attempters. Region-specific differences in serotonin-2A receptor binding related to diagnosis and gender predicted clinical expression of aggression and impulsivity. Vulnerability to suicidal behavior in BPD may be related to serotonin-2A binding through expression of personality risk factors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. The serotonin receptor 7 and the structural plasticity of brain circuits

    Directory of Open Access Journals (Sweden)

    Floriana eVolpicelli

    2014-09-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT modulates numerous physiological processes in the nervous system. Together with its function as neurotrasmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration.

  9. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.

    Science.gov (United States)

    Bonnin, A; Levitt, P

    2011-12-01

    In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Robust upregulation of serotonin 2A receptors after chronic spinal transection of rats: An immunohistochemical study

    DEFF Research Database (Denmark)

    Kong, Xiang-Yu; Wienecke, Jacob; Hultborn, Hans

    2010-01-01

    It is well known that spinal motoneurons below a spinal transection become supersensitive to a systemic administration of serotonin (5-HT) precursors, such as 5-hydroxytryptophan. This supersensitivity has been implicated in both the process of functional recovery following chronic lesions, and a...

  11. Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons

    NARCIS (Netherlands)

    Reneman, L.; Booij, J.; de Bruin, K.; Reitsma, J. B.; de Wolff, F. A.; Gunning, W. B.; den Heeten, G. J.; van den Brink, W.

    2001-01-01

    BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to damage brain serotonin neurons in high doses. However, effects of moderate MDMA use on serotonin neurons have not been studied, and sex differences and the long-term effects of MDMA

  12. Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    1999-08-05

    Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation. Copyright 1999 Elsevier Science B.V.

  13. Central Serotonin-2A (5-HT2A Receptor Dysfunction in Depression and Epilepsy: The Missing Link?

    Directory of Open Access Journals (Sweden)

    Bruno Pierre Guiard

    2015-03-01

    Full Text Available 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

  14. Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

    Science.gov (United States)

    Banerjee, S; Poddar, M K

    2016-04-05

    Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Csaba, G; Knippel, Barbara; Karabélyos, Cs; Inczefi-Gonda, Agnes; Hantos, Monika; Tóthfalusi, L; Tekes, Kornélia

    2003-05-23

    A single dose (3 microg) beta-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.

  16. A validated HPLC-UV method and optimization of sample preparation technique for norepinephrine and serotonin in mouse brain.

    Science.gov (United States)

    Thomas, Jaya; Khanam, Razia; Vohora, Divya

    2015-01-01

    Norepinephrine and serotonin are two important neurotransmitters whose variations in brain are reported to be associated with many common neuropsychiatric disorders. Yet, relevant literature on estimation of monoamines in biological samples using HPLC-UV is limited. The present study involves the development of a simultaneous HPLC-UV method for estimation of norepinephrine and serotonin along with optimization of the sample preparation technique. Chromatographic separation was achieved by injecting 20 µL of the sample after extraction into Quaternary pump HPLC equipped with C18 column using 0.05% formic acid and acetonitrile (90:10, v/v) as the mobile phase with 1 mL min(-1) flow rate. The developed method was validated as per the ICH guidelines in terms of linearity, accuracy, repeatability, precision, and robustness. The method showed a wide range of linearity (50-4000 and 31.25-4000 ng mL(-1) for norepinephrine and serotonin, respectively). The recovery was found to be in the range of 86.04-89.01% and 86.43-89.61% for norepinephrine and serotonin, respectively. The results showed low value of %RSD for repeatability, intra and inter-day precision, and robustness studies. Four different methods were used for the extraction of these neurotransmitters and the best one with maximum recovery was ascertained. Here, we developed and validated a simple, accurate, and reliable method for the estimation of norepinephrine and serotonin in mice brain samples using HPLC-UV. The method was successfully applied to quantify these neurotransmitters in mice brain extracted by optimized sample preparation technique.

  17. Serotonin: A mediator of the gut-brain axis in multiple sclerosis.

    Science.gov (United States)

    Malinova, Tsveta S; Dijkstra, Christine D; de Vries, Helga E

    2017-11-01

    The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a microbial-modulated neurotransmitter (NT) as a showcase to demonstrate that NTs regulated by the gut microbiome are potent candidates for mediators of the gut-brain axis in demyelinating disorders. Methods, Results, and Conclusion: Our comprehensive overview of literature provides evidence that 5-HT levels in the gut are controlled by the microbiome, both via secretion and through regulation of metabolites. In addition, we demonstrate that the gut microbiome can influence the formation of the serotonergic system (SS) in the brain. We also show that SS alterations have been related to MS directly-altered expression of 5-HT transporters in central nervous system (CNS) and indirectly-beneficial effects of 5-HT modulating drugs on the course of the disease and higher prevalence of depression in patients with MS. Finally, we discuss briefly the role of other microbiome-modulated NTs such as γ-aminobutyric acid and dopamine in MS to highlight a new direction for future research aiming to relate microbiome-regulated NTs to demyelinating disorders.

  18. [Spatial memory and regulation of brain adenylyl cyclase by serotonin and dopamine in rat with streptozotocin diabetes].

    Science.gov (United States)

    Sukhov, I B; Chistyakova, O V; Shipilov, V N; Doilnitsyn, A M; Shpakov, A O

    2015-03-01

    The most common complication of diabetes mellitus of the type 1 (DM1) is a cognitive deficiency, which develops as a result of neurodegenerative changes in the brain. The aim of this work was to study the learning and spatial memory in rats with streptozotocin DM1 with different duration (1.5 and 6 months), as well as the activity of adenylyl cyclase signaling system (ACSS) sensitive to agonists of the serotonin and the dopamine receptors in the brain of diabetic rats. Our experiments demonstrated that rats with 1.5-months DM1 has no changes in spatial memory which were evaluated in a Morris water maze whereas in rats with 6-months DM1 the spatial memory and learning ability were decreased. The alterations of the regulation of adenylyl cyclase by agonists of types 1 and 6 serotonin receptors and type 2 dopamine receptors were found in both the 1.5- and 6-months DM1 which indicates their importance in the development of cognitive deficiency. Abnormalities in the. brain ACSS can be considered as key factors in the etiology and pathogenesis of cognitive dysfunctions in DM1. Hypothesized that cognitive deficiency occurs only in the later stages of DM1 due to alterations in the serotonin and dopamine signaling systems of the brain.

  19. Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats.

    Science.gov (United States)

    Zhang, Erquan; Maruyama, Junko; Yokochi, Ayumu; Mitani, Yoshihide; Sawada, Hirofumi; Nishikawa, Masakatsu; Ma, Ning; Maruyama, Kazuo

    2015-10-01

    The purpose of the present study was to determine if sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling. Forty-one male Sprague-Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day -2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n = 9) for lung tissue were performed. Chronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p pulmonary arteries from chronic hypoxic rats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxic rats. The administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes.

  20. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon.

    Science.gov (United States)

    Stemme, Torben; Iliffe, Thomas M; Bicker, Gerd; Harzsch, Steffen; Koenemann, Stefan

    2012-09-05

    Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin) combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral olfactory neuropils with a glomerular organization

  1. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon

    Directory of Open Access Journals (Sweden)

    Stemme Torben

    2012-09-01

    Full Text Available Abstract Background Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. Results The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. Conclusions The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral

  2. SPECT imaging with the serotonin transporter radiotracer [{sup 123}I]p ZIENT in nonhuman primate brain

    Energy Technology Data Exchange (ETDEWEB)

    Cosgrove, Kelly P., E-mail: kelly.cosgrove@yale.ed [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Staley, Julie K.; Baldwin, Ronald M.; Bois, Frederic [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Plisson, Christophe [Emory University School of Medicine, Atlanta, GA 30322 (United States); Al-Tikriti, Mohammed S. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Seibyl, John P. [Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States); Goodman, Mark M. [Emory University School of Medicine, Atlanta, GA 30322 (United States); Tamagnan, Gilles D. [Yale University School of Medicine, VA Connecticut HCS (116A6), West Haven, CT 06516 (United States); Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States)

    2010-07-15

    Introduction: Serotonin dysfunction has been linked to a variety of psychiatric diseases; however, an adequate SPECT radioligand to probe the serotonin transporter system has not been successfully developed. The purpose of this study was to characterize and determine the in vivo selectivity of iodine-123-labeled 2{beta}-carbomethoxy-3{beta}-(4'-((Z)-2-iodoethenyl)phenyl)nortropane, [{sup 123}I]p ZIENT, in nonhuman primate brain. Methods: Two ovariohysterectomized female baboons participated in nine studies (one bolus and eight bolus to constant infusion at a ratio of 9.0 h) to evaluate [{sup 123}I]p ZIENT. To evaluate the selectivity of [{sup 123}I]p ZIENT, the serotonin transporter blockers fenfluramine (1.5, 2.5 mg/kg) and citalopram (5 mg/kg), the dopamine transporter blocker methylphenidate (0.5 mg/kg) and the norepinephrine transporter blocker nisoxetine (1 mg/kg) were given at 8 h post-radiotracer injection. Results: In the bolus to constant infusion studies, equilibrium was established by 4-8 h. [{sup 123}I]p ZIENT was 93% and 90% protein bound in the two baboons and there was no detection of lipophilic radiolabeled metabolites entering the brain. In the high-density serotonin transporter regions (diencephalon and brainstem), fenfluramine and citalopram resulted in 35-71% and 129-151% displacement, respectively, whereas methylphenidate and nisoxetine did not produce significant changes (<10%). Conclusion: These findings suggest that [{sup 123}I]p ZIENT is a favorable compound for in vivo SPECT imaging of serotonin transporters with negligible binding to norepinephrine and dopamine transporters.

  3. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kring, Sofia I I; Werge, Thomas; Holst, Claus

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these......BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs......) of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2)) and a randomly selected group (n = 831) were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49......). Anthropometric, physiological and biochemical measures were available. Logistic regression analyses were used to assess age-adjusted odds ratios. No significant associations were observed of 5HT2A rs6311, 5HT2C rs3813929 and COMT rs4680 with obesity, except that COMT rs4680 GG-genotype was associated with fat...

  4. Circannual variations in the binding of [3H]lysergic acid diethylamide to serotonin2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers.

    Science.gov (United States)

    Spigset, O; Allard, P; Mjörndal, T

    1998-05-15

    Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.

  5. Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort.

    Science.gov (United States)

    Tuominen, L; Salo, J; Hirvonen, J; Någren, K; Laine, P; Melartin, T; Isometsä, E; Viikari, J; Cloninger, C R; Raitakari, O; Hietala, J; Keltikangas-Järvinen, L

    2013-04-01

    The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT) density in vivo with positron emission tomography (PET) in healthy individuals with high or low HA scores using an 'oversampling' study design. Method Subjects consistently in either upper or lower quartiles for the HA trait were selected from a population-based cohort in Finland (n = 2075) with pre-existing Temperament and Character Inventory (TCI) scores. A total of 22 subjects free of psychiatric and somatic disorders were included in the matched high- and low-HA groups. The main outcome measure was regional 5-HTT binding potential (BPND) in high- and low-HA groups estimated with PET and [11C]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ([11C]MADAM). In secondary analyses, 5-HTT BPND was correlated with other TCI dimensions. 5-HTT BPND did not differ between high- and low-HA groups in the midbrain or any other brain region. This result remained the same even after adjusting for other relevant TCI dimensions. Higher 5-HTT BPND in the raphe nucleus predicted higher scores in 'self-directedness'. This study does not support an association between the temperament dimension HA and serotonin transporter density in healthy subjects. However, we found a link between high serotonin transporter density and high 'self-directedness' (ability to adapt and control one's behaviour to fit situations in accord with chosen goals and values). We suggest that biological factors are more important in explaining variability in character than previously thought.

  6. In vivo regulation of the serotonin-2 receptor in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Stockmeier, C.A.; Kellar, K.J.

    1986-01-13

    Serotonin-2 (5-HT-2) receptors in brain were measured using (/sup 3/H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on (/sup 3/H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC/sub 50/ nor the Hill coefficient of 5-HT in competing for (/sup 3/H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of (/sup 3/H)5-HT or (/sup 3/H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables.

  7. Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

    Science.gov (United States)

    Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

    2015-11-01

    A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

  8. Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome.

    Science.gov (United States)

    Valenti, Daniela; de Bari, Lidia; Vigli, Daniele; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Vacca, Rosa Anna; De Filippis, Bianca

    2017-07-15

    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder. Copyright © 2017. Published by Elsevier Ltd.

  9. Effect of selected anti-malarial drugs on the blood chemistry and brain serotonin levels in male rabbits.

    Science.gov (United States)

    Eigbibhalu, Ukpo Grace; Albert Taiwo, Ebuehi Osaretin; Douglass, Idiakheua Akhabue; Abimbola, Efunogbon Aderonke

    2013-01-01

    The effects of oral administration of sulfadoxine - pyrimethamine (SP), artesunate (A) and sulfadoxine - pyrimethamine - artesunate (SPA) on blood chemistry and brain serotonin in rabbits were investigated. Forty rabbits were divided into four groups of ten animals each. The group that served as the control received 2ml of distilled water while the other groups were received 1.25/25mg base/kg body weight of SP, 3.3mg/kg body weight of A and 1.25/25mg base/kg body weight of SP plus 3.3mg/kg body weight of A respectively by oral route daily for 3 days in a week for four weeks. At the end of each week of drug administration, three rabbits from each group were anaesthetized, blood was taken from the jugular veins using sterile needle and serum was extracted. The rabbits were sacrificed by decapitation; the liver and brain tissues were excised and homogenized. Total blood protein, cholesterol, triglyceride, albumin, creatinine and urea concentrations, creatine kinase, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, ALP activities were assayed using CX5 synchron autoanalyzer. The brain and liver serotonin levels were determined using high performance liquid chromatography (HPLC). There were no significant differences (P levels of rabbits administered SP, A and SPA were significantly higher as compared to the control throughout the duration of the study Data of the study indicate that oral administration of SP, A or SPA in rabbits do not affect blood chemistry, but affected brain serotonin levels and could alter some neural functions.

  10. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

    DEFF Research Database (Denmark)

    Mc Mahon, Brenda; Andersen, Sofie B.; Madsen, Martin K.

    2016-01-01

    Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data...... between summer and winter (Pserotonin transporter was sex-(P = 0.02) and genotype-(P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom...... severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure...

  11. Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice.

    Science.gov (United States)

    Waider, J; Popp, S; Lange, M D; Kern, R; Kolter, J F; Kobler, J; Donner, N C; Lowe, K R; Malzbender, J H; Brazell, C J; Arnold, M R; Aboagye, B; Schmitt-Böhrer, A; Lowry, C A; Pape, H C; Lesch, K P

    2017-10-03

    Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2(-/-)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph(+/)(-)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.

  12. Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

    Directory of Open Access Journals (Sweden)

    C.H.A. Schwanke

    2007-10-01

    Full Text Available The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 ± 6.35 years (60-100 years, with 16.9% males and 83.1% females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78%, the CT genotype frequency was 55.24% and the TT genotype frequency was 22.98%. We found an independent significant association between the TT genotype (35.7% and urinary incontinence (OR = 2.06, 95%CI = 1.16-3.65. Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.

  13. Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

    Directory of Open Access Journals (Sweden)

    C.H.A. Schwanke

    Full Text Available The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 ± 6.35 years (60-100 years, with 16.9% males and 83.1% females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78%, the CT genotype frequency was 55.24% and the TT genotype frequency was 22.98%. We found an independent significant association between the TT genotype (35.7% and urinary incontinence (OR = 2.06, 95%CI = 1.16-3.65. Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.

  14. A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

    Science.gov (United States)

    Dolder, Patrick C.; Grünblatt, Edna; Müller, Felix; Borgwardt, Stefan J.; Liechti, Matthias E.

    2017-01-01

    Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans. PMID:28701958

  15. Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures.

    Science.gov (United States)

    Pelliccioni, P; Gil, C; Najib, A; Sarri, E; Picatoste, F; Aguilera, J

    2001-12-01

    As has been previously described, tetanus toxin (TeTx) and its H(C) fragment inhibit the sodium-dependent 5-hydroxytryptamine (5-HT) uptake in rat-brain synaptosomes, probably through a kinase mechanism affecting the 5-HT transporter. Now, the inhibition of 5-HT uptake in neurons in primary culture by TeTx in a dose-dependent manner is described in this work. This effect is also produced by the nontoxic C-terminal fragment of the TeTx heavy chain (H(C)-fragment), indicating that 5-HT uptake inhibition is a consequence of the toxin binding to the plasmatic membrane and not to its catalytic activity. This conclusion is supported by the fact that the 5-HT accumulation was not inhibited by the light chain of TeTx or the toxoid, and was even potentiated by botulinum neurotoxin A. These results correlate with the activation of phosphoinositide-phospholipase C activity in the cultures used in this study, this activity only being enhanced by TeTx and by its Hc-fragment. On the other hand, the use of tyrosine phosphorylation modulators indicates that both Na3VO4 and basic fibroblast growth factor (bFGF) produce an enhancement of 5-HT uptake in this system, which is also sensitive to TeTx inhibition. On the other hand, genistein alone is able to reduce the 5-HT transport in cultured neurons, and this effect did not appear to be additive to that elicited by TeTx. This result suggests that TeTx and genistein may share some events in their respective mechanisms of action. Furthermore, the incubation at different concentrations of 12-O-tetradecanoylphorbol 13-acetate (TPA) confirms the involvement of protein kinase C (PKC) in 5-HT transport modulation in rat-brain neuronal primary cultures. In summary, we shall demonstrate in this work that TeTx induces, through its Hc fragment, an inhibition of both basal and stimulated serotonin uptakes in primary neuronal cultures, in parallel to the activation of phosphoinositide-phospholipase C activity and PKC activation.

  16. Binding of [(3)H]lysergic acid diethylamide to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites in platelets from healthy children, adolescents and adults.

    Science.gov (United States)

    Sigurdh, J; Spigset, O; Allard, P; Mjörndal, T; Hägglöf, B

    1999-11-01

    Possible age effects on binding of [(3)H]lysergic acid diethylamide ([(3)H]LSD) to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites were studied in platelets from healthy children (11-12 years of age), adolescents (16-17 years of age) and adults. Significant overall age effects were found both for the number of binding sites (B(max)) for [(3)H]LSD binding (p < 0.001), the affinity constant (K(d)) for [(3)H]LSD binding (p < 0.001), B(max) for [(3)H]paroxetine binding (p < 0.001) and K(d) for [(3)H] paroxetine binding (p = 0.006). In general, there was a decrease in B(max) with increasing age, which predominantly occurred between the ages 11-12 years and 16-17 years for the 5-HT(2A) receptor, and after 16-17 years of age for the serotonin uptake site. These developmental changes might have an impact on the effect of treatment with serotonergic drugs in children and adolescents. When the platelet serotonin variables investigated are employed in studies in children or adolescents, age matching or, alternatively, introduction of age control in the statistical analysis should be performed.

  17. Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

    Science.gov (United States)

    Gadow, Kenneth D; Smith, Ryan M; Pinsonneault, Julia K

    2014-06-01

    Our aim was to characterize the association of 2 functional single nucleotide polymorphisms (rs6311 and rs6314) in the serotonin 2A receptor gene (HTR2A) with severity of depression symptoms in children with autism spectrum disorder. These polymorphisms have been shown to be associated with depression symptom severity and response to selective serotonin reuptake inhibitor drugs in adults with diagnosed depressive disorder. Parents of 104 children with autism spectrum disorder rated their children's depressive symptoms using a validated scale based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. We compared severity of depression symptoms across the rs6311 and rs6314 genotypes, measured from the children's genomic DNA. Children homozygous for the G allele of rs6311 had significantly more severe depression symptoms than those with G/A or A/A genotypes (P=0.025). The effect size (partial eta-squared) was small (ηp=0.047) but was somewhat larger when we controlled for severity of generalized anxiety disorder symptoms (P=0.006, ηp=0.072). When we restricted our analyses to white participants, our results were essentially the same as for the entire sample (P=0.004, ηp=0.086). There was no significant association between rs6314 (C/C versus T carriers) and severity of depression. Our findings suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. These tentative, hypothesis-generating findings need replication with larger, independent samples.

  18. Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation

    DEFF Research Database (Denmark)

    Santini, Martin; Klein, A B; El-Sayed, M

    2011-01-01

    Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT(2A...

  19. Description and validation of a dynamical systems model of presynaptic serotonin function: genetic variation, brain activation and impulsivity.

    Science.gov (United States)

    Stoltenberg, Scott F; Nag, Parthasarathi

    2010-03-01

    Despite more than a decade of empirical work on the role of genetic polymorphisms in the serotonin system on behavior, the details across levels of analysis are not well understood. We describe a mathematical model of the genetic control of presynaptic serotonergic function that is based on control theory, implemented using systems of differential equations, and focused on better characterizing pathways from genes to behavior. We present the results of model validation tests that include the comparison of simulation outcomes with empirical data on genetic effects on brain response to affective stimuli and on impulsivity. Patterns of simulated neural firing were consistent with recent findings of additive effects of serotonin transporter and tryptophan hydroxylase-2 polymorphisms on brain activation. In addition, simulated levels of cerebral spinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) were negatively correlated with Barratt Impulsiveness Scale (Version 11) Total scores in college students (r = -.22, p = .002, N = 187), which is consistent with the well-established negative correlation between CSF 5-HIAA and impulsivity. The results of the validation tests suggest that the model captures important aspects of the genetic control of presynaptic serotonergic function and behavior via brain activation. The proposed model can be: (1) extended to include other system components, neurotransmitter systems, behaviors and environmental influences; (2) used to generate testable hypotheses.

  20. Brain serotonin depletion enhances the sodium appetite induced by sodium depletion or beta-adrenergic stimulation

    Directory of Open Access Journals (Sweden)

    Hawlinston R. C. Lima

    2004-03-01

    Full Text Available We investigate the influence of brain serotonin depletion on the sodium appetite. Rats depleted of serotonin through the systemic administration of p-chlorophenylalanine (300 mg/kg, ip, for 2 days showed an intense natriorexigenic response induced by sodium depletion (furosemide, 20 mg/kg, sc, 24 h before water and 1.8% NaCl presentation. Intake of 1.8% NaCl was always higher than that observed for the control group (12.9 ± 1.4 and 21.4 ± 3.0 mL vs 5.7 ± 1.2 and 12.7 ± 1.6 mL, 30 and 300 min after water and saline presentation. After 24 h, the natriorexigenic response continued to be significantly higher compared to control (33.6±5.1 vs 21.9±3.6 mL,P Objetivamos avaliar a influência da depleção cerebral de serotonina no apetite por sódio. Ratos depletados de serotonina através da administração sistêmica de paraclorofenilalanina (300 mg/kg, ip, por 2 dias exibiram intensa resposta natriorexigênica induzida pela depleção de sódio (furosemida, 20 mg/kg, sc, 24 h antes da oferta de água e NaCl 1.8%. A ingestão de NaCl 1,8% atingiu valores sempre acima do grupo controle (12,9 ±1,4 e 21,4 ±3,0 mL vs 5,7 ±1,2 e 12,7 ±1,6 mL, 30 e 300 min após apresentação de água e salina hipertônica, P < 0,05. Ao final de 24 h a resposta natriorexigênica ainda mantinha-se significativamente mais elevada em relação aos controles (33,6 ±5,1 vs 21,9 ±3,6 mL, P < 0,05 e comparável aos controles no 14° dia. Ratos depletados de serotonina exibiram uma precoce resposta natriorexigênica após administração de isoproterenol, no terceiro dia após a primeira injeção de paraclorofenilalanina. O aumento da ingestão de NaCl 1,8% iniciou-se aos 120 min (1,9 ±0,3 vs 0,45 ±0,3 mL, P < 0,05 e manteve-se elevada ao final de 24 h (17,3 ±3,2 vs 1,1 ±0,5 mL, P < 0,05 após a oferta de fluidos. Decorridos sete e 14 dias a resposta natriorexigênica tornou-se comparável à dos controles. Os dados apresentados demonstram que a depleção de

  1. Brain Networks Implicated in Seasonal Affective Disorder: A Neuroimaging PET Study of the Serotonin Transporter

    Directory of Open Access Journals (Sweden)

    Martin Nørgaard

    2017-11-01

    Full Text Available Background: Seasonal Affective Disorder (SAD is a subtype of Major Depressive Disorder characterized by seasonally occurring depression that often presents with atypical vegetative symptoms such as hypersomnia and carbohydrate craving. It has recently been shown that unlike healthy people, patients with SAD fail to globally downregulate their cerebral serotonin transporter (5-HTT in winter, and that this effect seemed to be particularly pronounced in female S-carriers of the 5-HTTLPR genotype. The purpose of this study was to identify a 5-HTT brain network that accounts for the adaption to the environmental stressor of winter in females with the short 5-HTTLPR genotype, a specific subgroup previously reported to be at increased risk for developing SAD.Methods: Nineteen females, either S' carriers (LG- and S-carriers without SAD (N = 13, mean age 23.6 ± 3.2 year, range 19–28 or S' carriers with SAD (N = 6, mean age 23.7 ± 2.4, range 21–26 were PET-scanned with [11C]DASB during both summer and winter seasons (asymptomatic and symptomatic phase, 38 scans in total in randomized order, defined as a 12-week interval centered on summer or winter solstice. We used a multivariate Partial Least Squares (PLS approach with NPAIRS split-half cross-validation, to identify and map a whole-brain pattern of 5-HTT levels that distinguished the brains of females without SAD from females suffering from SAD.Results: We identified a pattern of 5-HTT levels, distinguishing females with SAD from those without SAD; it included the right superior frontal gyrus, brainstem, globus pallidus (bilaterally and the left hippocampus. Across seasons, female S' carriers without SAD showed nominally higher 5-HTT levels in these regions compared to female S' carriers with SAD, but the group difference was only significant in the winter. Female S' carriers with SAD, in turn, displayed robustly increased 5-HTT levels in the ventral striatum (bilaterally, right orbitofrontal

  2. Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease

    DEFF Research Database (Denmark)

    Cremer, Signe Emilie; Moesgaard, S. G.; Rasmussen, C. E.

    2015-01-01

    Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been...... suggested. In an age-matched population of dogs with non-clinical and clinical MMVD, the objectives were to investigate (1) gene expression of 5-HT2AR and 5-HT2BR, (2) protein expression and spatial relationship of 5-HT2AR, 5-HT2BR and MF in the mitral valve (MV) and the cardiac anterior papillary muscle...

  3. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    Science.gov (United States)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

  4. Lower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine.

    Science.gov (United States)

    Dean, Brian; Tawadros, Nahed; Seo, Myoung Suk; Jeon, Won Je; Everall, Ian; Scarr, Elizabeth; Gibbons, Andrew

    2014-06-01

    We have attempted to replicate studies showing higher levels of serotonin 2A receptors (HTR2A) in the cortex of people with mood disorders and to determine the effects of treating rats with antidepressant drugs on levels of that receptor. In situ [3H]ketanserin binding and autoradiography was used to measure levels of HTR2A in Brodmann's area (BA) 46 and 24 from people with major depressive disorders (MDD, n = 16), bipolar disorders (BD, n = 14) and healthy controls (n = 14) as well as the central nervous system (CNS) of rats (20 per treatment arm) treated for 10 or 28 d with fluoxetine (10 mg/kg/d) or imipramine (20 mg/kg/d). Compared with controls, HTR2A were lower in BA 24, but not BA 46, from people with MDD (p = 0.005); HTR2A were not changed in BD. Levels of HTR2A were lower in BA 24 (p = 0.007), but not BA 46, from people who had died by suicide. Finally, levels of HTR2A were lower in the CNS of rats treated with imipramine, but not fluoxetine, for 28 d, but not 10 d. From our current and previous data we conclude cortical HTR2A are lower in schizophrenia, MDD, people with mood disorders who died by suicide, rats treated with some antipsychotic or some antidepressant drugs. As levels of cortical HTR2A can be affected by the aetiologies of different disorders and mechanisms of action of different drugs, a better understanding of how such changes can occur needs to be elucidated.

  5. Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder.

    Science.gov (United States)

    Petit, Anne-Cécile; Quesseveur, Gaël; Gressier, Florence; Colle, Romain; David, Denis J; Gardier, Alain M; Ferreri, Florian; Lépine, Jean-Pierre; Falissard, Bruno; Verstuyft, Céline; Guiard, Bruno P; Corruble, Emmanuelle

    2014-10-03

    An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a(-/-)) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a(-/-)mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a(-/-) mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher "emotionality score" (pdepressed patients (p=0.019) and was also associated with a more severe major depressive episode (p=0.03). This translational and ecological study involving constitutive Htr2a(-/-) knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Mifepristone modulates serotonin transporter function

    OpenAIRE

    Li, Chaokun; Shan, Linlin; Li, Xinjuan; Wei, Linyu; Li, Dongliang

    2014-01-01

    Regulating serotonin expression can be used to treat psychotic depression. Mifepristone, a glucocorticoid receptor antagonist, is an effective candidate for psychotic depression treatment. However, the underlying mechanism related to serotonin transporter expression is poorly understood. In this study, we cloned the human brain serotonin transporter into Xenopus oocytes, to establish an in vitro expression system. Two-electrode voltage clamp recordings were used to detect serotonin transporte...

  7. In vivo quantification by SPECT of [{sup 123}I] ADAM bound to serotonin transporters in the brains of rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Ye, X.-X. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hsieh, J.-F. [Department of Nuclear Medicine, Chi-Mei Foundation Medical Center, Yungkang City 710, Taiwan (China); Chen, J.-C. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jcchen@ym.edu.tw; Chou, Y.-T. [Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan (China); Tu, K.-Y. [Department of Nuclear Medicine, Mackey Memorial Hospital, Taipei, Taiwan 104 (China); Wey, S.-P. [Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taoyuan, Taiwan 333 (China); Ting Gann [Institute of Nuclear Energy Research, Tao- Yuan 335, Taiwan (China)

    2004-11-01

    Background: A novel radioiodine ligand [{sup 123}I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [{sup 123}I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [{sup 123}I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [{sup 123}I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89{+-}0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [{sup 123}I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with

  8. Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

    DEFF Research Database (Denmark)

    Stenbæk, Dea S; Fisher, Patrick M; Ozenne, Brice

    2017-01-01

    BACKGROUND: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT 4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining t...

  9. Serotonin: A mediator of the gut-brain axis in multiple sclerosis

    NARCIS (Netherlands)

    Malinova, Tsveta S.; Dijkstra, Christine D.; de Vries, Helga E.

    2017-01-01

    The significance of the gut microbiome for the pathogenesis of multiple sclerosis (MS) has been established, although the underlying signaling mechanisms of this interaction have not been sufficiently explored. We address this point and use serotonin (5-hydroxytryptamine (5-HT))-a

  10. Relationships among body mass, brain size, gut length, and blood tryptophan and serotonin in young wild-type mice

    Directory of Open Access Journals (Sweden)

    Tatevosyan Maggie

    2009-03-01

    Full Text Available Abstract Background The blood hyperserotonemia of autism is one of the most consistent biological findings in autism research, but its causes remain unclear. A major difficulty in understanding this phenomenon is the lack of information on fundamental interactions among the developing brain, gut, and blood in the mammalian body. We therefore investigated relationships among the body mass, the brain mass, the volume of the hippocampal complex, the gut length, and the whole-blood levels of tryptophan and 5-hydroxytryptamine (5-HT, serotonin in young, sexually immature wild-type mice. Results Three-dimensional reconstructions of the hippocampal complex were obtained from serial, Nissl-stained sections and the gut was allowed to attain its maximal relaxed length prior to measurements. The tryptophan and 5-HT concentrations in the blood were assessed with high-performance liquid chromatography (HPLC and the sex of mice was confirmed by genotyping. Statistical analysis yielded information about correlative relationships among all studied variables. It revealed a strong negative correlation between blood 5-HT concentration and body mass and a strong negative correlation between the brain mass/body mass ratio and gut length. Also, a negative correlation was found between the volume of the hippocampal complex and blood tryptophan concentration. Conclusion The study provides information on the covariance structure of several central and peripheral variables related to the body serotonin systems. In particular, the results indicate that body mass should be included as a covariate in studies on platelet 5-HT levels and they also suggest a link between brain growth and gut length.

  11. Decreased brain serotonin turnover rate following administration of Sharbat-e-Ahmed Shah produces antidepressant and anxiolytic effect in rats.

    Science.gov (United States)

    Ahmed, Muhammad; Azmat, Aisha

    2017-07-07

    Sharbat-e-Ahmed Shah (SAS) has usually been used in Traditional Unani Medicine (TUM) for depression and insomnia but still not evaluated for its anti-depressant and Neuropharmacological activity. In the present study, a Human dose of SAS (0.6 ml/kg/d) was administered orally to the rats for 15 consecutive days. Antidepressant and anxiolytic were screened scientifically in rats by using Forced swim test and light and dark box test. At the end of study high-performance liquid chromatographic (HPLC) method with electrochemical (EC) detector was used for the measurement of blood and brain tryptophan and brain serotonin levels. The present reported results are according to what is known in TUM, where is prescribed as an antidepressant agent. After the administration, SAS (at a human dose for 15 days) reduced the immobility time in rats analogous to Imipramine (positive control) indicating the antidepressant effect of SAS. In the present study, Diazepam or SAS (0.6 ml/kg/day) treated rats stayed in the illuminated side of the light-dark box, as compare to control rats (Veh, 134.62 ± 4.430 s; SAS 0.6 ml/kg, 192.2 ± 8.11 s; DZP 1.0 mg/kg, 205.21.20 ± 10.26 s, p < 0.05). It was also observed that SAS increased the availability of tryptophan in blood and brain and hence increases 5-hydroxytryptamine (Serotonin: 5HT) in the brain. At the end, it was concluded that SAS contains some active principles which increase the availability of neurochemical (tryptophan and 5HT) and decrease the 5HT turnover rate thus causes antidepressant and anxiolytic effects in experimental animals.

  12. Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

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    Hauser Michael A

    2011-05-01

    Full Text Available Abstract Background Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD. Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4 have been shown to modulate amygdala and prefrontal cortex (PFC activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. Methods We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531 and several downstream single nucleotide polymorphisms (SNPs modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22 and a trauma-exposed control group (n = 20 in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. Results In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. Conclusions The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify

  13. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

    Science.gov (United States)

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

    2005-10-01

    Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

  14. Similar serotonin-2A receptor binding in rats with different coping styles or levels of aggression

    DEFF Research Database (Denmark)

    Visser, Anniek Kd; Ettrup, Anders; Klein, Anders Bue

    2015-01-01

    is not an important molecular marker for coping style. Since neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA. This article is protected by copyright. All...

  15. The polymorphism of the serotonin-2A receptor T102C is associated with age

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    P.F.C. Jobim

    2008-11-01

    Full Text Available Epidemiological investigations suggest that T102C polymorphism of gene 5-HT2A may be associated with mean life span because diseases and behaviors related to this polymorphism, such as schizophrenia, suicide, aggression, and addiction, may potentially shorten mean life span. A sample of 687 individuals without previous neuropsychiatric disease was genotyped and separated into 3 groups according to their gender and age: 14-45 years old, 46-64 years old and 65-100 years old. Molecular genotyping was performed using the technique of polymerase chain reaction followed by restriction fragment length polymorphism using HpaII restriction enzyme. 5-HT2A genotype frequencies were: TT = 21.5% (148, CC = 16.6% (114 and TC = 61.9% (425 and allele frequencies were T = 52.5% and C = 46.5%. Significant differences were found between mean age of the TT genotype carriers (60.27 ± 12.60 years and TC genotype carriers (56.80 ± 13.18 years of T102C polymorphism of gene 5-HT2A (P = 0.026 as well as the age groups (P = 0.012. Carriers of genotype TT were older than the other two genotypes, whereas carriers of genotype CC had an intermediate age compared with TT and CC subjects. The present results demonstrate an association between T102C polymorphism of gene 5-HT2A and age. Our results suggest that T102C polymorphism of gene 5-HT2A is associated with mean life span, and thus this gene becomes a possible candidate for the group of adaptive genes to meat consumption proposed in the literature. Further studies should be conducted in order to elucidate this association.

  16. In vivo binding of /sup 125/I-LSD to serotonin 5-HT/sub 2/ receptors in mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Hartig, P.R.; Scheffel, U., Frost, J.J.; Wagner, H.N. Jr.

    1985-08-19

    The binding of /sup 125/I-LSD (2-(/sup 125/I)-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of /sup 125/I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of /sup 125/I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of /sup 125/I-LSD. Serotonergic compounds potently inhibited /sup 125/I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that /sup 125/I-LSD labels serotonin 5-HT/sub 2/ receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, /sup 125/I-LSD labeling occurs predominantly or entirely at serotonic 5-HT/sub 2/ sites. In the striatum, /sup 125/I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that /sup 125/I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT/sub 2/ receptors in the mammalian cortex.

  17. Gender, personality, and serotonin-2A receptor binding in healthy subjects

    OpenAIRE

    Soloff, Paul H.; Price, Julie C.; Mason, Neale Scott; Becker, Carl; Meltzer, Carolyn C.

    2010-01-01

    The vulnerability to mood disorders, impulsive-aggression, eating disorders, and suicidal behavior varies greatly with gender, and may reflect gender differences in central serotonergic function. We investigated the relationships of gender, mood, impulsivity, aggression and temperament to 5HT2A receptor binding in 21 healthy subjects using [18F]altanserin and PET neuro-imaging. Binding potentials in pre-defined Regions of Interest (ROI) were calculated using the Logan graphical method, correc...

  18. Social hierarchies, growth and brain serotonin metabolism in Atlantic salmon (Salmo salar) kept under commercial rearing conditions.

    Science.gov (United States)

    Cubitt, K Fiona; Winberg, Svante; Huntingford, Felicity A; Kadri, Sunil; Crampton, Vivian O; Overli, Oyvind

    2008-07-05

    Monitoring social interactions between individuals in large, high-density groups poses several challenges. Here we demonstrate that relative concentrations of serotonin (5-Hydroxytryptamine, 5-HT) and its principal catabolite 5-Hydroxyindoleacetic acid (5-HIAA) in brain tissue of individual fish reflect social organisation in large groups of farmed Atlantic salmon. In the central nervous system of vertebrates, the monoamine neurotransmitter/neuromodulator 5-HT is critical for maintaining adaptive physiological, cognitive and emotional processes. In both teleost fish and mammals it has previously been shown that social interactions in small groups lead to elevated 5-HT release and/or metabolism in subordinate individuals, as indicated by the 5-HIAA/5-HT concentration ratio. In the current study, evidence is presented of non-linear dominance hierarchies in farmed Atlantic salmon (Salmo salar) kept at high rearing densities. The physiological effect of these hierarchies was decreased when food resources were abundant, although some subordinate fish still showed altered brain serotonergic activity and failed to grow even feed was available in excess. The largest effect of decreased feed rations was seen in fish of intermediate size, where competition appeared to increase with reduced access to feed. The largest individuals in each rearing unit showed low 5-HIAA/5-HT ratios independent of feeding regime. A novel observation, with respect to previous studies, was that elevated brain 5-HIAA/5-HT ratios resulted from decreased 5-HT concentrations rather than elevated 5-HIAA in small fish. Thus, in light of the serotonin deficit hypothesis of depression, it cannot be excluded that social stress is important for animal welfare even in large, relatively homogenous groups of animals reared in captivity.

  19. Clozapine Acts as an Agonist at Serotonin 2A Receptors to Counter MK-801-Induced Behaviors through a βArrestin2-Independent Activation of Akt

    Science.gov (United States)

    Schmid, Cullen L; Streicher, John M; Meltzer, Herbert Y; Bohn, Laura M

    2014-01-01

    The G protein-coupled serotonin 2A receptor (5-HT2AR) is a prominent target for atypical antipsychotic drugs, such as clozapine. Although clozapine is known to inhibit 5-HT2AR signaling through G protein-dependent mechanisms, it differs from classic GPCR antagonists, in that it also induces 5-HT2AR internalization and activates Akt signaling via a 5-HT2AR-mediated event. In this regard, clozapine may also be considered a functionally selective agonist. The cognate neurotransmitter at the 5-HT2AR, serotonin, also induces 5-HT2AR internalization and Akt phosphorylation. Serotonin promotes interactions with the scaffolding and regulatory protein, βarrestin2, which results in the recruitment and activation of Akt. These interactions prove to be critical for serotonin-induced, 5-HT2AR-mediated behavioral responses in mice. Herein, we sought to determine whether clozapine also utilizes βarrestin2-mediated mechanisms to induce 5-HT2AR signaling, and whether this interaction contributes to its behavioral effects in mice. We demonstrate that unlike serotonin, clozapine-mediated 5-HT2AR internalization and Akt phosphorylation is independent of receptor interactions with βarrestin2. Moreover, clozapine-mediated suppression of MK-801 and phencyclidine (PCP)-induced hyperlocomotion is βarrestin2 independent, although it is dependent upon Akt. These results demonstrate that pharmacologically oppositional ligands, serotonin and clozapine, utilize differential mechanisms to achieve the same 5-HT2AR-meadiated downstream events: Akt phosphorylation and receptor internalization. Although βarrestin2 has no effect on clozapine's actions in vivo, Akt phosphorylation is required for clozapine's efficacy in blocking MK-801- and PCP-induced models of schizophrenic behaviors in mice. PMID:24531562

  20. A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A or Early Growth Response Genes (EGR1-3 in Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Patrick C. Dolder

    2017-06-01

    Full Text Available Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A and EGR1-3 genes.Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg and placebo in a randomized, double-blind, placebo-controlled, cross-over study.Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo.Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.

  1. Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia

    Directory of Open Access Journals (Sweden)

    Laura K. Nisenbaum

    2016-02-01

    Full Text Available This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05 greater improvement in Positive and Negative Syndrome Scale (PANSS total scores during treatment with pomaglumetad methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving pomaglumetad methionil had significantly (p ≤ 0.05 greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to pomaglumetad methionil compared to the A/A genotype.

  2. 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

    Science.gov (United States)

    Gresch, Paul J; Barrett, Robert J; Sanders-Bush, Elaine; Smith, Randy L

    2007-02-01

    d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

  3. Cognitive function is related to fronto-striatal serotonin transporter levels--a brain PET study in young healthy subjects

    DEFF Research Database (Denmark)

    Madsen, Karine; Erritzøe, David Frederik; Mortensen, Erik Lykke

    2011-01-01

    Pharmacological manipulation of serotonergic neurotransmission in healthy volunteers impacts on cognitive test performance. Specifically, markers of serotonin function are associated with attention and executive functioning, long-term memory, and general cognitive ability. The serotonin transporter...

  4. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R

    2016-01-01

    the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic...... receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding......The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...

  5. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors.

    Science.gov (United States)

    Frick, Luciana Romina; Bernardez-Vidal, Micaela; Hocht, Christian; Zanutto, Bonifacio Silvano; Rapanelli, Maximiliano

    2015-01-15

    Serotonin (5-HT) has been proposed as a possible encoder of reward. Nevertheless, the role of this neurotransmitter in reward-based tasks is not well understood. Given that the major serotonergic circuit in the rat brain comprises the dorsal raphe nuclei and the medial prefrontal cortex (mPFC), and because the latter structure is involved in the control of complex behaviors and expresses 1A (5-HT1A), 2A (5-HT2A), and 3 (5-HT3) receptors, the aim was to study the role of 5-HT and of these receptors in the acquisition and extinction of a reward-dependent operant conditioning task. Long Evans rats were trained in an operant conditioning task while receiving fluoxetine (serotonin reuptake inhibitor, 10mg/kg), tianeptine (serotonin reuptake enhancer, 10mg/kg), buspirone (5-HT1A partial agonist, 10mg/kg), risperidone (5-HT2A antagonist, 1mg/kg), ondansetron (5-HT3 antagonist, 2mg/kg) or vehicle. Then, animals that acquired the operant conditioning without any treatment were trained to extinct the task in the presence of the pharmacological agents. Fluoxetine impaired acquisition but improved extinction. Tianeptine administration induced the opposite effects. Buspirone induced a mild deficit in acquisition and had no effects during the extinction phase. Risperidone administration resulted in learning deficits during the acquisition phase, although it promoted improved extinction. Ondansetron treatment showed a deleterious effect in the acquisition phase and an overall improvement in the extinction phase. These data showed a differential role of 5-HT in the acquisition and extinction of an operant conditioning task, suggesting that it may have a dual function in reward encoding. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Coronary artery disease and depression: possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms.

    Science.gov (United States)

    Bozzini, Sara; Gambelli, Patrick; Boiocchi, Chiara; Schirinzi, Sandra; Falcone, Rossana; Buzzi, Paola; Storti, Cesare; Falcone, Colomba

    2009-12-01

    Cardiovascular disease (CVD) and depression are two of the most common human health problems. Patients with depression have an increased risk of developing cardiovascular disease and mortality after experiencing a cardiac event. Both diseases are complex disorders that are influenced by genetic and environmental factors. Brain-derived neuro-trophic factor (BDNF) plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in the peripheral and nervous system. Evidence suggests that BDNF can enhance serotoninergic transmission. Serotonin modulates different brain functions and is known to regulate sleep, appetite, pain and inflammation. The aims of the present case-control study were to investigate the possible role of BDNF Val66Met, 5-HTTLPR and -1438 G/A polymorphisms in the development of coronary artery disease (CAD) in patients with and without depression. Regarding BDNF, our data suggest an involvement of the AA genotype in the pathogenesis of CAD in females and in the predisposition to CAD associated with depression. Furthermore, it could be argued that the GG genotype is protective against CAD in the female population and against CAD associated with depression. In our CAD population we also observed a significant increase in the L/L genotype and a decrease in the S/L genotype with respect to the controls. A higher frequency of the L allele, responsible for enhancing the efficiency of transcription, was found in CAD patients. These findings may be responsible for the increased capacity of platelet serotonin uptake previously observed in patients with CAD. Although no differences were found for genotype and allelic frequencies of the -1438 G/A polymorphism between the CAD patients and controls, we cannot exclude the possible role of this receptor in coronary artery disease.

  7. Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

    DEFF Research Database (Denmark)

    Haahr, M. E.; Rasmussen, Peter Mondrup; Madsen, K.

    2012-01-01

    The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT4 receptor (5-HT4R) is involved...... between body mass index and the 5-HT4R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex.These findings suggest that the 5-HT4R is critically involved in reward circuits that regulate people...

  8. Serotonin 2A receptor disulfide bridge integrity is crucial for ligand binding to different signalling states but not for its homodimerization.

    Science.gov (United States)

    Iglesias, Alba; Cimadevila, Marta; la Fuente, Rocío Ailim de; Martí-Solano, María; Cadavid, María Isabel; Castro, Marián; Selent, Jana; Loza, María Isabel; Brea, José

    2017-11-15

    The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys148 (transmembrane helix 3, TM3) and Cys227 (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization. A DTT-induced decrease in the number of binding sites (1190 ± 63.55 fmol/mg protein for control cells compared with 921.2 ± 60.84 fmol/mg protein for DTT-treated cells) as well as in the efficacy of both signalling pathways characterized was observed, although the affinity and potency were unchanged. Bioluminiscence resonance energy transfer (BRET) assays revealed the DTT treatment did not modify the homodimeric nature of serotonin 5-HT2A receptors. In molecular dynamic simulations, the ECL-2 of the receptor with a broken cysteine bond adopts a wider variety of conformations, some of which protrude deeper into the receptor orthosteric binding pocket leading to collapse of the pocket. A shrunken binding pocket would be incapable of accommodating lysergic acid diethylamide (LSD). Our findings suggest that the decrease of efficacy may be due to disruption of disulfide bridge between TM3 and ECL-2. This reveals the integrity of the ECL-2 epitope, which should be explored in the development of novel ligands acting as allosteric modulators of serotonin 5-HT2A receptors. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

    OpenAIRE

    Yang, Kai-Chun; Stepanov, Vladimir; Martinsson, Stefan; Ettrup, Anders; Takano, Akihiro; Knudsen, Gitte M; Halldin, Christer; Farde, Lars; Finnema, Sjoerd J.

    2017-01-01

    Abstract Background [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (...

  10. The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: potential roles in genetic selection and gene × environment interactions.

    Science.gov (United States)

    Lindell, Stephen G; Yuan, Qiaoping; Zhou, Zhifeng; Goldman, David; Thompson, Robert C; Lopez, Juan F; Suomi, Stephen J; Higley, J Dee; Barr, Christina S

    2012-11-01

    In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.

  11. Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

    Science.gov (United States)

    Booij, Linda; Tremblay, Richard E.; Szyf, Moshe; Benkelfat, Chawki

    2015-01-01

    Background Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development. Methods Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists. Results Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region–specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms. Limitations There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain. Conclusion A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology. PMID:25285876

  12. [Increase of brain serotonin and its metabolite in rats caused by meclofenoxate].

    Science.gov (United States)

    Koga, T

    1976-05-01

    Influence of meclofenoxate (MF) on the 5-HT and 5-HIAA contents in the cortex, diencephalon and brain stem of the rat was studied with the following results. MF caused a dose-dependent elevation of 5-HIAA level in the three different brain regions and particularly in the brain stem. An increase of 5-HT was also noted in the brain stem, whereas 5-HT in the diencephalon tended to decrease. The increase of 5-HT after pargyline was accelerated and the pargyline-induced decrease of 5-HIAA was equally inhibited by MF and probenecid, which suggests that MF blocks the efflux of 5-HIAA from the brain. The effects of MF on the brain 5-HT and 5-HIAA contents were identical with those of its hydrolysate, p-chlorophenoxyacetic acid.

  13. The time course of serotonin 2A receptor expression after spinal transection of rats: an immunohistochemical study

    DEFF Research Database (Denmark)

    Kong, X-Y; Wienecke, Jacob; Chen, M

    2011-01-01

    Hyperexcitability of motoneurons is one of the key mechanism that has been demonstrated to underlie the pathogenesis of spasticity after spinal injury. Serotonin (5-HT) denervation supersensitivity is one of the mechanisms underlying this increased motoneuron excitability. In this study, to examine...... and thereby implicates their involvement in the pathogenesis of the subsequent development of spasticity....

  14. Sex Differences of Brain Serotonin Synthesis in Patients with Irritable Bowel Syndrome Using α-[11C]methyl-L-tryptophan, Positron Emission Tomography and Statistical Parametric Mapping

    Directory of Open Access Journals (Sweden)

    Akio Nakai

    2003-01-01

    Full Text Available BACKGROUND: Irritable bowel syndrome (IBS is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin (5-HT, a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS.

  15. Association between serotonin transporter genotype, brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study.

    Science.gov (United States)

    Little, K; Olsson, C A; Whittle, S; Youssef, G J; Byrne, M L; Simmons, J G; Yücel, M; Foley, D L; Allen, N B

    2014-09-16

    The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13-19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

  16. Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice.

    Science.gov (United States)

    Ledo, Jose Henrique; Azevedo, Estefania P; Beckman, Danielle; Ribeiro, Felipe C; Santos, Luis E; Razolli, Daniela S; Kincheski, Grasielle C; Melo, Helen M; Bellio, Maria; Teixeira, Antonio L; Velloso, Licio A; Foguel, Debora; De Felice, Fernanda G; Ferreira, Sergio T

    2016-11-30

    Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function. Copyright © 2016 the authors 0270-6474/16/3612106-11$15.00/0.

  17. Serotonin 2A and 2C receptor biosynthesis in the rodent striatum during postnatal development: mRNA expression and functional linkage to neuropeptide gene regulation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2000-11-01

    The present study was designed to determine if there are region-specific differences in serotonin (5-HT) neurotransmission and 5-HT receptor expression that may limit the stimulatory effects of the 5-HT releaser p-chloroamphetamine (pCA) on striatal neuropeptide gene expression to the posterior striatum (P-STR) during postnatal maturation. Sprague-Dawley rat brains from postnatal days (PND) 1-35 were processed for 5-HT(2A) and 5-HT(2C) receptor mRNA expression by in situ hybridization and monoamine analysis by HPLC. Within the P-STR, 5-HT(2A) receptor mRNA expression reached young adult (PND 35) levels by PND 3, while levels in the A-STR were significantly less (range: 1.43 +/- 0.219-6. 36 +/- 0.478) than P-STR (5.36 +/- 0.854-12.11 +/- 1.08) at each respective age throughout the time course. 5-HT(2C) receptor mRNA expression reached young adult levels at PND 7 in the A-STR and by PND 3 in the P-STR. At each PND age 5-HT(2C) receptor mRNA levels within the P-STR were significantly less (6.23 +/- 1.02-12.32 +/- 0.427) than the A-STR (7.31 +/- 1.65-26.84 +/- 2.24). 5-HT content increased across the developmental time course within the P-STR (5.01 +/- 0.327-15.7 +/- 1.03 ng/mg protein) and A-STR (2.97 +/- 0. 223-11.2 +/- 0.701 ng/mg protein). Four hours following injection (i. p.) of pCA (10 mg/kg), preprotachykinin (PPT) mRNA levels increased 89% in the P-STR but not the anterior (A-STR) striatum of the 3-week-old rat, which were prevented by preinjection (30 min, i.p.) of the 5-HT(2) receptor antagonist ritanserin (1 mg/kg). Together, these data suggest that faster maturity of 5-HT(2A) receptor expression in the P-STR may be sufficient to convey the region-specific acute stimulatory effects of pCA on PPT mRNA transcription in the developing rodent striatum. These results provide further evidence that the influence of 5-HT on neuropeptide gene expression is far stronger in caudal vs. rostral striatal regions during postnatal development. Copyright 2000 Wiley

  18. Brain serotonin 4 receptor binding is inversely associated with verbal memory recall.

    Science.gov (United States)

    Stenbæk, Dea S; Fisher, Patrick M; Ozenne, Brice; Andersen, Emil; Hjordt, Liv V; McMahon, Brenda; Hasselbalch, Steen G; Frokjaer, Vibe G; Knudsen, Gitte M

    2017-04-01

    We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT 4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5-HT 4R binding and affective verbal memory recall. Twenty-four healthy volunteers were scanned with the 5-HT 4R radioligand [11C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test-24. The association between 5-HT 4R binding and affective verbal memory was evaluated using a linear latent variable structural equation model. We observed a significant inverse association across all regions between 5-HT 4R binding and affective verbal memory performances for positive (p = 5.5 × 10-4) and neutral (p = .004) word recall, and an inverse but nonsignificant association for negative (p = .07) word recall. Differences in the associations with 5-HT 4R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance. Our findings replicate our previous observation of a negative association between 5-HT 4R binding and memory performance in an independent cohort and provide novel evidence linking 5-HT 4R binding, as a biomarker for synaptic 5-HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans.

  19. Synthesis and characterization of EADAM: a selective radioligand for mapping the brain serotonin transporters by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Jarkas, Nachwa [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); McConathy, Jonathan [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States); Votaw, John R. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Voll, Ronald J. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Malveaux, Eugene [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Camp, Vernon M. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Williams, Larry [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Goodman, Robin R. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States); Kilts, Clinton D. [Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States); Goodman, Mark M. [Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322 (United States) and Department of Psychiatry and Behavior Sciences, Emory University, Atlanta, GA 30322 (United States)]. E-mail: mgoodma@emory.edu

    2005-01-01

    [{sup 11}C]N,N-Dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine ([{sup 11}C]EADAM) was synthesized in the development of a serotonin transporter (SERT) imaging ligand for positron emission tomography (PET). The methods of ligand synthesis, results of in vitro characterization, {sup 11}C labeling and in vivo micro-PET imaging studies of [{sup 11}C]EADAM in cynomolgus monkey brain are described. {sup 11}C was introduced into N,N-dimethyl-2-(2'-amino-4'-ethylphenylthio)benzylamine () by alkylation of N-methyl-2-(2'-amino-4'-ethylphenylthio)benzylamine () in 32% radiochemical yield (end of bombardment [EOB], decay-corrected from [{sup 11}C]methyl iodide). Competition binding assays in cells stably expressing the transfected human dopamine transporter (DAT), SERT and norepinephrine transporter (NET) labeled with [{sup 3}H]WIN 35428 or [{sup 125}I]RTI-55, [{sup 3}H]citalopram and [{sup 3}H]nisoxetine, respectively, indicated the following order of SERT affinity: ADAM>EADAM>>fluvoxamine. The affinity of EADAM for DAT and NET was 500- and >1000-fold lower, respectively, than for SERT. Micro-PET brain imaging studies in a cynomolgus monkey demonstrated high [{sup 11}C]EADAM uptake in the striatum, thalamus and brainstem. [{sup 11}C]EADAM uptake in these brain regions peaked in less than 60 min following administration of [{sup 11}C]EADAM. The tissue-to-cerebellum ratios of the striatum, thalamus and brainstem were 1.67, 1.71 and 1.63, respectively, at 120 min postinjection of [{sup 11}C]EADAM. Analysis of monkey arterial plasma samples using high-pressure liquid chromatography determined there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In a displacement experiment with citalopram in a cynomolgus monkey, radioactivity in the striatum, thalamus and brainstem was displaced 20-60 min after administration of citalopram. In a blocking experiment with citalopram in a cynomolgus monkey

  20. 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of (/sup 3/H)paroxetine-labeled serotonin uptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Battaglia, G.; Yeh, S.Y.; O' Hearn, E.; Molliver, M.E.; Kuhar, M.J.; De Souza, E.B.

    1987-09-01

    This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%) in the density of (/sup 3/H)paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of (/sup 3/H)mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals.

  1. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans.

    Science.gov (United States)

    Valle, Marta; Maqueda, Ana Elda; Rabella, Mireia; Rodríguez-Pujadas, Aina; Antonijoan, Rosa Maria; Romero, Sergio; Alonso, Joan Francesc; Mañanas, Miquel Àngel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-07-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  2. Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

    Science.gov (United States)

    Hagbom, Marie; Istrate, Claudia; Engblom, David; Karlsson, Thommie; Rodriguez-Diaz, Jesus; Buesa, Javier; Taylor, John A; Loitto, Vesa-Matti; Magnusson, Karl-Eric; Ahlman, Håkan; Lundgren, Ove; Svensson, Lennart

    2011-07-01

    Rotavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca²⁺ concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP₃), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT₃ receptor antagonists.

  3. Rotavirus stimulates release of serotonin (5-HT from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

    Directory of Open Access Journals (Sweden)

    Marie Hagbom

    2011-07-01

    Full Text Available Rotavirus (RV is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT by enterochromaffin (EC cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca²⁺ concentration in a human midgut carcinoid EC cell line (GOT1 and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP₃, but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT₃ receptor antagonists.

  4. Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis.

    Science.gov (United States)

    Carlson, Kaitlin S; Whitney, Meredith S; Gadziola, Marie A; Deneris, Evan S; Wesson, Daniel W

    2016-01-01

    The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult brain tryptophan hydroxylase 2 ( Tph2 ), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT-depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task. Tph2 -targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT-depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.

  5. Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

    DEFF Research Database (Denmark)

    Holm, Peter; Ettrup, Anders; Klein, Anders B

    2010-01-01

    Intrahippocampal injections of aggregated amyloid-beta (Abeta)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Abeta protein, we studied 5......]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Abeta plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality......, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Abeta plaque burden was accompanied by a significant decrease...

  6. Effect of acute and chronic treatment with risperidone on the serotonin and dopamine receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Young; Moon, Dae Hyuk; Son, Hye Kyung; Kim, Chang Yoon; Lee, Chul; Lee, Hee Kyung [College of Medicine, Ulsan Univ., Seoul (Korea, Republic of)

    1997-03-01

    The therapeutic efficacy of antipsychotic drugs is generally attributed to their ability to block dopamine D{sub 2} receptors. Classical D{sub 2} antagonists are not effective to treat negative symptoms and produce extrapyramidal side effects. On the other hand, atypical antipsychotic agents ameliorate negative symptoms without producing extrapyramidal side effects, and it is reported to be associated with blockade of serotonin 5-HT{sub 2} receptors. The purpose of this study was to evaluate the effect of risperidone on neuroreceptors in the rat brain by quantitative autoradiography method. In acute treatment group, risperidone was injected into peritoneal cavity of male Wistar rats with dose of 0, 0.1, 0.25, 0.5, 1.0 and 2.0mg/kg in each group (5/group), and they were decapitated after 2 hours. In chronic treatment group, risperidone was injected with dose of 0, 0.1, and 1m/kg (I.P.) for 21 ays and decapitated after 24 hours following last treatment. The effect of risperodone on the binding of [{sup 3}H) spiperone to 5-HT{sub 2} and D{sub 2} receptors were analysed in 4 discrete regions of the striatum, nucleus accumbens, and frontal cortex by quantitative autoradiography. Acute treatment with risperidone reduced cortical 5-HT{sub 2} specific [{sup 3}H]spiperone binding to 32% of vehicle-treated control. Subcortical 5-HR{sub 2} specific [{sup 3}H]spiperone binding was not affected at all dose groups whereas a significant reduction (57%) in D{sub 2} specific [{sup 3}H]spiperone binding was observed in risperidone treated group at doses of 1-2mg/kg. Chronic treatment with risperidone produced a decrease in the maximal number of cortical 5-HT{sub 2} receptors to 51% and 46% of control in 0.1mg/kg and 1mg/kg treated group respectively. In conclusion, risperidone is a cortical serotonin receptor antagonist with relatively weak antagonistic action on dopamine receptors. These effects on neuroreceptors may explain the therapeutic effect of risperidone as a atypical

  7. In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.

    2011-01-01

    (methyl) amino) methyl] phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 (F-18)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n=10) and MDMA-preferring users (n=14...... (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA......(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence....

  8. Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frøkjær, Vibe Gedsø; Vinberg, Maj; Erritzoe, David

    2010-01-01

    Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability...... and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co......-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [(18)F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT(2A) receptor binding (p=0...

  9. (3H)WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Norman, A.B.; Battaglia, G.; Creese, I.

    1985-12-01

    In the presence of a 30 nM prazosin mask, (/sup 3/H)-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ((/sup 3/H)WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for (/sup 3/H) WB4101 binding in cerebral cortex. We have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at (/sup 3/H)WB4101-binding sites in the presence of 30 nM prazosin and (/sup 3/H) lysergic acid diethylamide ((/sup 3/H)LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of (/sup 3/H)WB4101 is significantly lower than the Bmax of (/sup 3/H)LSD in various brain regions. WB4101 competition for (/sup 3/H) LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of (/sup 3/H)WB4101 binding derived from saturation experiments. This suggests that (/sup 3/H)WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by (/sup 3/H)LSD. The selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for (/sup 3/H)WB4101 but compete for multiple (/sup 3/H)LSD 5-HT1 binding sites. These data indicate that (/sup 3/H)WB4101 selectively labels the 5-HT1A serotonin receptor, whereas (/sup 3/H) LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of (/sup 3/H)WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of (/sup 3/H)WB4101 binding.

  10. Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2001-08-15

    Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

  11. Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

    Science.gov (United States)

    Zghoul, Tarek; Blier, Pierre

    2003-03-01

    Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

  12. The relationship between the daily dose, the plasma concentration of blonanserin, and its plasma anti-dopamine D2 and anti-serotonin 5-HT2A activity.

    Science.gov (United States)

    Suzuki, Hidenobu; Gen, Keishi

    2010-01-01

    Blonanserin (BNS) possesses anti-serotonin 5-HT(2A) activity in addition to anti-dopamine D(2) activity, which is characteristic of second-generation antipsychotics, little information is available on its pharmacologic profile in vivo. We investigated the BNS daily dose, plasma concentration, plasma anti-D(2) activity, and plasma anti-5-HT(2A) activity in schizophrenia in a total of 14 subjects. Blood samples were taken 14 days after the BNS dose was fixed, and the plasma concentration was measured by means of high-performance liquid chromatographic (HPLC) method. In addition, the plasma anti-D(2) activity and anti-5-HT(2A) activity were measured by means of radioreceptor assays in which [(3)H]-spiperone and [(3)H]-ketanserin were used. The results revealed a statistically significant correlation between the daily dose and the plasma concentration (p = 0.04). Statistically significant correlations were also observed between the plasma concentration and the anti-D(2) activity and between the plasma concentration and the anti-5-HT(2A) activity (p = 0.003 and 0.04). It is therefore believed that both the anti-D(2) activity in plasma and the anti-5-HT(2A) activity in plasma are regulated almost solely by the unchanged principal. Moreover, the mean plasma serotonin/dopamine (S/D) ratio was 0.9 and BNS exhibited both anti-D(2) activity and also anti-5-HT(2A) activity in vivo, as well, so it was clear that the in vitro pharmacological profile was retained in vivo.

  13. Cerebral serotonin release correlates with [(11)C]AZ10419369 PET measures of 5-HT1B receptor binding in the pig brain

    DEFF Research Database (Denmark)

    Jørgensen, Louise M; Weikop, Pia; Svarer, Claus

    2017-01-01

    of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release...

  14. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered...... by BDNF depletion. 5-HT(2A) ([(3)H]-MDL100907) and 5-HT(1A) ([(3)H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT(2A) receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT(1A) receptor binding...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  15. Distribution of serotonin and FMRF-amide in the brain of Lymnaea stagnalis with respect to the visual system.

    Science.gov (United States)

    Tuchina, Oksana P; Zhukov, Valery V; Meyer-Rochow, Victor B

    2012-06-01

    Despite serotonin's and FMRF-amide's wide distribution in the nervous system of invertebrates and their importance as neurotransmitters, the exact roles they play in neuronal networks leaves many questions. We mapped the presence of serotonin and FMRF-amide-immunoreactivity in the central nervous system and eyes of the pond snail Lymnaea stagnalis and interpreted the results in connection with our earlier findings on the central projections of different peripheral nerves. Since the chemical nature of the intercellular connections in the retina of L. stagnalis is still largely unknown, we paid special attention to clarifying the role of serotonin and FMRF-amide in the visual system of this snail and compared our findings with those reported from other species. At least one serotonin- and one FMRF-amidergic fibre were labeled in each optic nerve, and since no cell bodies in the eye showed immunoreactivity to these neurotransmitters, we believe that efferent fibres with somata located in the central ganglia branch at the base of the eye and probably release 5HT and FMRF-amide as neuro-hormones. Double labelling revealed retrograde transport of neurobiotin through the optic nerve, allowing us to conclude that the central pathways and serotonin- and FMRF-amide-immunoreactive cells and fibres have different locations in the CNS in L. stagnalis. The chemical nature of the fibres, which connect the two eyes in L. stagnalis, is neither serotoninergic nor FMRF-amidergic.

  16. Synthesis, radiofluorination and first evaluation of [{sup 18}F]fluorophenylsulfonyl- and [{sup 18}F]fluorophenylsulfinyl-piperidines as serotonin 5-HT{sub 2A} receptor antagonists for PET

    Energy Technology Data Exchange (ETDEWEB)

    Muehlhausen, Ute; Sihver, Wiebke [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany); Ermert, Johannes, E-mail: j.ermert@fz-juelich.d [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany); Coenen, Heinz H. [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany)

    2010-07-15

    In psychiatric disorders, 5-HT{sub 2A} receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT{sub 2A} receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been {sup 18}F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [{sup 18}F]9 in a radiochemical yield (RCY) of 34.5{+-}8% and [{sup 18}F]15 of 9.5{+-}2.5%. The K{sub i} values of 9 and 15 at 5-HT{sub 2A} receptors towards [{sup 3}H]ketanserin were determined to be 1.9{+-}0.6 and 198{+-}8 nM, respectively. Autoradiography with [{sup 18}F]9 and [{sup 18}F]15 on rat brain sections showed a very high nonspecific binding of >80% for [{sup 18}F]9 and 30% to 40% nonspecific binding for [{sup 18}F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT{sub 2A} receptors in humans.

  17. Female sexual dysfunction in patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitor (SSRI) and its association with serotonin 2A-1438 G/A single nucleotide polymorphisms.

    Science.gov (United States)

    Masiran, Ruziana; Sidi, Hatta; Mohamed, Zahurin; Mohd Nazree, Nur Elia; Nik Jaafar, Nik Ruzyanei; Midin, Marhani; Das, Srijit; Mohamed Saini, Suriati

    2014-04-01

    Selective serotonin reuptake inhibitors (SSRIs) are known for their sexual side effects. Different SSRIs may affect different areas of sexual function at different rates. The study aimed to determine the prevalence of female sexual dysfunction (FSD), its clinical correlates, and association with 5HT2A (rs6311) single nucleotide polymorphisms (SNPs) in patients with major depressive disorder (MDD) who were on SSRI therapy. This was a cross-sectional study on 95 female outpatients with MDD treated with SSRI. The patients were in remission as determined by Montgomery-Asberg Depression Rating Scale. Genomic DNA was isolated from buccal swabs and samples were processed using a real time polymerase chain reaction. The presence or absence of FSD as measured by the Malay Version of Female Sexual Function Index and 5HT2A-1438 G/A (rs6311) SNP. The overall prevalence of FSD was 32.6%. After controlling for age, number of children, education level, total monthly income, SSRI types, and SSRI dosing, being employed significantly enhanced FSD by 4.5 times (odds ratio [OR] = 4.51; 95% confidence interval [CI] 1.00, 20.30; P = 0.05). Those having marital problems were 6.7 times more likely to have FSD (OR = 6.67; 95% CI 1.57, 28.34). 5HT2A-1438 G/A (rs6311) SNP was not significantly associated with FSD. There was no significant association between FSD and the 5HT2A (rs6311) SNP in patients with MDD on SSRI therapy. Employment status and marital state were significantly associated with FSD among these patients. © 2014 International Society for Sexual Medicine.

  18. Serotonin Test

    Science.gov (United States)

    ... acute myocardial infarction ( heart attack ), cystic fibrosis , and dumping syndrome . The serotonin test is not usually ordered ... Thank you. Contact a Scientist Find Us On Social Media: Facebook Twitter Google Plus Footer Menu Home ...

  19. Serotonin Test

    Science.gov (United States)

    ... High-sensitivity C-reactive Protein (hs-CRP) Histamine Histone Antibody HIV Antibody and HIV Antigen (p24) HIV ... 282515-overview. Accessed December 2010. (© 1995-2010). Unit Code 84395: Serotonin, Serum. Mayo Clinic, Mayo Medical Laboratories [ ...

  20. Gender differences in tryptophan hydroxylase-2 mRNA, serotonin, and 5-hydroxytryptophan levels in the brain of catfish, Clarias gariepinus, during sex differentiation.

    Science.gov (United States)

    Raghuveer, K; Sudhakumari, C C; Senthilkumaran, B; Kagawa, H; Dutta-Gupta, A; Nagahama, Y

    2011-03-01

    Tryptophan hydroxylase (tph) is the key regulator in serotonin (5-HT) biosynthesis that stimulates the release of GnRH and gonadotropins by acting at the level of hypothalamo-hypophyseal axis. In brain, 5-HT is expressed predominantly in preoptic area-hypothalamus (POA-HYP) region in teleosts. Therefore, in the present study we isolated tph2 from catfish brain to evaluate its expression pattern in male and female brains during early development. Tph2 cloned from catfish brain is 2.768 Kb in length which encodes predicted protein of 488 amino acid residues. The characterization of recombinant tph2 was done by transient transfection in CHO cells. Tissue distribution of tph2 revealed ubiquitous expression except ovary. Real time PCR analysis in discrete regions of adult male brain revealed that tph2 mRNA was abundant in the POA-HYP and optic tectum+cerebellum+thalamus (OCT) regions. Differential expression of tph2 was observed at mRNA and protein levels in the POA-HYP and OCT regions of male and female brains during development that further correlate with the 5-hydroxytryptophan (5-HTP) and 5-HT levels measured using HPLC method in these regions of male and female brains. Tph2 immunoreactive neurons were observed in different regions of brain at 50 days post hatch using catfish specific tph2 antibody. Changes in tph2 mRNA expression, 5-HTP, and 5-HT levels in the POA-HYP+OCT region of brains of methyltestosterone and para-chlorophenylalanine treated fishes during development further endorse our results. Based on our results, we propose that the serotonergic system is involved in brain sex differentiation in teleosts. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Chronic spinal cord injury causes upregulation of serotonin (5-HT)2A and 5-HT2C receptors in lumbosacral cord motoneurons.

    Science.gov (United States)

    Cao, Nailong; Ni, Jianshu; Wang, Xiaohu; Tu, Hongjian; Gu, Baojun; Si, Jiemin; Wu, Gang; Andersson, Karl-Erik

    2018-01-01

    To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropanehydrochloride (DOI), and to discuss whether the mechanism can be ascribed to 5-HT2A and 5-HT 2C receptor upregulation in lumbosacral cord motoneurons. Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT2A and -2C receptors in the lumbosacral cord were also investigated using immunohistochemical staining and Western blot analysis. Compared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons. In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT2A and -2C receptor upregulation in lumbosacral cord motoneurons controlling EUS activity. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

  2. Effects of Phellinus linteus administration on serotonin synthesis in the brain and expression of monocarboxylate transporters in the muscle during exhaustive exercise in rats.

    Science.gov (United States)

    Seo, Jin-Hee; Sung, Yun-Hee; Kim, Ki-Jeong; Shin, Mal-Soon; Lee, Eun-Kyu; Kim, Chang-Ju

    2011-01-01

    This study was conducted to determine the effects of Phellinus linteus (PL) on serotonin synthesis in the brain and on the expression of monocarboxylate transporters (MCTs) in muscles during exhaustive exercise in rats. In this study, 60 male Sprague-Dawley rats were divided into the following 6 groups: control; exercise; exercise and 50 mg/kg of PL treatment; exercise and 100 of mg/kg PL treatment; exercise and 200 mg/kg of PL treatment; and exercise and 100 mg/kg of caffeine treatment. Treatment with 200 mg/kg of PL led to a significant increase in the time to exhaustion in response to running on a treadmill and a significant decrease in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats. MCT1 and MCT4 expression of the gastrocnemius muscles was also increased in response to treatment with 200 mg/kg of PL. The results of the present study demonstrated that the administration of PL increased endurance exercise performance through inhibition of serotonin production in the brain and increased the expression of MCT1 and MCT4 in muscles. These results suggest that PL exerts an ergogenic effect.

  3. A prospective, longitudinal study of platelet serotonin and plasma brain-derived neurotrophic factor concentrations in major depression: effects of vortioxetine treatment.

    Science.gov (United States)

    Sagud, Marina; Nikolac Perkovic, Matea; Vuksan-Cusa, Bjanka; Maravic, Anja; Svob Strac, Dubravka; Mihaljevic Peles, Alma; Zivkovic, Maja; Kusevic, Zorana; Pivac, Nela

    2016-09-01

    Various antidepressants occupy brain serotonin transporter (SERT), decrease platelet serotonin (5-HT) concentration, and normalize reduced plasma brain-derived neurotrophic factor (BDNF) concentrations in depressed patients. Vortioxetine is a recently introduced antidepressant with a multimodal mechanism of action. In addition to SERT inhibition, vortioxetine acts via different 5-HT receptors. To further elucidate its mechanism of action, we have investigated the effects of vortioxetine on platelet 5-HT and plasma BDNF concentrations in patients with major depression. Platelet 5-HT and plasma BDNF concentrations were determined in 44 healthy subjects at baseline and in 44 depressed patients before and after 4 weeks of treatment with vortioxetine (5-15 mg daily). Platelet 5-HT concentration was determined using the ortho-phthalaldehyde-enhanced fluorometric method, and plasma BDNF concentration using a commercial enzyme-linked immunosorbent assay (Quantikine ELISA, R&D Systems). At baseline, platelet 5-HT concentrations did not differ between depressed and control subjects, but plasma BDNF values were lower (p = 0.011; ω = 0.80) in depressed patients than in healthy subjects. Vortioxetine treatment significantly (p vortioxetine shares some common effects with other antidepressants. This study is the first to show that, in addition to clinical improvement, 4 weeks of treatment with vortioxetine (5-15 mg daily), decreased platelet 5-HT and increased plasma BDNF concentrations in depressed patients.

  4. No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

    Directory of Open Access Journals (Sweden)

    Dea Siggaard Stenbæk

    Full Text Available Serotonin (5-HT brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R brain availability, which has recently become possible to image with Positron Emission Tomography (PET. This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females, the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17 or the latent construct of global 5-HT4R levels (all p-values > .37. Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

  5. Differential A-to-I RNA editing of the serotonin-2C receptor G-protein-coupled, HTR2C, in porcine brain tissues.

    Science.gov (United States)

    Larsen, Knud; Momeni, Jamal; Farajzadeh, Leila; Bendixen, Christian

    2016-02-01

    The HTR2C gene encodes the 5-Hydroxytryptamine (serotonin) receptor 2C, G-protein-coupled protein which functions as a serotonin receptor. The HTR2C mRNA is subject to A-to-I RNA editing mediated by adenosine deaminases acting on RNA 1 and 2 (ADAR1 and ADAR2). In the current study we examined the molecular characteristics of the porcine HTR2C gene and determined the mRNA editing of the HTR2C transcript in different tissues. The A-to-I RNA editing of HTR2C was shown to be conserved in the porcine homologue with five nucleotides edited in exon 5. A differential editing was demonstrated with a high editing frequency in the frontal cortex, parietal cortex, occipital cortex, hypothalamus, brain stem and spinal cord and significantly lower in the cerebellum. No editing was seen in the liver and kidney. The porcine HTR2C gene was found to be exclusively expressed in brain tissues. The HTR2C gene was mapped to pig chromosome X. The methylation status of the HTR2C gene was examined in brain and liver by bisulfate sequencing and a high degree of methylation was found in the two tissues, at 89 and 72%, respectively. Our data describe differences in RNA editing in various regions of the porcine brain. The differences might reflect functional differences. Similarities between pigs and humans in differential RNA editing support the use of the pig as a model organism for the study of neurological diseases. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  6. Sensorimotor Gating Depends on Polymorphisms of the Serotonin-2A Receptor and Catechol-O-Methyltransferase, but Not on Neuregulin-1 Arg38Gln Genotype: A Replication Study

    Science.gov (United States)

    Quednow, Boris B.; Schmechtig, Anne; Ettinger, Ulrich; Petrovsky, Nadine; Collier, David A.; Vollenweider, Franz X.; Wagner, Michael; Kumari, Veena

    2009-01-01

    Background Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT2AR) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers. Methods We analyzed the 5-HT2AR A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. Results Subjects homozygous for the 5-HT2AR T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms. Conclusions We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT2AR gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating. PMID:19545856

  7. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders

    2010-01-01

    the effect of plasma sex hormone levels on neocortical 5-HT2A receptor binding as imaged with [18F]altanserin PET. The effect of endogenous sex-hormone levels was evaluated by multiple linear regression analysis. Results: Mean neocortical 5-HT2A receptor binding was positively correlated with estradiol (p...... = 0.0001), whereas no independent effects of testosterone could be demonstrated. Correction for other factors of importance for 5-HT2A receptor binding did not change the result. A voxel-based analysis suggested that there were no regional differences in the estradiol effect on cortical 5-HT2A...

  8. Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

    DEFF Research Database (Denmark)

    Hornboll, Bettina; Macoveanu, Julian; Rowe, James

    2013-01-01

    blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp . The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending...... on the amount of blocked 5-HT2A receptors. Conclusions: 5-HT2A receptor mediated signaling increases the sensitivity of the OFC to fearful facial expressions and regulates the strength of a negative feedback signal from the OFC to amygdala during processing of fearful faces....

  9. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

    Science.gov (United States)

    Kometer, Michael; Schmidt, André; Jäncke, Lutz; Vollenweider, Franz X

    2013-06-19

    Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 μg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

  10. Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties.

    Science.gov (United States)

    Shan, Jufang; Khelashvili, George; Mondal, Sayan; Mehler, Ernest L; Weinstein, Harel

    2012-01-01

    From computational simulations of a serotonin 2A receptor (5-HT(2A)R) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT(2A)R, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.

  11. Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry.

    Science.gov (United States)

    Pratelli, Marta; Migliarini, Sara; Pelosi, Barbara; Napolitano, Francesco; Usiello, Alessandro; Pasqualetti, Massimo

    2017-01-01

    Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2(fl)°(x) conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

  12. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

    OpenAIRE

    Valle, Marta; Ana Elda, Maqueda; Rabella, Mireia; Rodríguez Pujadas, Aina; Antonijoan Arbós, Rosa Maria; Romero Lafuente, Sergio; Alonso López, Joan Francesc; Mañanas Villanueva, Miguel Ángel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-01-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus ß-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimental...

  13. Amphetamine Withdrawal Differentially Increases the Expression of Organic Cation Transporter 3 and Serotonin Transporter in Limbic Brain Regions

    Directory of Open Access Journals (Sweden)

    Rajeshwari R. Solanki

    2016-01-01

    Full Text Available Amphetamine withdrawal increases anxiety and stress sensitivity related to blunted ventral hippocampus (vHipp and enhances the central nucleus of the amygdala (CeA serotonin responses. Extracellular serotonin levels are regulated by the serotonin transporter (SERT and organic cation transporter 3 (OCT3, and vHipp OCT3 expression is enhanced during 24 hours of amphetamine withdrawal, while SERT expression is unaltered. Here, we tested whether OCT3 and SERT expression in the CeA is also affected during acute withdrawal to explain opposing regional alterations in limbic serotonergic neurotransmission and if respective changes continued with two weeks of withdrawal. We also determined whether changes in transporter expression were confined to these regions. Male rats received amphetamine or saline for two weeks followed by 24 hours or two weeks of withdrawal, with transporter expression measured using Western immunoblot. OCT3 and SERT expression increased in the CeA at both withdrawal timepoints. In the vHipp, OCT3 expression increased only at 24 hours of withdrawal, with an equivalent pattern seen in the dorsomedial hypothalamus. No changes were evident in any other regions sampled. These regionally specific changes in limbic OCT3 and SERT expression may partially contribute to the serotonergic imbalance and negative affect during amphetamine withdrawal.

  14. Increase in serotonin 5-HT sub 1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Takeshi; Nishino, Naoki; Nakai, Hisao; Tanaka, Chikako (Kobe Univ. School of Medicine (Japan))

    1991-01-01

    Binding studies with ({sup 3}H)8-hydroxy-2-(di-n-propylamino)tetralin (({sup 3}H)8-OH-DPAT), a specific serotonin{sub 1A} (5-HT{sub 1A}) receptor agonist, were done on the autopsied brains from control subjects and from patients with chronic schizophrenia. In the controls, representative Scatchard plots for the specific ({sup 3}H)8-OH-DPAT bindings in the prefrontal cortex and hippocampus revealed a single component of high affinity binding site. The ({sup 3}H)8-OH-DPAT bindings to the prefrontal cortex and hippocampus were potently inhibited by serotonin and 5-HT{sub 1A} agonists, while other neurotransmitters, 5-HT{sub 2} and 5-HT{sub 3} related compounds did not inhibit the binding. The bindings were decreased in the presence of 0.1mM GTP and 0.1mM GppNHp but not in the presence of 0.1mM GMP. In the prefrontal and temporal cortices of schizophrenics, there was a significant increase in the specific ({sup 3}H)8-OH-DPAT binding, by 40% and 60%, respectively, with no change in the hippocampus, amygdala, cingulum, motor cortex, parietal or occipital cortex, as compared to findings in the controls.

  15. Dorsal prefrontal cortical serotonin 2A receptor binding indices are differentially related to individual scores on harm avoidance.

    Science.gov (United States)

    Baeken, Chris; Bossuyt, Axel; De Raedt, Rudi

    2014-02-28

    Although the serotonergic system has been implicated in healthy as well as in pathological emotional states, knowledge about its involvement in personality is limited. Earlier research on this topic suggests that post-synaptic 5-HT2A receptors could be involved in particular in frontal cortical areas. In drug-naïve healthy individuals, we examined the relationship between these 5-HT2A receptors and the temperament dimension harm avoidance (HA) using 123I-5-I-R91150 single photon emission computed tomography (SPECT). HA is a personality feature closely related to stress, anxiety and depression proneness, and it is thought to be mediated by the serotonergic system. We focused on the prefrontal cortices as these regions are frequently implicated in cognitive processes related to a variety of affective disorders. We found a positive relationship between dorsal prefrontal cortical (DPFC) 5-HT2A receptor binding indices (BI) and individual HA scores. Further, our results suggest that those individuals with a tendency to worry or to ruminate are particularly prone to display significantly higher 5-HT2A receptor BI in the left DPFC. Although we only examined psychologically healthy individuals, this relationship suggests a possible vulnerability for affective disorders. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats.

    Science.gov (United States)

    Boban Blagaic, Alenka; Blagaic, Vladimir; Mirt, Mirela; Jelovac, Nikola; Dodig, Goran; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Anic, Tomislav; Dubovecak, Miroslav; Staresinic, Mario; Seiwerth, Sven; Sikiric, Predrag

    2005-04-11

    Serotonin syndrome commonly follows irreversible monoamine oxidase (MAO)-inhibition and subsequent serotonin (5-HT) substrate (in rats with fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia). A stable gastric pentadecapeptide BPC 157 with very safe profile (inflammatory bowel disease clinical phase II, PL-10, PLD-116, PL-14736, Pliva) reduced the duration of immobility to a greater extent than imipramine, and, given peripherally, has region specific influence on brain 5-HT synthesis (alpha-[14C]methyl-L-tryptophan autoradiographic measurements) in rats, different from any other serotonergic drug. Thereby, we investigate this peptide (10 microg, 10 ng, 10 pg/kg i.p.) in (i) full serotonin syndrome in rat combining pargyline (irreversible MAO-inhibition; 75 mg/kg i.p.) and subsequent L-tryptophan (5-HT precursor; 100 mg/kg i.p.; BPC 157 as a co-treatment), or (ii, iii) using pargyline or L-tryptophan given separately, as a serotonin-substrate with (ii) pargyline (BPC 157 as a 15-min posttreatment) or as a potential serotonin syndrome inductor with (iii) L-tryptophan (BPC 157 as a 15 min-pretreatment). In all experiments, gastric pentadecapeptide BPC 157 contrasts with serotonin-syndrome either (i) presentation (i.e., particularly counteracted) or (ii) initiation (i.e., neither a serotonin substrate (counteraction of pargyline), nor an inductor for serotonin syndrome (no influence on L-tryptophan challenge)). Indicatively, severe serotonin syndrome in pargyline + L-tryptophan rats is considerably inhibited even by lower pentadecapeptide BPC 157 doses regimens (particularly disturbances such as hyperthermia and wet dog shake thought to be related to stimulation of 5-HT2A receptors), while the highest pentadecapeptide dose counteracts mild disturbances present in pargyline rats (mild hypothermia, feeble hind limbs abduction). Thereby, in severe serotonin syndrome, gastric pentadecapeptide BPC 157 (alone, no behavioral or

  17. Influence of serotonin transporter gene polymorphism (5-HTTLPR polymorphism on the relation between brain 5-HT transporter binding and heart rate corrected cardiac repolarization interval.

    Directory of Open Access Journals (Sweden)

    Esa Kauppila

    Full Text Available OBJECTIVE: Serotonin transporter gene polymorphism (5-HTTLPR polymorphism predicts the degree of structural and functional connectivity in the brain, and less consistently the degree of vulnerability for anxiety and depressive disorders. It is less known how 5-HTTLPR polymorphism influences on the coupling between brain and neuronal cardiovascular control. The present study demonstrates the impact of 5-HTTLPR polymorphism on the relations between heart rate (HR corrected cardiac repolarization interval (QTc interval and the brain 5-HTT binding. MATERIAL AND METHODS: Thirty healthy young adults (fifteen monozygotic twin pairs (mean age 26±1.3 years, 16 females were imagined with single-photon emission computed tomography (SPECT using iodine-123 labeled 2β-carbomethoxy-3β-(4-iodophenyl nortropane (nor-β-CIT. Continuous ECG recording was obtained from each participant at supine rest. Signal averaged QTc interval on continuous ECG was calculated and compared with the brain imaging results. RESULTS: In the two groups [l homozygotes (n = 16, 10 females, s carriers (n = 14, 8 female] HR and the length of QTc interval were not influenced by 5-HTTLPR polymorphism. There were no significant relations between HR and 5-HTT binding in the brain. There were significant associations between QTc interval and nor-β-CIT binding in the brain in l homozygotes, but not in s carriers (correlations for QTc interval and nor-β-CIT binding of striatum, thalamus and right temporal region were -0.8--0.9, (p<0.0005, respectively. CONCLUSION: The finding of longer QTc interval with less 5-HTT binding availability in major serotonergic binding sites in l homozygotes, but not in s carriers, implicate to differentiated control of QTc interval by 5-HTTLPR polymorphism.

  18. Distribution of serotonin 2A and 2C receptor mRNA expression in the cervical ventral horn and phrenic motoneurons following spinal cord hemisection.

    Science.gov (United States)

    Basura, G J; Zhou, S Y; Walker, P D; Goshgarian, H G

    2001-06-01

    Cervical spinal cord injury leads to a disruption of bulbospinal innervation from medullary respiratory centers to phrenic motoneurons. Animal models utilizing cervical hemisection result in inhibition of ipsilateral phrenic nerve activity, leading to paralysis of the hemidiaphragm. We have previously demonstrated a role for serotonin (5-HT) as one potential modulator of respiratory recovery following cervical hemisection, a mechanism that likely occurs via 5-HT2A and/or 5-HT2C receptors. The present study was designed to specifically examine if 5-HT2A and/or 5-HT2C receptors are colocalized with phrenic motoneurons in both intact and spinal-hemisected rats. Adult female rats (250-350 g; n = 6 per group) received a left cervical (C2) hemisection and were injected with the fluorescent retrograde neuronal tracer Fluorogold into the left hemidiaphragm. Twenty-four hours later, animals were killed and spinal cords processed for in situ hybridization and immunohistochemistry. Using (35)S-labeled cRNA probes, cervical spinal cords were probed for 5-HT2A and 5-HT2C receptor mRNA expression and double-labeled using an antibody to Fluorogold to detect phrenic motoneurons. Expression of both 5-HT2A and 5-HT2C receptor mRNA was detected in motoneurons of the cervical ventral horn. Despite positive expression of both 5-HT2A and 5-HT2C receptor mRNA-hybridization signal over phrenic motoneurons, only 5-HT2A silver grains achieved a signal-to-noise ratio representative of colocalization. 5-HT2A mRNA levels in identified phrenic motoneurons were not significantly altered following cervical hemisection compared to sham-operated controls. Selective colocalization of 5-HT2A receptor mRNA with phrenic motoneurons may have implications for recently observed 5-HT2A receptor-mediated regulation of respiratory activity and/or recovery in both intact and injury-compromised states. Copyright 2001 Academic Press.

  19. A PET [18F]altanserin study of 5-HT2A receptor binding in the human brain and responses to painful heat stimulation

    DEFF Research Database (Denmark)

    Kupers, Ronny Clement Florent; Frokjaer, Vibe G; Naert, Arne

    2009-01-01

    stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT(2A) antagonist, [(18)F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short...... cingulate (r=0.63; p=0.009) cortices. In contrast, measures of regional [(18)F]altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT(2A) receptor availability co-varies with responses to tonic pain......There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT(2A) binding in the brain and responses to noxious heat...

  20. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Jennifer S. Yokoyama

    2015-01-01

    Full Text Available The serotonin transporter length polymorphism (5-HTTLPR short allele (5-HTTLPR-s has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD, a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2 of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03 and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01. These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.

  1. Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

    OpenAIRE

    Marie Hagbom; Claudia Istrate; David Engblom; Thommie Karlsson; Jesus Rodriguez-Diaz; Javier Buesa; Taylor, John A.; Vesa-Matti Loitto; Karl-Eric Magnusson; Håkan Ahlman; Ove Lundgren; Lennart Svensson

    2011-01-01

    otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves...

  2. Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A receptor determine its activation and membrane-driven oligomerization properties.

    Directory of Open Access Journals (Sweden)

    Jufang Shan

    Full Text Available From computational simulations of a serotonin 2A receptor (5-HT(2AR model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011, we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i-the involvement of cholesterol in the activation of the 5-HT(2AR, and (ii-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.

  3. [{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

    2006-01-15

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  4. Providing male rats deficient in iron and n-3 fatty acids with iron and alpha-linolenic acid alone affects brain serotonin and cognition differently from combined provision.

    Science.gov (United States)

    Baumgartner, Jeannine; Smuts, Cornelius M; Zimmermann, Michael B

    2014-06-13

    We recently showed that a combined deficiency of iron (ID) and n-3 fatty acids (n-3 FAD) in rats disrupts brain monoamine metabolism and produces greater memory deficits than ID or n-3 FAD alone. Providing these double-deficient rats with either iron (Fe) or preformed docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) alone affected brain monoamine pathways differently from combined repletion and even exacerbated cognitive deficits associated with double-deficiency. Iron is a co-factor of the enzymes responsible for the conversion of alpha-linolenic acid (ALA) to EPA and DHA, thus, the provision of ALA with Fe might be more effective in restoring brain EPA and DHA and improving cognition in double-deficient rats than ALA alone. In this study we examined whether providing double-deficient rats with ALA and Fe, alone or in combination, can correct deficits in monoamine metabolism and cognition associated with double-deficiency. Using a 2 × 2 design, male rats with concurrent ID and n-3 FAD were fed an Fe + ALA, Fe + n-3 FAD, ID + ALA, or ID + n-3 FAD diet for 5 weeks (postnatal day 56-91). Biochemical measures, and spatial working and reference memory (using the Morris water maze) were compared to age-matched controls. In the hippocampus, we found a significant Fe × ALA interaction on DHA: Compared to the group receiving ALA alone, DHA was significantly higher in the Fe + ALA group. In the brain, we found significant antagonistic Fe × ALA interactions on serotonin concentrations. Provision of ALA alone impaired working memory compared with age-matched controls, while in the reference memory task ALA provided with Fe significantly improved performance. These results indicate that providing either iron or ALA alone to double-deficient rats affects serotonin pathways and cognitive performance differently from combined provision. This may be partly explained by the enhancing effect of Fe on the conversion of ALA to EPA and DHA.

  5. Brain SPECT imaging and whole-body biodistribution with [{sup 123}I]ADAM - a serotonin transporter radiotracer in healthy human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Lin, K.-J. [Graduate Institute of Clinical Medical Sciences, Chang-Gung University, Tao-Yuan 333, Taiwan (China); Molecular Imaging Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Department of Nuclear Medicine, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Liu, C.-Y. [Neuroscience Research Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Department of Psychiatry, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Wey, S.-P. [Molecular Imaging Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Tao-Yuan 333, Taiwan (China); Hsiao, I.-T. [Molecular Imaging Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Tao-Yuan 333, Taiwan (China); Wu, Jay [Health Physics Divisions, Atomic Energy Council, Institute of Nuclear Energy Research, Tao-Yuan 325, Taiwan (China); Fu, Y.-K. [Atomic Energy Council, Institute of Nuclear Energy Research, Tao-Yuan 325, Taiwan (China); Yen, T.-C. [Molecular Imaging Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China) and Department of Nuclear Medicine, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan (China)]. E-mail: yen1110@adm.cgmh.org.tw

    2006-02-15

    Introduction: [{sup 123}I]-2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([{sup 123}I]ADAM), a novel radiotracer, has promising application in the imaging of the serotonin transporter (SERT) in the human brain. In this study, the optimal scanning time for acquiring brain single photon emission computed tomography (SPECT) images was determined by performing dynamic SPECT studies at intervals from 0 to 6 h postinjection of [{sup 123}I]ADAM. Additionally, radiation-absorbed doses were determined for three healthy human subjects using attenuation-corrected images. Methods: Twelve subjects were randomized into one of three study groups as follows: whole-body distribution imaging (n=3), dynamic SPECT imaging (n=3) and brain SPECT imaging (n=6). The radiation-absorbed dose was calculated using MIRDOSE 3.0 software with attenuation-corrected data. The specific binding (SB) ratio of the brain stem was measured from dynamic SPECT images to determine the optimal scanning time. Results: Dynamic SPECT images showed that the SB of the brain stem gradually increased to a maximum 4 h postinjection. Single photon emission computed tomography images at 4 h postinjection showed a high uptake of the radiotracer (SB) in the hypothalamus (1.40{+-}0.12), brain stem (1.44{+-}0.16), pons (1.13{+-}0.14) and medial temporal lobe (0.59{+-}0.10). The mean adult male value of effective dose was 3.37x10{sup -2} mSv/MBq with a 4.8-h urine-voiding interval. Initial high uptake in SERT-rich sites was demonstrated in the lung and brain. A prominent washout of the radiotracer from the lung further increased brain radioactivity that reached a peak value of 5.03% of injected dose 40 min postinjection. Conclusions: [{sup 123}I]ADAM is a promising radiotracer for SPECT imaging of SERT in humans with acceptable dosimetry and high uptake in SERT-rich regions. Brain SPECT images taken within 4 h following injection show optimal levels of radiotracer uptake in known SERT sites. However, dynamic

  6. Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats

    Directory of Open Access Journals (Sweden)

    Laura A. León

    2017-07-01

    Full Text Available The role of serotonin (5-hydroxytryptamine [5-HT] and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]. The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM. In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL and prelimbic (PL cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices.Highlights-CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more “anxious” phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF or increased (CLF anxiety-like behavior.-PL injections either decreased (CHF anxiety

  7. Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats

    Science.gov (United States)

    León, Laura A.; Castro-Gomes, Vitor; Zárate-Guerrero, Santiago; Corredor, Karen; Mello Cruz, Antonio P.; Brandão, Marcus L.; Cardenas, Fernando P.; Landeira-Fernandez, J.

    2017-01-01

    The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more “anxious” phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or

  8. How serotonin shapes moral judgment and behavior

    National Research Council Canada - National Science Library

    Siegel, Jenifer Z; Crockett, Molly J

    2013-01-01

    .... Here, we review recent studies showing how altering brain chemistry can alter moral judgment and behavior, focusing in particular on the neuromodulator serotonin and its role in shaping values...

  9. Comparative evaluation of two serotonin transporter ligands in the human brain: [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Suhara, Tetsuya; Sudo, Yasuhiko; Inoue, Makoto; Ichimiya, Tetsuya; Yasuno, Fumihiko [Brain Imaging Project, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); CREST, Japan Science and Technology Corporation, Kawaguchi (Japan); Hashimoto, Kenji [Welfide Corporation, Iruma (Japan); Zhang, Ming-Rong; Suzuki, Kazutoshi [Brain Imaging Project, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan)

    2002-10-01

    Serotonin (5-HT) is considered to be an important transmitter underlying mood and behaviour. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. A number of ligands have been developed to visualise the 5-HT transporter in vivo, but only a few have successfully visualised specific binding in vivo. In this study, we comparatively evaluated two ligands for 5-HT transporter, [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine, in the human brain. Brain uptake of [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine was measured with PET in 15 healthy volunteers. Second PET scans were performed after pretreatment with the potent 5-HT reuptake inhibitor clomipramine. Data were analysed as regional brain uptake as well as whole brain uptake. In six healthy volunteers uptake of the two ligands was also measured in the lung since it is one of the high-uptake organs in the body. In the brain, high accumulation was observed in the thalamus and striatum, the regions known to contain high densities of 5-HT transporter, for both [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine. The average ratio of thalamus to cerebellum uptake at 90 min after the tracer injection was approximately 1.6 for [{sup 11}C](+)McN5652 and 1.7 for [{sup 11}C]cyanoimipramine, while the ratios obtained after pretreatment with clomipramine were approximately 1.2. However, the whole brain uptake of [{sup 11}C](+)McN5652 was approximately twice that of [{sup 11}C]cyanoimipramine, while the lung uptake of [{sup 11}C](+)McN5652 was approximately half that of [{sup 11}C]cyanoimipramine. Both [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine showed sufficient specific binding for performance of a quantitative analysis in the brain. [{sup 11}C](+)McN5652 could be superior because of its higher distribution to the brain. (orig.)

  10. How serotonin shapes moral judgment and behavior

    Science.gov (United States)

    Siegel, Jenifer Z; Crockett, Molly J

    2013-01-01

    Neuroscientists are now discovering how hormones and brain chemicals shape social behavior, opening potential avenues for pharmacological manipulation of ethical values. Here, we review recent studies showing how altering brain chemistry can alter moral judgment and behavior, focusing in particular on the neuromodulator serotonin and its role in shaping values related to harm and fairness. We synthesize previous findings and consider the potential mechanisms through which serotonin could increase the aversion to harming others. We present a process model whereby serotonin influences social behavior by shifting social preferences in the positive direction, enhancing the value people place on others’ outcomes. This model may explain previous findings relating serotonin function to prosocial behavior, and makes new predictions regarding how serotonin may influence the neural computation of value in social contexts. PMID:25627116

  11. The new PET imaging agent [{sup 11}C]AFE is a selective serotonin transporter ligand with fast brain uptake kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Zhihong [Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032 (United States); Guo Ningning [Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032 (United States); Narendran, Raj [Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032 (United States)] [and others

    2004-11-01

    A new positron emission tomography (PET) radioligand for the serotonin transporter (SERT), [{sup 11}C]2-[2-[[(dimethylamino)methyl]phenyl]thio]-5-(2-fluoroethyl)phenylamine ([{sup 11}C]AFE, 12), was synthesized and evaluated in vivo in rats and baboons. [{sup 11}C]AFE (12) was prepared from its monomethylamino precursor 11 by reaction with high specific activity [{sup 11}C]methyl triflate. Radiochemical yield was 32{+-}17% based on [{sup 11}C]methyl triflate (n=6) and specific activity was 1670{+-}864 Ci/mmol at end of synthesis (EOS, n=6). Binding assays indicated that AFE displays high affinity for SERT (K{sub i}=1.80 nM for hSERT) and lower affinity for norepinephrine transporter (K{sub i}=946 nM for hNET) or dopamine transporter (K{sub i}>10,000 nM for hDAT). In addition, AFE displays negligible binding affinities for other serotonin and dopamine receptors, indicating an excellent binding selectivity in vitro. Biodistribution studies in rats indicated that [{sup 11}C]AFE enters the brain readily and localizes in regions known to contain high concentrations of SERT, such as the thalamus, hypothalamus, frontal cortex and striatum. Moreover, such binding in SERT-rich brain regions is reduced significantly by pretreatment with either citalopram or the cold compound itself, but not by nisoxetine or GBR 12935, thus demonstrating that [{sup 11}C]AFE binding in the rat brain is saturable, specific and selective for the SERT. Imaging experiments in baboons indicated that the uptake pattern of [{sup 11}C]AFE is consistent with the known distribution of SERT in the baboon brain, with high levels of radioactivity detected in the midbrain and thalamus, moderate levels in the hippocampus and striatum and low levels in the cortical regions. The uptake kinetics of [{sup 11}C]AFE in the baboon brain is rapid, with activity in the midbrain and thalamus peaking at 15-40 min postinjection. Pretreatment of the baboon with citalopram (4 mg/kg) 20 min before radioactivity injection

  12. EFFECTS OF 5, 7-DIHYDROXYTRYPTAMINE-INDUCED DEPLETION OF BRAIN SEROTONIN ON RADIAL ARM-MAZE TASK IN RATS

    Directory of Open Access Journals (Sweden)

    Vasile Hefco

    2005-08-01

    Full Text Available Adult rats pretreated with desipramine (25 mg/kg i.p.30 min before anesthesia in order to protect noradrenergic system, were subjected to intracerebroventriculare injection of 5, 7 –dihydroxytryptamine (5, 7-DHT, 150 μg, 4.5 μl/ventricle, a chronic neurotoxin of the central serotonergic function. After 1.5 months later, we assessed the working memory and reference memory in radial 8 arm-mazes. Serotonergic depletion impaired more significantly shortterm memory tested by means of the average working memory errors, entries to repeat and average time taken to consume all five baits during 12 days training. Long-term memory, explored by means of reference memory errors, was less impaired. It is concluded that serotonin, among other neurotransmitters, play one important role in cognitive functions, including learning and memory.

  13. Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

    Science.gov (United States)

    Rawson, Kerri S.; Dixon, David; Nowotny, Petra; Ricci, William M.; Binder, Ellen F.; Rodebaugh, Thomas L.; Wendleton, Leah; Doré, Peter; Lenze, Eric J.

    2015-01-01

    Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID:25781924

  14. Regional changes in brain dopamine and serotonin metabolism induced by conditioned circling in rats: effects of water deprivation, learning and individual differences in asymmetry.

    Science.gov (United States)

    Glick, S D; Carlson, J N

    1989-12-18

    Rats were trained, using water reinforcement, to turn in circles (rotation) during 1 h daily test sessions. After achieving criterion performance (100 full turns per hour) for at least 10 consecutive sessions, rats were sacrificed 20 min after starting a session and levels of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), serotonin, and 5-HIAA (5-hydroxyindoleacetic acid) were assayed in nigrostriatal (corpus striatum), mesolimbic (nucleus accumbens) and mesocortical (medial prefrontal cortex) brain regions. Other control groups of rats were comparably water deprived or satiated at the time of sacrifice. Although, as previously reported, evidence of 'two populations' of rats was again apparent with respect to the relationship between direction of spontaneous turning and asymmetry in striatal dopamine levels, there were no lateralized effects of operant rotational training on striatal dopamine and DOPAC levels nor on the DOPAC/dopamine ratio. There were, however, bilateral neurochemical effects of both rotational training and water deprivation in striatum: an increase in the 5-HIAA/serotonin ratio in both sexes was attributable to learning whereas an increase in the DOPAC/dopamine ratio in males was attributed to water deprivation. A bilateral decrease in the DOPAC/dopamine ratio in the mesolimbic and mesocortical regions of both sexes was also induced by water deprivation. The only lateralized neurochemical changes associated with learning to rotate in the operant task occurred in the medial prefrontal cortex: in both sexes, dopamine levels were higher in the ipsilateral than in the contralateral cortex and the DOPAC/dopamine ratio was greater in the contralateral than in the ipsilateral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Microbiome-Gut-Brain Axis: A Pathway for Improving Brainstem Serotonin Homeostasis and Successful Autoresuscitation in SIDS-A Novel Hypothesis.

    Science.gov (United States)

    Praveen, Vijayakumar; Praveen, Shama

    2016-01-01

    Sudden infant death syndrome (SIDS) continues to be a major public health issue. Following its major decline since the "Back to Sleep" campaign, the incidence of SIDS has plateaued, with an annual incidence of about 1,500 SIDS-related deaths in the United States and thousands more throughout the world. The etiology of SIDS, the major cause of postneonatal mortality in the western world, is still poorly understood. Although sleeping in prone position is a major risk factor, SIDS continues to occur even in the supine sleeping position. The triple-risk model of Filiano and Kinney emphasizes the interaction between a susceptible infant during a critical developmental period and stressor/s in the pathogenesis of SIDS. Recent evidence ranges from dysregulated autonomic control to findings of altered neurochemistry, especially the serotonergic system that plays an important role in brainstem cardiorespiratory/thermoregulatory centers. Brainstem serotonin (5-HT) and tryptophan hydroxylase-2 (TPH-2) levels have been shown to be lower in SIDS, supporting the evidence that defects in the medullary serotonergic system play a significant role in SIDS. Pathogenic bacteria and their enterotoxins have been associated with SIDS, although no direct evidence has been established. We present a new hypothesis that the infant's gut microbiome, and/or its metabolites, by its direct effects on the gut enterochromaffin cells, stimulates the afferent gut vagal endings by releasing serotonin (paracrine effect), optimizing autoresuscitation by modulating brainstem 5-HT levels through the microbiome-gut-brain axis, thus playing a significant role in SIDS during the critical period of gut flora development and vulnerability to SIDS. The shared similarities between various risk factors for SIDS and their relationship with the infant gut microbiome support our hypothesis. Comprehensive gut-microbiome studies are required to test our hypothesis.

  16. Microbiome–Gut–Brain Axis: A Pathway for Improving Brainstem Serotonin Homeostasis and Successful Autoresuscitation in SIDS—A Novel Hypothesis

    Science.gov (United States)

    Praveen, Vijayakumar; Praveen, Shama

    2017-01-01

    Sudden infant death syndrome (SIDS) continues to be a major public health issue. Following its major decline since the “Back to Sleep” campaign, the incidence of SIDS has plateaued, with an annual incidence of about 1,500 SIDS-related deaths in the United States and thousands more throughout the world. The etiology of SIDS, the major cause of postneonatal mortality in the western world, is still poorly understood. Although sleeping in prone position is a major risk factor, SIDS continues to occur even in the supine sleeping position. The triple-risk model of Filiano and Kinney emphasizes the interaction between a susceptible infant during a critical developmental period and stressor/s in the pathogenesis of SIDS. Recent evidence ranges from dysregulated autonomic control to findings of altered neurochemistry, especially the serotonergic system that plays an important role in brainstem cardiorespiratory/thermoregulatory centers. Brainstem serotonin (5-HT) and tryptophan hydroxylase-2 (TPH-2) levels have been shown to be lower in SIDS, supporting the evidence that defects in the medullary serotonergic system play a significant role in SIDS. Pathogenic bacteria and their enterotoxins have been associated with SIDS, although no direct evidence has been established. We present a new hypothesis that the infant’s gut microbiome, and/or its metabolites, by its direct effects on the gut enterochromaffin cells, stimulates the afferent gut vagal endings by releasing serotonin (paracrine effect), optimizing autoresuscitation by modulating brainstem 5-HT levels through the microbiome–gut–brain axis, thus playing a significant role in SIDS during the critical period of gut flora development and vulnerability to SIDS. The shared similarities between various risk factors for SIDS and their relationship with the infant gut microbiome support our hypothesis. Comprehensive gut-microbiome studies are required to test our hypothesis. PMID:28111624

  17. Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels.

    Science.gov (United States)

    Huggins, Kimberly N; Mathews, Tiffany A; Locke, Jason L; Szeliga, Kendall T; Friedman, David P; Bennett, Allyson J; Jones, Sara R

    2012-06-01

    Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression

    Directory of Open Access Journals (Sweden)

    Simona eSpinelli

    2013-12-01

    Full Text Available In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC, amygdala (AMY, and hippocampus (HC and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s variant of the serotonin transporter (5-HTT gene-linked polymorphic region (5-HTTLPR. Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype x developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET versus wildtype (WT on early-adulthood behavioral measures and brain structure (using magnetic resonance imaging relevant to human major depression. Behaviorally, adolescent stress (AS increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HTT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract and the cerebral peduncle, in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HTT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression.

  19. On the association between lipopolysaccharide induced catalepsy and serotonin metabolism in the brain of mice genetically different in the predisposition to catalepsy.

    Science.gov (United States)

    Bazhenova, Ekaterina Yu; Kulikov, Alexander V; Tikhonova, Maria A; Bazovkina, Daria V; Fursenko, Daria V; Popova, Nina K

    2013-10-01

    The study of the interaction between nervous and immune systems in the mechanism of psychopathology is an important problem of neuroscience. Catalepsy (freezing reaction) is a passive defensive strategy in response to threatening stimuli. An exaggerated form of catalepsy is a syndrome of some grave mental disorders. Both the brain serotonin (5-HT) and immune systems were shown to be involved in the mechanism of catalepsy. Here we compared the effects of two doses (50 or 200 μg/kg, ip) of innate immune system activator, bacterial lipopolysaccharide (LPS), on catalepsy, 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the hippocampus, striatum, and midbrain of mice of catalepsy-prone (CBA/Lac and AKR.CBA-D13Mit76) and catalepsy-resistant (AKR/J) strains. The expression of LPS-induced catalepsy as well as 5-HIAA/5-HT ratio in the midbrain and striatum were significantly higher in mice of the catalepsy-prone strains compared with animals of the catalepsy-resistant strains. These results indicated an involvement of the brain 5-HT system in the cataleptogenic effect of LPS and open up new vistas for understanding the nervous-immune mechanism of behavioral disorders. © 2013.

  20. Elevated expression of serotonin 5-HT2A receptors in the rat ventral tegmental area enhances vulnerability to the behavioral effects of cocaine

    Directory of Open Access Journals (Sweden)

    David V. Herin

    2013-02-01

    Full Text Available The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT at 5-HT2A receptors (5-HT2AR localized to the VTA. In the present study, we tested the hypothesis that virally-mediated overexpression of 5-HT2AR in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT2AR linked to a synthetic marker peptide (Flag was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT2AR-Flag. This viral vector (2 µl; 109-10 transducing units/ml was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer’s solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip, both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p<0.05. Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT2AR protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT2AR in the VTA and suggest that the 5-HT2AR receptor in the VTA plays a role in regulation of responsiveness to cocaine.

  1. Simultaneous measurement of serotonin and 5-hydroxyindoleacetic acid in rat brain using a liquid chromatographic method with electrochemical detection

    NARCIS (Netherlands)

    Vries, M. de; Odink, J.

    1991-01-01

    A simple and sensitive method for the simultaneous measurement of 5-hydroxytryptamine and its main metabolite 5-hydroxyindoleacetic acid in rat brain is described. Brain tissue samples were only deproteinated and, without further extraction, were injected directly onto a high-performance liquid

  2. Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.

    Science.gov (United States)

    Anderberg, Rozita H; Richard, Jennifer E; Eerola, Kim; López-Ferreras, Lorena; Banke, Elin; Hansson, Caroline; Nissbrandt, Hans; Berqquist, Filip; Gribble, Fiona M; Reimann, Frank; Wernstedt Asterholm, Ingrid; Lamy, Christophe M; Skibicka, Karolina P

    2017-04-01

    Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation. © 2017 by the American Diabetes Association.

  3. [C-11]{beta}CNT: A new monoamine uptake ligand for studying serotonin and dopamine transporter sites in the living brain with PET

    Energy Technology Data Exchange (ETDEWEB)

    Mulholland, G.K.; Zheng, Q.H.; Zhou, F.C. [Indiana Univ. Medical Center, Indianapolis, IN (United States)] [and others

    1996-05-01

    There is considerable interest in measuring serotonin (5HT) and dopamine (DA) function in the human brain. Altered levels of 5HT and DA are recognized in drug abuse, neurotoxicities, psychiatric disorders, and neurodegenerative conditions including Alzheimer`s and Parkinson`s disease. Several phenyltropane analogs of cocaine bind tightly to both DA and 5HT uptake proteins. We have made a new agent from this class called {beta}CNT, 2{beta}-carboxymethyl-3{beta}-(2-naphthyl)-tropane, the isosteric O-for-CH{sub 2} analog of a compound reported to have among the highest measured affinities for DA and 5HT transporters and studied its in vivo brain distributions in animals for the first time. Optically pure {beta}CNT was made from cocaine, and labeled at the O-methyl position by esterification of {beta}CNT-acid with [C-11]CH{sub 3}OTfl under conditions similar to Wilson`s. HPLC-purified (99+%) final products (15-50% eob yield from CO{sub 2}, 40 min synth) had specific activities 0.1-1.2 Ci/{mu}mol at the time of injection. Preliminary [C-11]{beta}{beta}CNT rodent distribution showed very high brain uptake (3% ID at 60 min) and localization (striat: fr cort: hypo: cer: blood, 11: 5: 4: 1: 06). {beta}CNT-PET studies in juvenile pigs (5-20 mCi, 20-35 kg) found rapid brain uptake, and prominent retention (85 min) in midbrain, anterior brainstem and striatum, followed by cortex and olfactory bulb. Paroxetine pretreatment (5HT uptake blocker, 2mg/kg), diminished retention in most brain areas; nomifensine (DA/NE uptake blocker, 6 mg/kg) reduced striatum selectively. Direct comparisons of [C-11]{beta}CNT with other PET transporter radioligands {beta}CFT, {beta}CIT, and {beta}CTT (RTI-32) in the same pig found {beta}CNT had highest overall brain uptake among the agents. These initial results suggest {beta}CNT has favorable properties for imaging both 5HT and DA transporters in vivo, and further evaluation of its potential as a human PET agent is warranted.

  4. Early-life stress induces persistent alterationsin 5-HT1Areceptor and serotonin transporter mRNA expression in the adultrat brain.

    Directory of Open Access Journals (Sweden)

    Javier A. Bravo

    2014-04-01

    Full Text Available Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT mRNA expression in brain areas involved in the control of emotions, memory and fear as well as in regions controlling the central serotonergic tone.To test this, Sprague-Dawley rats were subjected to MS for 3h daily during post-natal days 2-12. As control, age matched rats were not separated (NS from their dams. When animals reached adulthood (11-13 weeks brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN and SERT in the DRN was analyzed through in-situ hybridisation.Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats.These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood.

  5. Comparing the Expression of Genes Related to Serotonin (5-HT in C57BL/6J Mice and Humans Based on Data Available at the Allen Mouse Brain Atlas and Allen Human Brain Atlas

    Directory of Open Access Journals (Sweden)

    C. A. Acevedo-Triana

    2017-01-01

    Full Text Available Brain atlases are tools based on comprehensive studies used to locate biological characteristics (structures, connections, proteins, and gene expression in different regions of the brain. These atlases have been disseminated to the point where tools have been created to store, manage, and share the information they contain. This study used the data published by the Allen Mouse Brain Atlas (2004 for mice (C57BL/6J and Allen Human Brain Atlas (2010 for humans (6 donors to compare the expression of serotonin-related genes. Genes of interest were searched for manually in each case (in situ hybridization for mice and microarrays for humans, normalized expression data (z-scores were extracted, and the results were graphed. Despite the differences in methodology, quantification, and subjects used in the process, a high degree of similarity was found between expression data. Here we compare expression in a way that allows the use of translational research methods to infer and validate knowledge. This type of study allows part of the relationship between structures and functions to be identified, by examining expression patterns and comparing levels of expression in different states, anatomical correlations, and phenotypes between different species. The study concludes by discussing the importance of knowing, managing, and disseminating comprehensive, open-access studies in neuroscience.

  6. Brain serotonin synthesis in adult males characterized by physical aggression during childhood: a 21-year longitudinal study.

    Directory of Open Access Journals (Sweden)

    Linda Booij

    2010-06-01

    Full Text Available Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait.In the present study, positron emission tomography with the tracer alpha-[(11C]methyl-L-tryptophan ((11C-AMT was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age +/- SD: 27.1+/-0.7: individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8 and individuals with normal (low patterns of physical aggression (LPA; N = 18. The C-LHPA males had significantly lower trapping of (11C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders.These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.

  7. The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

    Science.gov (United States)

    Tonello, Lucio; Gashi, Bekim; Scuotto, Alessandro; Capello, Glenda; Cocchi, Massimo; Gabrielli, Fabio; Tuszynski, Jack A

    2017-09-15

    Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with bio-photons and use them for proper brain function. Further, as auxin drives roots "arborescence" within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastro-intestinal tract. This auxin/serotonin parallel suggests the root-branches axis in plants may be an evolutionary precursor to the gastro-intestinal-brain axis in humans. Finally, we hypothesize that light might be an important factor, both in gastro-intestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness.

  8. Peripheral SLC6A4 DNA Methylation Is Associated with In Vivo Measures of Human Brain Serotonin Synthesis and Childhood Physical Aggression

    Science.gov (United States)

    Wang, Dongsha; Szyf, Moshe; Benkelfat, Chawki; Provençal, Nadine; Turecki, Gustavo; Caramaschi, Doretta; Côté, Sylvana M.; Vitaro, Frank; Tremblay, Richard E.; Booij, Linda

    2012-01-01

    The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. PMID:22745770

  9. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.

    Directory of Open Access Journals (Sweden)

    Dongsha Wang

    Full Text Available The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET measures of brain serotonin (5-HT synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC. Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25 who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20 where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

  10. Serotonin and arginine-vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain.

    Science.gov (United States)

    Terranova, Joseph I; Song, Zhimin; Larkin, Tony E; Hardcastle, Nathan; Norvelle, Alisa; Riaz, Ansa; Albers, H Elliott

    2016-11-15

    There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.

  11. Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats Role of serotonin synthesis

    NARCIS (Netherlands)

    Bosker, Fokko J.; Tanke, Marit A. C.; Jongsma, Minke E.; Cremers, Thomas I. F. H.; Jagtman, Evelien; Pietersen, Charmaine Y.; van der Hart, Marieke G. C.; Gladkevich, Anatoliy V.; Kema, Ido P.; Westerink, Ben H. C.; Korf, Jakob; den Boer, Johan A.

    2010-01-01

    We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function and attempted to identify underlying mechanisms Biochemistry of serotonin was assessed with brain tissue assays and microdialysis behavior

  12. Perspectives on genetic animal models of serotonin toxicity.

    Science.gov (United States)

    Kalueff, Allan V; LaPorte, Justin L; Murphy, Dennis L

    2008-01-01

    Serotonin syndrome, or serotonin toxicity, is a serious disorder attributable to exaggerated serotonergic function in the brain, most commonly after antidepressant overdose or after combining several psychotropic medications. Similar condition (serotonin syndrome-like behavior) can be evoked in animals experimentally, following administration of serotonergic drugs. In addition to pharmacological stimulation, some genetic and other factors may contribute to serotonin toxicity, prompting the need for new experimental genetic models relevant to this disorder. Here we discuss current problems and perspectives regarding genetic animal models of serotonin-related syndromes, and outline the potential utility of these models in experimental neurochemistry and clinical research.

  13. Brain-derived neurotrophic factor (Val66Met and serotonin transporter (5-HTTLPR polymorphisms modulate plasticity in inhibitory control performance over time but independent of inhibitory control training

    Directory of Open Access Journals (Sweden)

    Sören Enge

    2016-07-01

    Full Text Available Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N=122 and a three-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal was employed and genetic variation (Val66Met in the brain-derived neurotrophic factor (BDNF promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HT transporter (5-HTTLPR was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting

  14. Differential brain activation in exclusively homosexual and heterosexual men produced by the selective serotonin reuptake inhibitor, fluoxetine.

    Science.gov (United States)

    Kinnunen, Leann H; Moltz, Howard; Metz, John; Cooper, Malcolm

    2004-10-22

    A number of studies have shown a relationship between "sexual orientation" and size of various brain nuclei. We hypothesized that neurotransmitter differences might parallel neuroanatomical differences in the hypothalamus. We administered 40 mg of fluoxetine as a challenge to the serotonergic systems of exclusively homosexual and exclusively heterosexual men and measured cerebral metabolic changes with fluorodeoxyglucose positron emission tomography (FDG-PET). The metabolic differences we observed might reflect underlying neurochemical differences between homosexual and heterosexual men.

  15. Serotonin and benzylamine oxidation by type A and type B MAO of rat brain in presence of organophosphate pesticides.

    Science.gov (United States)

    Nag, M; Nandy, N

    2001-08-01

    Organophosphate (OP) pesticides, monocrotophos (MCP), dichlorvos (DDVP) and phosphamidon significantly inhibit both MAO-A and MAO-B activities in rat brain mitochondria. The inhibition of MAO-A by MCP is reversible whereas the inhibition by DDVP and phosphamidon is irreversible. MAO-B is inhibited irreversibly by all these organophosphates suggesting that the mechanism of action of OP pesticides is through phosphorylation of serine residue present in active centre of MAO.

  16. Molecular fMRI of Serotonin Transport.

    Science.gov (United States)

    Hai, Aviad; Cai, Lili X; Lee, Taekwan; Lelyveld, Victor S; Jasanoff, Alan

    2016-11-23

    Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread nonsaturating serotonin removal with maximal rates in the lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate the utility of molecular fMRI for characterization of neurochemical dynamics. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Evening intake of α-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention

    NARCIS (Netherlands)

    Markus, C.R.; Jonkman, L.M.; Lammers, J.H.C.M.; Deutz, N.E.P.; Messer, M.H.; Rigtering, N.

    2005-01-01

    Background: Brain serotonin function is thought to promote sleep regulation and cognitive processes, whereas sleep abnormalities and subsequent behavioral decline are often attributed to deficient brain serotonin activity. Brain uptake of the serotonin precursor tryptophan is dependent on nutrients

  18. The influence of selective serotonin reuptake inhibitors on the plasma and brain pharmacokinetics of the simplest phenothiazine neuroleptic promazine in the rat.

    Science.gov (United States)

    Daniel, W A; Syrek, M; Wójcikowski, J

    1999-06-01

    The aim of the present study was to investigate a possible impact of the three selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline on the pharmacokinetics of promazine in a steady state in rats. Promazine was administered twice a day for 2 weeks, alone or jointly with one of the antidepressants. Concentrations of promazine and its two main metabolites (N-desmethylpromazine and sulfoxide) in the plasma and brain were measured at 30 min and 6 and 12 h after the last dose of the drugs. All the investigated SSRIs increased the plasma and brain concentrations of promazine up to 300% of the control value, their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in the promazine metabolites' concentrations and in the promazine-metabolite concentration ratios were observed. In vitro studies with liver microsomes of rats treated chronically with promazine, SSRIs or their combination did not show any significant changes in the concentrations of cytochromes P-450 and b-5. However, treatment with fluoxetine, alone or in a combination with promazine, decreased the rates of promazine N-demethylation and sulfoxidation. A similar effect was observed in the case of promazine and fluvoxamine combination. Kinetic studies into promazine metabolism, carried out on control liver microsomes in the absence or presence of SSRIs added in vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the antidepressants. The results of in vivo and in vitro studies indicate the following mechanisms of the observed interactions: (a) competition for an active site of promazine N-demethylase and sulfoxidase; (b) adaptive changes in cytochrome P-450, produced by chronic treatment with fluoxetine or fluvoxamine; (c) additionally, increases in the sum of concentrations of promazine+ metabolites, produced by fluoxetine and sertraline in vivo, suggest simultaneous inhibition of another, not investigated by us

  19. A PET study of effects of chronic 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on serotonin markers in Göttingen minipig brain

    DEFF Research Database (Denmark)

    Cumming, Paul; Møller, Mette; Benda, Kjeld

    2007-01-01

    The psychostimulant 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive and neuroch...

  20. Serotonin and Blood Pressure Regulation

    Science.gov (United States)

    Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

    2012-01-01

    5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

  1. Serotonin transporter genotype and mild traumatic brain injury independently influence resilience and perception of limitations in veterans.

    Science.gov (United States)

    Graham, David P; Helmer, Drew A; Harding, Mark J; Kosten, Thomas R; Petersen, Nancy J; Nielsen, David A

    2013-06-01

    Evidence indicates that individuals with the 5-HTTLPR variant short/short genotype have increased sensitivity to both positive and negative perceptions of perceived social support. The aim of this study was to evaluate this association among Veterans in the context of mild traumatic brain injury (TBI). As part of a larger TBI center, we performed a cross-sectional study of 67 OEF/OIF/OND Veterans (41 with TBI and 26 controls without TBI) who completed the questionnaires and consented to genetic testing. The primary measures included the Connor-Davidson Resilience Scale (CDRISC) and the Perceived Limitations in community participation subscale of the Community Reintegration of Service Members Instrument (CRIS-PL). Both 5-HTTLPR genotype and TBI status were independently associated with the CRIS-PL (p = .009 for genotype, p = .001 for TBI) and the CDRISC (p = .015 for genotype, p = .003 for TBI) scores. This study suggests that both the 5-HTTLPR genotype and TBI status independently, in an almost equal but opposite direction, influence resilience and perceived limitations to social participation. Further, resilience appears more sensitive to perceived limitations in Veterans carrying an S'S' genotype than in L' carriers, but only in the context of having sustained a TBI. While having a TBI appeared to increase a Veteran's sensitivity to social stress, the Veteran's who were L' allele carriers with a TBI fared the worst, with lower resilience and more perceived limitations for community participation compared to L' carrier Veterans without a TBI or Veterans with the S'S' genotype regardless of TBI status. Published by Elsevier Ltd.

  2. Novel fused pyrrole heterocyclic ring systems as structure analogs of LE 300: Synthesis and pharmacological evaluation as serotonin 5-HT(2A), dopamine and histamine H(1) receptor ligands.

    Science.gov (United States)

    Rostom, Sherif A F

    2010-02-01

    LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D(1)/D(5 )receptors and the serotonin 5-HT(2A )receptor. This compound consists of a ten-membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz-indolo-azecine, both rings were removed and replaced with a 1H-pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3-g]indolizine, pyrrolo[3,2-a]quinolizine rings and their corresponding dimethylpyrrolo[2,3-d]azonine, and dimethylpyrrolo[2,3-d]azecine were synthesized to be evaluated for their activity at the 5-HT(2A) and dopamine D(1), D(2L), D(4), D(5) receptors in relation to LE 300. In addition, their activity at the H(1)-histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3-g]indolizine 7 and pyrrolo[3,2-a]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3-d]azonine 11 and pyrrolo[2,3-d]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5-HT(2A )and histamine H(1 )receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1H-pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine-type compounds.

  3. Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment.

    Science.gov (United States)

    Bixo, M; Allard, P; Bäckström, T; Mjörndal, T; Nyberg, S; Spigset, O; Sundström-Poromaa, I

    2001-08-01

    Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.

  4. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.

    Directory of Open Access Journals (Sweden)

    Xavier Viñals

    2015-07-01

    Full Text Available Activation of cannabinoid CB1 receptors (CB1R by delta9-tetrahydrocannabinol (THC produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

  5. Measuring the serotonin uptake site using (/sup 3/H)paroxetine--a new serotonin uptake inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Gleiter, C.H.; Nutt, D.J.

    1988-01-01

    Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand.

  6. Imaging of the brain serotonin transporters (SERT) with {sup 18}F-labelled fluoromethyl-McN5652 and PET in humans

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Swen [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Medical Center, AdiposityDiseases, Leipzig (Germany); Brust, Peter [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Research Site Leipzig, Leipzig (Germany); Maeding, Peter; Zessin, Joerg; Fuechtner, Frank [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Dresden (Germany); Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Sorger, Dietlind; Meyer, Philipp M.; Habermann, Bernd; Luthardt, Julia; Bresch, Anke; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Laudi, Sven [University of Leipzig, Department of Anaesthesiology and Intensive Care, Leipzig (Germany); Steinbach, Joerg [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Dresden (Germany); Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Research Site Leipzig, Leipzig (Germany)

    2012-06-15

    [{sup 11}C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of {sup 11}C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with {sup 18}F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective {sup 18}F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[{sup 18}F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification. The PET data from five healthy volunteers (three men, two women, age 39 {+-} 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V{sub T}) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [{sup 11}C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 {+-} 8 years). The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V{sub T}) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V{sub T} <10%). Compared with [{sup 11}C]DASB PET, there was a tendency to lower mean uptake values in (+)-[{sup 18}F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[{sup 18}F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans. The results showed that (+)-[{sup 18}F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of

  7. Polimorfismos dos genes do receptor de serotonina (5-HT2A e da catecol-O-metiltransferase (COMT: fatores desencadeantes da fibromialgia? Serotonin receptor (5-HT 2A and catechol-O-methyltransferase (COMT gene polymorphisms: Triggers of fibromyalgia?

    Directory of Open Access Journals (Sweden)

    Josie Budag Matsuda

    2010-04-01

    fatigue, sleep disorders, anxiety, depression, memory loss, and dizziness. Although the physiological mechanisms that control fibromyalgia have not been precisely established, neuroendocrine, genetic or molecular factors may be involved in fibromyalgia. OBJECTIVE: The aim of the present study was to characterize serotonin receptor (5-HT2A and catecholO-methyltransferase (COMT gene polymorphisms in Brazilian patients with fibromyalgia and to evaluate the participation of these polymorphisms in the etiology of the disease. MATERIAL AND METHODS: Genomic DNA extracted from 102 blood samples (51 patients, 51 controls was used for molecular characterization of the 5-HT2A and COMT gene polymorphisms by PCR-RFLP. RESULTS: Analysis of the 5-HT2A polymorphism revealed a frequency of 25.49% C/C, 49.02% T/C and 25.49% T/T in patients, and of 17.65% C/C, 62.74% T/C and 19.61% T/T in the control group, with no differences between the two groups.Analysis of the COMT polymorphism in patients showed a frequency of 17.65% and 45.10% for genotypes H/H and L/H, respectively. In the control group the frequency was 29.42% for H/H and 60.78% for L/H, also with no differences between the two groups. However, there was a significant difference in the frequency of the L/L genotype between patients (37.25% and controls (9.8%, which permitted differentiation between the two groups. CONCLUSION: The L/L genotype was more frequent among fibromyalgia patients. Though considering a polygenic situation and environmental factors, the molecular study of the rs4680 SNP of the COMT gene may be helpful to the identification of susceptible individuals.

  8. Peripheral Serotonin: a New Player in Systemic Energy Homeostasis.

    Science.gov (United States)

    Namkung, Jun; Kim, Hail; Park, Sangkyu

    2015-12-01

    Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.

  9. Serotonin: a regulator of neuronal morphology and circuitry

    Science.gov (United States)

    Daubert, Elizabeth A.; Condron, Barry G.

    2010-01-01

    Serotonin is an important neuromodulator associated with a wide range of physiological effects in the central nervous system. The exact mechanisms for how serotonin influences brain development are not well understood, although studies in invertebrate and vertebrate model organisms are beginning to unravel a regulatory role for serotonin in neuronal morphology and circuit formation. Recent data suggests a developmental window during which altered serotonin levels permanently impact circuitry, however, the temporal constraints and molecular mechanisms responsible are still under investigation. Growing evidence suggests that alterations in early serotonin signaling contribute to a number of neurodevelopmental and neuropsychiatric disorders. Thus, understanding how altered serotonin signaling affects neuronal morphology and plasticity, and ultimately animal physiology and pathophysiology, will be of great significance. PMID:20561690

  10. Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

    NARCIS (Netherlands)

    Doelen, R.H. van der; Arnoldussen, I.A.C.; Ghareh, H.; Och, L. van; Homberg, J.R.; Kozicz, L.T.

    2015-01-01

    The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene x Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid

  11. Revisiting the Serotonin Hypothesis: Implications for Major Depressive Disorders.

    Science.gov (United States)

    Fakhoury, Marc

    2016-07-01

    Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. Its diagnosis mainly relies on the characterization of a wide range of symptoms including changes in mood and behavior. Despite the availability of antidepressant drugs, 10 to 30 % of patients fail to respond after a single or multiple treatments, and the recurrence of depression among responsive patients is very high. Evidence from the past decades suggests that the brain neurotransmitter serotonin (5-HT) is incriminated in MDD, and that a dysfunction of 5-HT receptors may play a role in the genesis of this disease. The 5-HT membrane transporter protein (SERT), which helps regulate the serotonergic transmission, is also implicated in MDD and is one of the main targets of antidepressant therapy. Although a number of behavioral tests and animal models have been developed to study depression, little is known about the neurobiological bases of MDD. Understanding the role of the serotonergic pathway will significantly help improve our knowledge of the pathophysiology of depression and may open up avenues for the development of new antidepressant drugs. The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5-HT1B), and serotonin 2A (5-HT2A) receptors. This paper also describes some of the main molecules involved in the internalization of 5-HT receptors and illustrates the changes in 5-HT neurotransmission in knockout mice and animal model of depression.

  12. Autoradiographic imaging of the serotonin transporter, using S-[{sup 18}F](fluoromethyl)-(+)-McN5652 ([{sup 18}F]Me-McN) in the brains of several animal species

    Energy Technology Data Exchange (ETDEWEB)

    Kretzschmar, M.; Zessin, J.; Brust, P.; Cumming, P. [PET Centre of Aarhus Univ. Hospitals, Aarhus C (Denmark); Bergmann, R.

    2002-01-01

    The [{sup 18}F]fluoromethyl analogue of (+)-McN5652 ([{sup 18}F]Me-McN) was recently proposed as a new potential PET tracer [1]. To further validate its use in PET, we studied the binding of [{sup 18}F]Me-McN in the brains of rats and pigs using autoradiography. The binding was compared with the uptake of the known 5-HT uptake inhibitor [{sup 3}H] citalopram [2] and the radioligand (+)-[{sup 11}C]McN5652. The binding of the three compounds was qualitatively identical in the autoradiograms of the individual brains. Intense labelling was observed in regions known to be serotonin uptake sites. The binding was specifically inhibited, using the 5-HT uptake inhibitors citalopram and fluoxetine. (orig.)

  13. Age-related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

    OpenAIRE

    Wiggins, Jillian Lee; Bedoyan, Jirair K.; Carrasco, Melisa; Swartz, Johnna R.; Martin, Donna M.; Monk, Christopher S.

    2012-01-01

    The S and LG alleles of the serotonin transporter-linked polymorphic region (5-HTTLPR) lower serotonin transporter expression. These low expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala-prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces de...

  14. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

    Directory of Open Access Journals (Sweden)

    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  15. Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity.

    Science.gov (United States)

    Anastasio, Noelle C; Stutz, Sonja J; Fink, Latham H L; Swinford-Jackson, Sarah E; Sears, Robert M; DiLeone, Ralph J; Rice, Kenner C; Moeller, F Gerard; Cunningham, Kathryn A

    2015-07-15

    A feature of multiple neuropsychiatric disorders is motor impulsivity. Recent studies have implicated serotonin (5-HT) systems in medial prefrontal cortex (mPFC) in mediating individual differences in motor impulsivity, notably the 5-HT2AR receptor (5-HT2AR) and 5-HT2CR. We investigated the hypothesis that differences in the ratio of 5-HT2AR:5-HT2CR protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT2CR would result in high motor impulsivity concomitant with elevated 5-HT2AR expression and pharmacological sensitivity to the selective 5-HT2AR antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT2AR and the 5-HT2CR predicted the intensity of motor impulsivity and the 5-HT2AR:5-HT2CR ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT2AR and 5-HT2CR act in concert to control motor impulsivity is supported by the observation that high phenotypic motor impulsivity associated with a diminished mPFC synaptosomal 5-HT2AR:5-HT2CR protein:protein interaction. Knockdown of mPFC 5-HT2CR resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT2AR:5-HT2CR balance as evidenced by a compensatory upregulation of 5-HT2AR protein expression and a leftward shift in the potency of M100907 to suppress impulsive behavior. We infer that there is an interactive relationship between the mPFC 5-HT2AR and 5-HT2CR, and that a 5-HT2AR:5-HT2CR imbalance may be a functionally relevant mechanism underlying motor impulsivity.

  16. Serotonin enhances solitariness in phase transition of the migratory locust

    Directory of Open Access Journals (Sweden)

    Xiaojiao eGuo

    2013-10-01

    Full Text Available The behavioral plasticity of locusts is a striking trait presented during the reversible phase transition between solitary and gregarious individuals. However, the results of serotonin as a neurotransmitter from the migratory locust Locusta migratoria in phase transition showed an alternative profile compared to the results from the desert locust Schistoserca gregaria. In this study, we investigated the roles of serotonin in the brain during the phase change of the migratory locust. During the isolation of gregarious nymphs, the concentration of serotonin in the brain increased significantly, whereas serotonin receptors (i.e. 5-HT1, 5-HT2 and 5-HT7 we identified here showed invariable expression patterns. Pharmacological intervention showed that serotonin injection in the brain of gregarious nymphs did not induced the behavior change toward solitariness, but injection of this chemical in isolated gregarious nymphs accelerated the behavioral change from gregarious to solitary phase. During the crowding of solitary nymphs, the concentration of serotonin in the brain remained unchanged, whereas 5-HT2 increased after 1 h of crowding and maintained stable expression level thereafter. Activation of serotonin-5-HT2 signaling with a pharmaceutical agonist inhibited the gregariousness of solitary nymphs in crowding treatment. These results indicate that the fluctuations of serotonin content and 5-HT2 expression are results of locust phase change. Overall, this study demonstrates that serotonin enhances the solitariness of the gregarious locusts. Serotonin may regulate the withdrawal-like behavioral pattern displayed during locust phase change and this mechanism is conserved in different locust species.

  17. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered......)R binding was reflected in reduced functional output in two 5-HT(2A)-receptor mediated behavioral tests, the head-twitch response (HTR) and the ear-scratch response (ESR). BDNF(2L/2LCk-cre) mutants treated with the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly...

  18. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Directory of Open Access Journals (Sweden)

    Gabriela Hurtado-Alvarado

    Full Text Available Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261 in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1, adherens junction protein (E-cadherin, A2A adenosine receptor, adenosine-synthesizing enzyme (CD73, and neuroinflammatory markers (Iba-1 and GFAP in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent

  19. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  20. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  1. Brain Basics

    Medline Plus

    Full Text Available ... they can cause tremors or symptoms found in Parkinson's disease. Serotonin —helps control many functions, such as ... brain. Problems in producing dopamine can result in Parkinson's disease, a disorder that affects a person's ability ...

  2. Brain Basics

    Medline Plus

    Full Text Available ... related to changes in the anatomy, physiology, and chemistry of the nervous system. When the brain cannot ... people with depression often have lower than normal levels of serotonin. The types of medications most commonly ...

  3. Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

    Science.gov (United States)

    Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

    2014-01-01

    The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

  4. Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.

    Science.gov (United States)

    Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

    2014-03-01

    Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. © 2013 International Society for Neurochemistry.

  5. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  6. Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation

    DEFF Research Database (Denmark)

    Santini, Martin; Klein, A B; El-Sayed, M

    2011-01-01

    , indicating that the involvement of 5-HT(2A)R in this response is restricted to the FC. Similarly, the novelty-induced stress as determined by increasing levels of plasma corticosterone, was not influenced by 5-HT(2A)R antagonism suggesting that Arc mRNA and stress are activated via distinct mechanisms. Taken...... environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (∼160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT(2A......)R antagonists ketanserin and MDL100907, but not with the selective 5-HT(2C)R antagonist SB242084. Novelty-exposure also induced Arc mRNA expression in hippocampus (∼150%), but not in cerebellum or brainstem. Pretreatment with 5-HT(2A)R antagonist ketanserin did not repress the Arc induction in hippocampus...

  7. Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells.

    Science.gov (United States)

    Cussac, Didier; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Martel, Jean-Claude; Danty, Nathalie; Rauly-Lestienne, Isabelle

    2008-10-10

    Several examples of agonist-directed trafficking of receptor signalling at 5-HT2A and 5-HT2C receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT2A, h5-HT2B and h5-HT2C-VSV by examining two related responses, the upstream activation of Gq/11 proteins in comparison with its associated cascade of calcium mobilisation. At the h5-HT2A receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT2B and h5-HT2C-VSV receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT2 receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT2A (and possibly h5-HT2B and/or h5-HT2C-VSV) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT2-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects.

  8. Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action.

    Science.gov (United States)

    Nicolas, Jean-Marie; Hannestad, Jonas; Holden, Daniel; Kervyn, Sophie; Nabulsi, Nabeel; Tytgat, Dominique; Huang, Yiyun; Chanteux, Hugues; Staelens, Ludovicus; Matagne, Alain; Mathy, François-Xavier; Mercier, Joël; Stockis, Armel; Carson, Richard E; Klitgaard, Henrik

    2016-02-01

    Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara-cetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV). In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood-brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical

  9. Maternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin.

    Science.gov (United States)

    Murthi, Padma; Davies-Tuck, Miranda; Lappas, Martha; Singh, Harmeet; Mockler, Joanne; Rahman, Rahana; Lim, Rebecca; Leaw, Bryan; Doery, James; Wallace, Euan M; Ebeling, Peter R

    2017-03-01

    Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P serotonin release in cultured HUVECs. These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children. © 2016 John Wiley & Sons Ltd.

  10. Association between 5HT2A polymorphism and selective serotonin re-uptake inhibitor (SSRI)-induced sexual desire disorder (SDD) among Malaysian women.

    Science.gov (United States)

    Masiran, Ruziana; Sidi, Hatta; Mohamed, Zahurin; Mohamed Saini, Suriati; Nik Jaafar, Nik Ruzyanei

    2013-04-01

    SSRIs are known for their sexual side-effects with a variable rate of sexual dysfunction (SD). 5HT2A (rs6311) single nucleotide polymorphism (SNP) was found to have significant association with SD. The purpose of this study was to determine the prevalence of female SDD, its clinical correlates and association with 5HT2A (rs6311) SNP in patients with major depressive disorder (MDD) treated with SSRIs. This was a cross-sectional study. We evaluated 95 female outpatients with MDD treated with SSRIs who were in remission. Outcome measures were stratified by the presence or absence of SDD. A buccal swab was obtained from each patient and sent for genotyping in the Pharmacogenomics and Medical Biotechnology Laboratory of Universiti Malaya. The overall prevalence of female SD was 32.6%. The prevalence of female SDD was 62.1%. Those with arousal problem, lubrication problem, sexual satisfaction problem, orgasm problem and problematic marriage were more likely to have sexual desire disorder. The majority of participants who had sexual desire disorder had genotype TT (42.4%) but there was no significant association observed. After controlling for age, number of children, education level, SSRI type, lubrication problem, orgasm problem, satisfaction problem and marital problem, only arousal problem significantly enhanced the presence of sexual desire disorder by 8.5 times (odds ratio = 8.46, 95% confidence interval = 1.24-57.58; P = 0.018). This study showed that there was no significant association between SDD and the 5HT2A (rs6311) SNP. Arousal problem significantly enhanced the presence of sexual desire disorder. Copyright © 2013 Wiley Publishing Asia Pty Ltd.

  11. G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

    DEFF Research Database (Denmark)

    Ísberg, Vignir; Balle, Thomas; Sander, Tommy

    2011-01-01

    of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug...... molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability...

  12. Changes of Serotonin (5-HT), 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression, Myocardial Infarction and Myocardial Infarction Co-exist with Depression.

    Science.gov (United States)

    Liu, Mei-Yan; Ren, Yan-Ping; Wei, Wan-Lin; Tian, Guo-Xiang; Li, Guo

    2015-07-20

    To evaluate whether serotonin (5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression, myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats. After established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate. The serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs. 352.98 ± 13.73; P = 0.000), while that in MI group increased (381.78 ± 14.17 vs. 352.98 ± 13.73; P = 0.000). However, the depression + MI group had no change compared with control group (360.62 ± 11.40 vs. 352.98 ± 13.73; P = 0.036). The changes of the platelet concentration of 5-HT in the depression, MI, and depression + MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90, 387.75 ± 22.28, 246.40 ± 18.99 vs. 500.29 ± 20.91; P = 0.000). The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression + MI group compared with the control group (370.75 ± 14.75, 393.47 ± 15.73, 446.66 ± 18.86 vs. 273.66 ± 16.90; P = 0.000). The serum and platelet concentration of SERT in the depression group, MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32, 602.02 ± 23.32, 734.76 ± 29.59 vs. 490.56 ± 16.90; P = 0.047, P = 0.000, P = 0.000 in each and 906.38 ± 51.84, 897.33 ± 60.34, 1030.17 ± 58.73 vs. 708.62 ± 51.15; P = 0.000 in each). The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

  13. The serotonin system in autism spectrum disorder: from biomarker to animal models

    Science.gov (United States)

    Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

    2015-01-01

    Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker. PMID:26577932

  14. (+/-)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2), a novel putative anxiolytic agent lacking affinity for benzodiazepine sites and serotonin-1A receptors.

    Science.gov (United States)

    Reyes-Parada, M; Scorza, C; Romero, V; Silveira, R; Medina, J H; Andrus, D; Nichols, D E; Cassels, B K

    1996-11-01

    Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some symptoms of the serotonergic syndrome, e.g. forepaw treading and flat body posture. Additionally, a decrease in motor activity was observed. No significant effects on the number of head shakes were observed after injection, although high inter-subject variability was noted. Higher doses of ALEPH-2, in the range exhibiting anxiolytic properties (4mg/kg), elicited significant hypothermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([3H]ketanserin sites) was in the nanomolar range (Ki = 173 nM), whereas for 5-HT1A, benzodiazepine sites, and GABAA receptors, the affinity was micromolar of lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.

  15. Individual differences in emotion-cognition interactions: Emotional valence interacts with serotonin transporter genotype to influence brain systems involved in emotional reactivity and cognitive control

    Directory of Open Access Journals (Sweden)

    Melanie eStollstorff

    2013-07-01

    Full Text Available The serotonin transporter gene (5-HTTLPR influences emotional reactivity and attentional bias towards or away from emotional stimuli and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention towards negatively-valenced emotional information, whereas the long allele is associated with that towards positively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Two groups, homozygous 5-HTTLPR long allele carriers or homozygous short allele carriers, underwent functional magnetic resonance imaging (fMRI while completing an Emotional Stroop-like task that varied with regards to the congruency of task-relevant and task-irrelevant information and the emotional valence of the task-irrelevant information. Behaviorally, participants demonstrated the classic Stroop effect (slower responses for incongruent than congruent trials, which did not differ by 5-HTTLPR genotype. However, fMRI results revealed that genotype influenced the degree to which neural systems were engaged depending on the valence of the conflicting task-irrelevant information. While the Long group recruited prefrontal control regions and superior temporal sulcus during conflict when task-irrelevant information was positively-valenced, the "Short" group recruited these regions when task-irrelevant information was negatively-valenced. Thus, participants successfully engaged cognitive control to overcome conflict in an emotional context using similar neural circuitry, but the engagement of this circuitry depended on emotional valence and 5-HTTLPR status. These results suggest that the interplay between emotion and cognition is modulated, in part, by a genetic polymorphism that influences serotonin

  16. High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV

    Directory of Open Access Journals (Sweden)

    Stéphanie eMiceli

    2013-06-01

    Full Text Available Homeostatic regulation of serotonin (5-HT concentration is critical for normal topographical organization and development of thalamocortical (TC afferent circuits. Down-regulation of the serotonin transporter (SERT and the consequent impaired reuptake of 5-HT at the synapse, results in a reduced terminal branching of developing TC afferents within the primary somatosensory cortex (S1. Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood. Here, using juvenile SERT knockout (SERT-/- rats we investigated, in vitro, the effect of increased 5-HT levels on the structural organization of (i the thalamocortical projections of the ventroposteromedial thalamic nucleus towards S1, (ii the general barrel-field pattern and (iii the electrophysiological and morphological properties of the excitatory cell population in layer IV of S1 (spiny stellate and pyramidal cells. Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections towards the barrel cortex. Also, the barrel pattern was altered but not abolished in SERT-/- rats. In layer IV, both excitatory spiny stellate and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections. In addition, the layer IV spiny stellate cells gave rise to a prominent projection towards the infragranular layer Vb. Our findings point to a structural and functional reorganization, of TCAs, as well as early stage intracortical microcircuitry, following the disruption of 5-HT reuptake during critical developmental periods. The increased projection pattern of the layer IV neurons suggests that the intracortical network changes are not limited to the main entry layer IV but may also affect the subsequent stages of the canonical circuits of the barrel

  17. Evening dietary tryptophan improves post-sleep behavioral and brain measures of memory function in healthy subjects

    NARCIS (Netherlands)

    Markus, C.R.; Jonkman, L.M.; Lammers, J.H.C.M.; Deutz, N.E.P.

    2006-01-01

    Brain serotonin function has been implicated in the control of sleep and sleep related memory dysfunctions are attributed to deficient brain serotonin activity. Depletion of the serotonin precursor tryptophan reduces brain serotonin function and is found to cause sleep abnormalities and cognitive

  18. Gene expression of serotonin and dopamine receptors and monoamine oxidase-A in the brain of dominant and subordinate pubertal domestic pigs (Sus scrofa) fed a β-adrenoreceptor agonist.

    Science.gov (United States)

    Poletto, Rosangela; Cheng, Heng-Wei; Meisel, Robert L; Richert, Brian T; Marchant-Forde, Jeremy N

    2011-03-24

    Aggression is a major source of social stress with negative effects on health and well-being, yet limited information is known about the molecular mechanisms mediating aggressive behavior in swine. Ractopamine (RAC) is a β-adrenoreceptor agonist that enhances growth but increases aggressive behaviors in female pigs. Thus, the effects of RAC, sex, and social rank on the mRNA abundance of genes encoding serotonin and dopamine receptors, and monoamine oxidase (MAO)-A in brains of sub-adult pigs were evaluated. Top dominant and bottom subordinate pigs (16/sex) in pens of 4 pigs were determined, and fed either the control or RAC diets. At day 31, their raphe nuclei (RN), amygdala (AMY), frontal cortex (FC), and hypothalamus (HYP) were dissected; relative mRNA abundance for 5-HT₁(B), 5-HT₂(A), 5-HT₂(B), and D₁ receptors, and MAO-A was determined by Q-RT-PCR and data subjected to multivariate linear mixed model analysis and Tukey post-hoc test. Expression of 5-HT₁(B) and MAO-A was suppressed in the AMY of female pigs; 5-HT₂(B) expression was also suppressed in the RN, FC and HYP of females and RN of dominant pigs (P brain of pigs, especially in females independent of social rank, may be mediating the inter-individual offensive aggression. Published by Elsevier B.V.

  19. Association of serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder: A preliminary study.

    Science.gov (United States)

    Basu, Aniruddha; Chadda, R K; Sood, Mamta; Kaur, Harpreet; Kukreti, Ritushree

    2015-07-01

    Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD). In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms. Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295), HTR2A (rs6311 and rs6313) and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR) were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Thirty six (65.5%) patients responded to treatment, and 19 (34.5%) had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs) among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 ( p0 =0.03). No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients.

  20. Association of serotonin transporter (SLC6A4 & receptor (5HTR1A, 5HTR2A polymorphisms with response to treatment with escitalopram in patients with major depressive disorder : A preliminary study

    Directory of Open Access Journals (Sweden)

    Aniruddha Basu

    2015-01-01

    Full Text Available Background & objectives: Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD. In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4 and receptor (5HTR1A, 5HTR2A polymorphisms. Methods: Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295, HTR2A (rs6311 and rs6313 and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Results: Thirty six (65.5% patients responded to treatment, and 19 (34.5% had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 ( p0 =0.03. Interpretation & conclusions: No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients.

  1. Serotonin receptor expression in human prefrontal cortex: balancing excitation and inhibition across postnatal development.

    Directory of Open Access Journals (Sweden)

    Evelyn K Lambe

    Full Text Available Serotonin and its receptors (HTRs play critical roles in brain development and in the regulation of cognition, mood, and anxiety. HTRs are highly expressed in human prefrontal cortex and exert control over prefrontal excitability. The serotonin system is a key treatment target for several psychiatric disorders; however, the effectiveness of these drugs varies according to age. Despite strong evidence for developmental changes in prefrontal Htrs of rodents, the developmental regulation of HTR expression in human prefrontal cortex has not been examined. Using postmortem human prefrontal brain tissue from across postnatal life, we investigated the expression of key serotonin receptors with distinct inhibitory (HTR1A, HTR5A and excitatory (HTR2A, HTR2C, HTR4, HTR6 effects on cortical neurons, including two receptors which appear to be expressed to a greater degree in inhibitory interneurons of cerebral cortex (HTR2C, HTR6. We found distinct developmental patterns of expression for each of these six HTRs, with profound changes in expression occurring early in postnatal development and also into adulthood. However, a collective look at these HTRs in terms of their likely neurophysiological effects and major cellular localization leads to a model that suggests developmental changes in expression of these individual HTRs may not perturb an overall balance between inhibitory and excitatory effects. Examining and understanding the healthy balance is critical to appreciate how abnormal expression of an individual HTR may create a window of vulnerability for the emergence of psychiatric illness.

  2. Quantitative changes in intracellular calcium and extracellular-regulated kinase activation measured in parallel in CHO cells stably expressing serotonin (5-HT 5-HT2A or 5-HT2C receptors

    Directory of Open Access Journals (Sweden)

    Seitz Patricia K

    2012-03-01

    Full Text Available Abstract Background The serotonin (5-HT 2A and 2C receptors (5-HT2AR and 5-HT2CR are involved in a wide range of physiological and behavioral processes in the mammalian central and peripheral nervous systems. These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems. We have developed quantitative assays for cells stably expressing these two receptors involving minimal cell sample manipulations that dramatically improve parallel assessments of two signaling responses: intracellular calcium (Cai++ changes and activation (phosphorylation of downstream kinases. Such profiles are needed to begin to understand the simultaneous contributions from the multiplicity of signaling cascades likely to be initiated by serotonergic ligands. Results We optimized the Cai++ assay for stable cell lines expressing either 5-HT2AR or 5-HT2CR (including dye use and measurement parameters; cell density and serum requirements. We adapted a quantitative 96-well plate immunoassay for pERK in the same cell lines. Similar cell density optima and time courses were observed for 5-HT2AR- and 5-HT2CR-expressing cells in generating both types of signaling. Both cell lines also require serum-free preincubation for maximal agonist responses in the pERK assay. However, 5-HT2AR-expressing cells showed significant release of Cai++ in response to 5-HT stimulation even when preincubated in serum-replete medium, while the response was completely eliminated by serum in 5-HT2CR-expressing cells. Response to another serotonergic ligand (DOI was eliminated by serum-replete preincubation in both cells lines. Conclusions These data expand our knowledge of differences in ligand-stimulated signaling cascades between 5-HT2AR and 5-HT2CR. Our parallel assays can be applied to other cell and receptor systems for monitoring and dissecting concurrent signaling responses.

  3. Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder.

    Science.gov (United States)

    Nazree, Nur Elia; Mohamed, Zahurin; Reynolds, Gavin P; Mohd Zain, Shamsul; Masiran, Ruziana; Sidi, Hatta; Chong, Lu Ann; Hway, Anne Yee; Adlan, Aida Syarinaz; Zainal, Nor Zuraida

    2016-12-01

    The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013). This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs. © 2015 Wiley Publishing Asia Pty Ltd.

  4. Regulation of Corticoid and Serotonin Receptor Brain System following Early Life Exposure of Glucocorticoids: Long Term Implications for the Neurobiology of Mood

    Science.gov (United States)

    Vázquez, Delia M.; Neal, Charles R.; Patel, Paresh D.; Kaciroti, Niko; López, Juan F.

    2011-01-01

    Potent glucocorticoids (GC) administered early in life has improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA, glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT–related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life. PMID:21855221

  5. Serotonin receptors in depression: from A to B

    Science.gov (United States)

    Nautiyal, Katherine M.; Hen, René

    2017-01-01

    The role of serotonin in major depressive disorder (MDD) is the focus of accumulating clinical and preclinical research. The results of these studies reflect the complexity of serotonin signaling through many receptors, in a large number of brain regions, and throughout the lifespan. The role of the serotonin transporter in MDD has been highlighted in gene by environment association studies as well as its role as a critical player in the mechanism of the most effective antidepressant treatments – selective serotonin reuptake inhibitors. While the majority of the 15 known receptors for serotonin have been implicated in depression or depressive-like behavior, the serotonin 1A (5-HT 1A) and 1B (5-HT 1B) receptors are among the most studied. Human brain imaging and genetic studies point to the involvement of 5-HT 1A and 5-HT 1B receptors in MDD and the response to antidepressant treatment. In rodents, the availability of tissue-specific and inducible knockout mouse lines has made possible the identification of the involvement of 5-HT 1A and 5-HT 1B receptors throughout development and in a cell-type specific manner. This, and other preclinical pharmacology work, shows that autoreceptor and heteroreceptor populations of these receptors have divergent roles in modulating depression-related behavior as well as responses to antidepressants and also have different functions during early postnatal development compared to during adulthood. PMID:28232871

  6. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior

    DEFF Research Database (Denmark)

    Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe

    2009-01-01

    with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c...

  7. The effects of ecstasy (MDMA on brain serotonin transporters are dependent on age-of-first exposure in recreational users and animals.

    Directory of Open Access Journals (Sweden)

    Anne Klomp

    Full Text Available RATIONALE AND OBJECTIVE: Little is known on the effects of ecstasy (MDMA, a potent 5-HT-releaser and neurotoxin exposure on brain development in teenagers. The objective of this study was to investigate whether in humans, like previous observations made in animals, the effects of MDMA on the 5-HT system are dependent on age-of-first exposure. METHODS: 5-HT transporter (SERT densities in the frontal cortex and midbrain were assessed with [(123I]β-CIT single photon emission computed tomography in 33 users of ecstasy. Subjects were stratified for early-exposed users (age-at-first exposure 14-18 years; developing brain, and late-exposed users (age-at-first exposure 18-36 years; mature brain. In parallel, we investigated the effects of age experimentally with MDMA in early-exposed (adolescent rats and late-exposed (adult rats using the same radioligand. RESULTS: On average, five years after first exposure, we found a strong inverse relationship, wherein age-at-first exposure predicted 79% of the midbrain SERT variability in early (developing brain exposed ecstasy users, whereas this was only 0.3% in late (mature brain exposed users (p=0.007. No such effect was observed in the frontal cortex. In rats, a significant age-BY-treatment effect (p<0.01 was observed as well, however only in the frontal cortex. CONCLUSIONS: These age-related effects most likely reflect differences in the maturational stage of the 5-HT projection fields at age-at-first exposure and enhanced outgrowth of the 5-HT system due to 5-HT's neurotrophic effects. Ultimately, our findings stress the need for more knowledge on the effects of pharmacotherapies that alter brain 5-HT levels in the pediatric population.

  8. Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain.

    Science.gov (United States)

    El Mansari, Mostafa; Lecours, Maurice; Blier, Pierre

    2015-07-01

    Vortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors. The aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus. These receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers. Vortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration. Desensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

  9. Brain Basics

    Medline Plus

    Full Text Available ... her symptoms were not caused by a stroke, brain tumor, or similar conditions, Sarah's doctor referred her to a psychiatrist, a type of medical doctor who is an expert on mental ... of serotonin in the brain and help reduce symptoms of depression. Sarah also ...

  10. Effects of early serotonin programming on behavior and central monoamine concentrations in an avian model

    Science.gov (United States)

    Serotonin (5-HT) acts as a neurogenic compound in the developing brain; however serotonin altering drugs such as SSRIs are often prescribed to pregnant and lactating mothers. Early agonism of 5-HT receptors could alter the development of serotonergic circuitry, altering neurotransmission and behavio...

  11. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity

    NARCIS (Netherlands)

    Krabbe, Grietje; Matyash, Vitali; Pannasch, Ulrike; Mamer, Lauren; Boddeke, Hendrikus W. G. M.; Kettenmann, Helmut

    Microglia, the brain immune cell, express several neurotransmitter receptors which modulate microglial functions. In this project we studied the impact of serotonin receptor activation on distinct microglial properties as serotonin deficiency not only has been linked to a number of psychiatric

  12. The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

    Directory of Open Access Journals (Sweden)

    Craig F. Ferris

    2017-06-01

    Full Text Available The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054 is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs. We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent functional magnetic resonance imaging (fMRI in the awake rat. Idalopirdine (2 mg/kg, i.v. alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.. Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

  13. Mercuric chloride-induced alterations of levels of noradrenaline, dopamine, serotonin and acetylcholine esterase activity in different regions of rat brain during postnatal development

    Energy Technology Data Exchange (ETDEWEB)

    Lakshmana, M.K. (Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore (India)); Desiraju, T. (Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore (India)); Raju, T.R. (Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore (India))

    1993-07-01

    Wistar rats were fed mercuric chloride, 4 mg/kg body weight per day chronically from postnatal day 2 to 60 by gastric intubation. Mercury consumption was then discontinued until 170 days to allow time for recovery. Since mercury caused reduction in body weight, an underweight group was also included besides the normal saline group. Levels of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and the activity of acetylcholine esterase (AChE) were assayed in various brain regions in different age groups. By 60 days of age, the mercury group showed elevations of NA levels in olfactory bulb (OB), visual cortex (VC) and brain stem (BS) but not in striatumaccumbens (SA) and hippocampus (HI). DA levels were also increased in OB, HI, VC and BS but not in SA. AChE activity was decreased in the mercury group only in HI and VC at 20 days of age. The Mercury group showed no behavioural abnormality outwardly; however, operant conditioning relevated a dificiency in performance. Nevertheless, all these changes disappeared after discontinuation of mercury intake. Thus the changes occurring in the brain at this level of oral mercuric chloride intake seem to reflect adaptive neural mechanisms rather than pathological damage. (orig.)

  14. Serotonin-immunoreactive sensory neurons in the antenna of the cockroach Periplaneta americana.

    Science.gov (United States)

    Watanabe, Hidehiro; Shimohigashi, Miki; Yokohari, Fumio

    2014-02-01

    The antennae of insects contain a vast array of sensory neurons that process olfactory, gustatory, mechanosensory, hygrosensory, and thermosensory information. Except those with multimodal functions, most sensory neurons use acetylcholine as a neurotransmitter. Using immunohistochemistry combined with retrograde staining of antennal sensory neurons in the cockroach Periplaneta americana, we found serotonin-immunoreactive sensory neurons in the antenna. These were selectively distributed in chaetic and scolopidial sensilla and in the scape, the pedicel, and first 15 segments of the flagellum. In a chaetic sensillum, A single serotonin-immunoreactive sensory neuron cohabited with up to four serotonin-negative sensory neurons. Based on their morphological features, serotonin-immunopositive and -negative sensory neurons might process mechanosensory and contact chemosensory modalities, respectively. Scolopidial sensilla constitute the chordotonal and Johnston's organs within the pedicel and process antennal vibrations. Immunoelectron microscopy clearly revealed that serotonin-immunoreactivities selectively localize to a specific type of mechanosensory neuron, called type 1 sensory neuron. In a chordotonal scolopidial sensillum, a serotonin-immunoreactive type 1 neuron always paired with a serotonin-negative type 1 neuron. Conversely, serotonin-immunopositive and -negative type 1 neurons were randomly distributed in Johnston's organ. In the deutocerebrum, serotonin-immunoreactive sensory neuron axons formed three different sensory tracts and those from distinct types of sensilla terminated in distinct brain regions. Our findings indicate that a biogenic amine, serotonin, may act as a neurotransmitter in peripheral mechanosensory neurons. Copyright © 2013 Wiley Periodicals, Inc.

  15. The Effect of Traumatic Stress on Multiple Aminergic Systems in the Basolateral Amygdala and Hypothalamus: Specific Impairment of Serotonin 5 HT2A Receptor Signaling and its Pathophysiological Role in an Animal Model of Post Traumatic Stress Disorder

    Science.gov (United States)

    2007-02-27

    Serotonin alterations in anorexia and bulimia nervosa: New insights from imaging studies. Physiology & Behavior 85:73-81. Kaye WH, Frank GK, Meltzer CC...Cote, Dr. Nelson Arispe, and Dr. Maria Braga. Their thoughts, suggestions and criticisms have truly strengthened this body of work. Furthermore, I...5-HT2C, 5-T1A, 5- HT1B receptors, provides an important mechanism mediating feeding and body weight, the present study also examined whether

  16. Chronic exposure to a predator or its scent does not inhibit male–male competition in male mice lacking brain serotonin

    OpenAIRE

    Huo, Ying; Fang, Qi; Shi, Yao-Long; Zhang, Yao-Hua; Zhang, Jian-Xu

    2014-01-01

    Although it is well-known that defective signaling of the 5-HT system in the brain and stressful stimuli can cause psychological disorders, their combined effects on male–male aggression and sexual attractiveness remain unknown. Our research aimed at examining such effects using tryptophan hydroxylase 2 (Tph2) knockout male mice vs. a rat- or rat scent-based chronic stress model. Tph2+/+ and Tph2−/− male mice were placed individually into the rat home cage (rat), a cage containing soiled rat ...

  17. Development of a stir bar sorptive extraction based HPLC-FLD method for the quantification of serotonin reuptake inhibitors in plasma, urine and brain tissue samples.

    Science.gov (United States)

    Unceta, Nora; Ugarte, Ana; Sánchez, Alicia; Gómez-Caballero, Alberto; Goicolea, Maria Aránzazu; Barrio, Ramón J

    2010-01-05

    The aim of this article is to present an analytical application of stir bar sorptive extraction (SBSE) coupled to HPLC-fluorescence detection (FLD) for the quantification of fluoxetine (FLX), citalopram (CIT) and venlafaxine (VLF) and their active metabolites - norfluoxetine (NFLX), desmethyl- (DCIT) and didesmethylcitalopram (DDCIT) and o-desmethylvenlafaxine (ODV) - in plasma, urine and brain tissue samples. All the parameters influencing adsorption (pH, ion strength, organic modifier addition, volume, extraction time and temperature) and desorption (desorption solvent composition, time, temperature and desorption mode) of the analytes on the stir bar have been optimized. For each matrix, the analytical method has been assessed by studying the linearity and the intra- and interday accuracy (89-113%) and precision (RSD<13%). The improvement of the quantification limits (0.2-2 microg l(-1) for plasma, 2-20 ng g(-1) for brain tissue and 1-10 microg l(-1) for urine, depending on the respective response for analytes) and the development of a procedure for all the matrices make this method useful in clinical and forensic analysis.

  18. Effect of endurance training on hypothalamic serotonin concentration and performance.

    Science.gov (United States)

    Caperuto, E C; dos Santos, R V T; Mello, M T; Costa Rosa, L F B P

    2009-02-01

    1. Serotonin is a neurotransmitter that modulates several functions, such as food intake, energy expenditure, motor activity, mood and sleep. Acute exhaustive endurance exercise increases the synthesis, concentration and metabolism of serotonin in the brain. This phenomenon could be responsible for central fatigue after prolonged and exhaustive exercise. However, the effect of chronic exhaustive training on serotonin is not known. The present study was conducted to examine the effect of exhaustive endurance training on performance and serotonin concentrations in the hypothalamus of trained rats. 2. Rats were divided into three groups: sedentary rats (SED), moderately trained rats (MOD) and exhaustively trained rats (EXT), with an increase of 200% in the load carried during the final week of training. 3. Hypothalamic serotonin concentrations were similar between the SED and MOD groups, but were higher in the EXT group (P MOD group (P < 0.05). 4. Thus, the present study demonstrates that exhaustive training increases serotonin concentrations in the hypothalamus, together with decreased endurance performance after inadequate recovery time. However, the mechanism underlying these changes remains unknown.

  19. Developmental exposure to fluoxetine modulates the serotonin system in hypothalamus.

    Directory of Open Access Journals (Sweden)

    Cecilia Berg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI fluoxetine (FLU, Prozac® is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.

  20. Effects of Postnatal Serotonin Agonism on Fear Response and Memory

    Science.gov (United States)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

  1. Serotonin 5-HT(3) receptors in the central nervous system

    NARCIS (Netherlands)

    Chameau, P.J.P.; van Hooft, J.A.

    2006-01-01

    The 5-HT(3) receptor is a ligand-gated ion channel activated by serotonin (5-HT). Although originally identified in the peripheral nervous system, the 5-HT(3) receptor is also ubiquitously expressed in the central nervous system. Sites of expression include several brain stem nuclei and higher

  2. How the cerebral serotonin homeostasis predicts environmental changes

    DEFF Research Database (Denmark)

    Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos

    2013-01-01

    Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which...

  3. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    Depletion of central serotonin (5-HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig...... concentrations of 5-HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused...

  4. The Effects of Serotonin in Immune Cells

    OpenAIRE

    Nadine Herr; Christoph Bode; Daniel Duerschmied

    2017-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] plays an important role in many organs as a peripheral hormone. Most of the body’s serotonin is circulating in the bloodstream, transported by blood platelets and is released upon activation. The functions of serotonin are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), the serotonin transporter (SERT), and by covalent binding of serotonin to different effector proteins. Almost all immune cells express...

  5. BDNF val66met association with serotonin transporter binding in healthy humans

    DEFF Research Database (Denmark)

    Fisher, P. M.; Ozenne, B.; Svarer, C.

    2017-01-01

    The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted......-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT...

  6. Increased orbitofrontal brain activation after administration of a selective adenosine A2A antagonist in cocaine dependent subjects

    Directory of Open Access Journals (Sweden)

    F. Gerard eMoeller

    2012-05-01

    Full Text Available Background: Positron Emission Tomography imaging studies provide evidence of reduced dopamine function in cocaine dependent subjects in the striatum, which is correlated with prefrontal cortical glucose metabolism, particularly in the orbitofrontal cortex. However, whether enhancement of dopamine in the striatum in cocaine dependent subjects would be associated with changes in prefrontal cortical brain activation is unknown. One novel class of medications that enhance dopamine function via heteromer formation with dopamine receptors in the striatum is the selective adenosine A2A receptor antagonists. This study sought to determine the effects administration of the selective adenosine A2A receptor antagonist SYN115 on brain function in cocaine dependent subjects. Methodology/Principle Findings: Twelve cocaine dependent subjects underwent two fMRI scans (one after a dose of placebo and one after a dose of 100 mg of SYN115 while performing a working memory task with 3 levels of difficulty (3, 5, and 7 digits. fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole. Conclusion/Significance: These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of adenosine A2A receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A2A receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.

  7. Adenosine through the A2A adenosine receptor increases IL-1β in the brain contributing to anxiety

    Science.gov (United States)

    Chiu, Gabriel S.; Darmody, Patrick T.; Walsh, John P.; Moon, Morgan L.; Kwakwa, Kristin A.; Bray, Julie K.; McCusker, Robert H.; Freund, Gregory G.

    2014-01-01

    Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by two-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain. PMID:24907587

  8. Effects of chronic mild stress on apomorphine induced behavioral sensitization in different brain regions of rats in relation to serotonin change

    Directory of Open Access Journals (Sweden)

    Muhammad Farhan

    2015-11-01

    Full Text Available Background: The impacts of unpredictable stressors have influence on neurochemical and behavioral parameters in laboratory animals. Stress induced behavioral changes particularly those associated with anxiety like behavior may activate topographically organized mesolimbic cortical serotonergic system. This study was designed to investigate the influence of unpredictable stress on behavioral and neurochemical parameters in apomorphine treated rats. Methods: Initially, the animals were divided into two groups as Unstressed and stressed (uncontrollable chronic mild stress or UCMS. Both groups of animals were subdivided into two groups; i.e. saline and apomorphine administrated animals at dose 1.0 mg/kg. Behavioral manipulations was observed by monitoring the locomotor activity and exploratory activity. Neurochemical estimation of 5-hydroxytryptamine (5-HT was done by High performance liquid chromatography (HPLC. Animals were decapitated 24hr post apomorphine injection and different regions of brain (dorsal and ventral striatum, of animals were collected and stored at -70°C. Results: This preclinical study showed that the UCMS induced hypophagia were promoted in apomorphine administrated animals. Apomorphine induced hyperlocomotion were more prominent in unstressed animals than that of stressed groups. It implies that apomorphine is effective in the retrieval from UCMS induced depressive symptoms in rats. Neurochemical study showed decreased level of 5-HT in unstressed animals than stressed animals in response to apomorphine administration. Conclusion: This study, therefore establish the relation between stress and addiction at behavioral as well as neurochemical level to better understand the idea whether intolerable stress promotes addiction.

  9. Pre-gestational stress reduces the ratio of 5-HIAA to 5-HT and the expression of 5-HT1A receptor and serotonin transporter in the brain of foetal rat

    Directory of Open Access Journals (Sweden)

    Huang Yuejun

    2012-02-01

    Full Text Available Abstract Background Many studies have found that stress before or during pregnancy is linked to an increased incidence of behavioural disorders in offspring. However, few studies have investigated hypothalamic-pituitary-adrenal (HPA axis activity and the serotonergic system as a consequence of pregestational stress. In the present study, we investigated the effect of pre-gestational stress on HPA axis activity in maternal rats and their foetuses and examined whether changes in HPA axis activity of maternal rats produced functional changes in the serotonergic system in the brain of foetuses. Results We used the behavioural tests to assess the model of chronic unpredictable stress (CUS in maternal rats. We found the activity in the open field and sucrose consumption was lower for rats with CUS than for the controls. Body weight but not brain weight was higher for control foetuses than those from the CUS group. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for mothers with CUS before pregnancy and their foetuses than for the controls. Levels of 5-hydroxytryptamine (5-HT were higher in the hippocampus and hypothalamus of foetuses in the CUS group than in the controls, and 5-hydroxyindoleacetic acid (5-HIAA levels were lower in the hippocampus in foetuses in the CUS group than in the control group. Levels of 5-HIAA in the hypothalamus did not differ between foetuses in the CUS group and in the control group. The ratio of 5-HIAA to 5-HT was significantly lower for foetuses in the CUS group than in the control group. Levels of 5-HT1A receptor were significantly lower in the foetal hippocampus in the CUS group than in the control group, with no significant difference in the hypothalamus. The levels of serotonin transporter (SERT were lower in both the foetal hippocampus and foetal hypothalamus in the CUS group than in the control group. Conclusions Our data demonstrate that pre-gestational stress alters HPA

  10. Interaction of antidepressants with the serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Sørensen, Lena; Andersen, Jacob; Thomsen, Mette

    2012-01-01

    The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used...... as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis...

  11. Effects of ageing on serotonin transporters in healthy females

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T. [Dept. of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital (Finland); Dept. of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Tammela, L.; Karhunen, L.; Uusitupa, M. [Dept. of Clinical Nutrition, University of Kuopio and Kuopio University Hospital, Kuopio (Finland); Bergstroem, K.A. [Dept. of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital (Finland); Tiihonen, J. [Dept. of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland)

    2001-07-01

    The effect of ageing on brain serotonin transporters was evaluated in 19 healthy female volunteers (age range 22-74 years) using single-photon emission tomography and [{sup 123}I] nor-{beta}-CIT. The study subjects were scanned 0.3, 3, 6 and 23 h after injection of 185 MBq of [{sup 123}I] nor-{beta}-CIT. The ratio of the distribution volume for tracer in the midbrain to that in the cerebellum minus 1 was used as an index for serotonin transporter binding. An age-related decline of 2% per decade (r=-0.47; P<0.05) was found in the midbrain. The decline in [{sup 123}I] nor-{beta}-CIT binding in the serotonin transporter-rich area is much less than that in dopamine transporters in the striatum (6% per decade). (orig.)

  12. On the Relationship between Brain Laterality and Language Proficiency in L2: A Replication Study

    Directory of Open Access Journals (Sweden)

    Nima Shakouri

    2016-06-01

    Full Text Available The present paper attempted to investigate whether there is any significant relationship between participants' brain laterality and L2 proficiency level. To carry out the experiment, 30 participants administered in the present study. Fifteen of them did not have any English language learning experience and were at the start of language learning, while the rest had attended L2 learning classes for about 2 years in a popular English language center, located in Bandar-e Anzali, Iran. Finally, the researchers concluded that the activity of the right hemisphere went up by the increase in language proficiency among bilinguals. Thereupon, the result of the paper was at variance with Albert and Obler's (1978 early work on hemispheric differentiation, which indicated that bilinguals were less hemispheric dominant than monolinguals.

  13. Characterization of electroencephalographic and biochemical responses at 5-HT promoting drug-induced onset of serotonin syndrome in rats

    Science.gov (United States)

    Ma, Zhiyuan; Rudacille, Mary; Prentice, Howard M.; Tao, Rui

    2014-01-01

    Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5HT) in the CNS. 5HT is well known to improve mood, however, only when the levels of its release are in an appropriate range. Excessive 5HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of the present study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5HT-promoting drugs: 1) (±)-3,4-methylenedioxymethamphetamine (MDMA); 2) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; 3) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography (EEG), tremor and brain/plasma 5HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5HT efflux in brain dialysate and the increased concentration of unbound 5HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5HT concentration in the plasma. PMID:23286698

  14. [Serotonin dysfunctions in the background of the seven deadly sins].

    Science.gov (United States)

    Janka, Zoltán

    2003-11-20

    The symbolic characters of the Seven Deadly Sins can be traced from time to time in the cultural history of human mankind, being directly specified in certain artistic products. Such are, among others, the painting entitled "The Seven Deadly Sins and the Four Lost Things" by Hieronymus Bosch and the poems Divina Commedia and The Foerie Queene by Dante Alighieri and Edmund Spenser, respectively. However, there are several paragraphs referring to these behaviours of the Seven Deadly Sins in the Bible and in the dramas of William Shakespeare. The objective of the present review is to propose that dysfunctions in the central serotonergic system might be involved in the neurobiology of these 'sinful' behaviour patterns. Evidences indicate that behaviour traits such as Accidia (Sloth), Luxuria (Lust, Lechery), Superbia (Pride), Ira (Wrath, Anger), Invidia (Envy), Avaritia (Greed, Avarice), and Gula (Gluttony) can relate to the functional alterations of serotonin in the brain. Results of biochemical and molecular genetic (polymorphism) studies on the human serotonergic system (receptor, transporter, enzyme), findings of functional imaging techniques, effects of depletion (or supplementation) of the serotonin precursor tryptophan, data of challenge probe investigations directed to testing central serotonergic functions, alterations in the peripheral serotonin measures (platelet), and the changes in the CSF 5-hydroxy-indoleacetic acid content indicate such serotonergic involvement. Furthermore, results of animal experiments on behaviour change (aggressive, dominant or submissive, appetite, alcohol preference) attributed to serotonin status modification and the clinically evidenced therapeutic efficacy of pharmacological interventions, based on the modulation and perturbation of the serotonergic system (e.g. selective serotonin reuptake inhibitors), in treating the 'sinful' behaviour forms and analogous pathological states reaching the severity of psychiatric disorders

  15. Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies.

    Science.gov (United States)

    Kaye, Walter H; Frank, Guido K; Bailer, Ursula F; Henry, Shannan E; Meltzer, Carolyn C; Price, Julie C; Mathis, Chester A; Wagner, Angela

    2005-05-19

    Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders with relatively homogenous presentations such as age of onset and gender distribution. In addition, they share symptoms, such as extremes of food consumption, body image distortion, anxiety and obsessions, and ego-syntonic neglect, raises the possibility that these symptoms reflect disturbed brain function that contributes to the pathophysiology of this illness. Recent brain imaging studies have identified altered activity in frontal, cingulate, temporal, and parietal cortical regions in AN and BN. Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions. In specific, recent studies using PET with serotonin specific radioligands implicate alterations of 5-HT1A and 5-HT2A receptors and the 5-HT transporter. Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

  16. Brain Basics

    Medline Plus

    Full Text Available ... they can cause tremors or symptoms found in Parkinson's disease. Serotonin —helps control many functions, such as mood, ... brain. Problems in producing dopamine can result in Parkinson's disease, a disorder that affects a person's ability to ...

  17. Brain Basics

    Medline Plus

    Full Text Available ... at the front of the brain that, in humans, plays a role in executive functions such as judgment, decision making and problem solving, as well as emotional control and memory. serotonin —A neurotransmitter that regulates many functions, including ...

  18. Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

    Directory of Open Access Journals (Sweden)

    Torrão A.S.

    1997-01-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

  19. DNA methylation of the serotonin transporter gene in peripheral cells and stress-related changes in hippocampal volume: a study in depressed patients and healthy controls.

    Directory of Open Access Journals (Sweden)

    Linda Booij

    Full Text Available Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD (23 females and 36 matched healthy controls (21 females were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.

  20. Progression of brain atrophy in spinocerebellar ataxia type 2: a longitudinal tensor-based morphometry study.

    Directory of Open Access Journals (Sweden)

    Mario Mascalchi

    Full Text Available Spinocerebellar ataxia type 2 (SCA2 is the second most frequent autosomal dominant inherited ataxia worldwide. We investigated the capability of magnetic resonance imaging (MRI to track in vivo progression of brain atrophy in SCA2 by examining twice 10 SCA2 patients (mean interval 3.6 years and 16 age- and gender-matched healthy controls (mean interval 3.3 years on the same 1.5 T MRI scanner. We used T1-weighted images and tensor-based morphometry (TBM to investigate volume changes and the Inherited Ataxia Clinical Rating Scale to assess the clinical deficit. With respect to controls, SCA2 patients showed significant higher atrophy rates in the midbrain, including substantia nigra, basis pontis, middle cerebellar peduncles and posterior medulla corresponding to the gracilis and cuneatus tracts and nuclei, cerebellar white matter (WM and cortical gray matter (GM in the inferior portions of the cerebellar hemisphers. No differences in WM or GM volume loss were observed in the supratentorial compartment. TBM findings did not correlate with modifications of the neurological deficit. In conclusion, MRI volumetry using TBM is capable of demonstrating the progression of pontocerebellar atrophy in SCA2, supporting a possible role of MRI as biomarker in future trials.

  1. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

    Science.gov (United States)

    Miller, Jeffrey M; Hesselgrave, Natalie; Ogden, R Todd; Sullivan, Gregory M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V

    2013-08-15

    Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. Epigenetic Mechanisms of Serotonin Signaling.

    Science.gov (United States)

    Holloway, Terrell; González-Maeso, Javier

    2015-07-15

    Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.

  3. Serotonin, inhibition, and negative mood

    National Research Council Canada - National Science Library

    Dayan, Peter; Huys, Quentin J M

    2008-01-01

    .... There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two...

  4. Selective Serotonin Reuptake Inhibitors (SSRIs)

    Science.gov (United States)

    ... Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. http://www.uptodate.com/home. Accessed June 2, 2016. Mental health medications. National Institute of Mental Health. http://www. ...

  5. Plasma anti-serotonin and serotonin anti-idiotypic antibodies are elevated in panic disorder.

    Science.gov (United States)

    Coplan, J D; Tamir, H; Calaprice, D; DeJesus, M; de la Nuez, M; Pine, D; Papp, L A; Klein, D F; Gorman, J M

    1999-04-01

    The psychoneuroimmunology of panic disorder is relatively unexplored. Alterations within brain stress systems that secondarily influence the immune system have been documented. A recent report indicated elevations of serotonin (5-HT) and ganglioside antibodies in patients with primary fibromyalgia, a condition with documented associations with panic disorder. In line with our interest in dysregulated 5-HT systems in panic disorder (PD), we wished to assess if antibodies directed at the 5-HT system were elevated in patients with PD in comparison to healthy volunteers. Sixty-three patients with panic disorder and 26 healthy volunteers were diagnosed by the SCID. Employing ELISA, we measured anti-5-HT and 5-HT anti-idiotypic antibodies (which are directed at 5-HT receptors). To include all subjects in one experiment, three different batches were run during the ELISA. Plasma serotonin anti-idiotypic antibodies: there was a significant group effect [patients > controls (p = .007)] and batch effect but no interaction. The mean effect size for the three batches was .76. Following Z-score transformation of each separate batch and then combining all scores, patients demonstrated significantly elevated levels of plasma serotonin anti-idiotypic antibodies. Neither sex nor age as covariates affected the significance of the results. There was a strong correlation between anti-serotonin antibody and serotonin anti-idiotypic antibody measures. Plasma anti-serotonin antibodies: there was a significant diagnosis effect [patients > controls (p = .037)]. Mean effect size for the three batches was .52. Upon Z-score transformation, there was a diagnosis effect with antibody elevations in patients. Covaried for sex and age, the result falls below significance to trend levels. The data raise the possibility that psychoimmune dysfunction, specifically related to the 5-HT system, may be present in PD. Potential interruption of 5-HT neurotransmission through autoimmune mechanisms may be of

  6. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H.

    Science.gov (United States)

    Bahri, Mohamed Ali; Plenevaux, Alain; Aerts, Joël; Bastin, Christine; Becker, Guillaume; Mercier, Joël; Valade, Anne; Buchanan, Tim; Mestdagh, Nathalie; Ledoux, Didier; Seret, Alain; Luxen, André; Salmon, Eric

    2017-11-01

    Brain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([ 18 F]UCB-H) and positron emission tomography (PET). Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume. [ 18 F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship. The cerebral distribution of [ 18 F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([ 11 C]UCB-J). An accurate [ 18 F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.

  7. Serotonin transporter gene polymorphisms in Southwestern Iranian patients with irritable bowel syndrome.

    Science.gov (United States)

    Farjadian, Shirin; Fakhraei, Bahareh; Moeini, Maryam; Nasiri, Mahboubeh; Fattahi, Mohammad Reza

    2013-06-01

    Irritable bowel syndrome is a common chronic functional gastrointestinal disorder of unknown etiology. Serotonin is an important factor in sensory signaling in the brain-gut axis, which plays a key role in intestinal motility and secretion. Serotonin clearance is mediated by a specific protein called the serotonin reuptake transporter. Transcription activity of the serotonin transporter gene is affected by some polymorphisms in this gene. The aim of this study was to investigate the relationship between serotonin transporter gene polymorphisms and irritable bowel syndrome. The 5-HTTLPR, rs25531 and STin2VNTR polymorphisms of the serotonin transporter gene were analyzed by PCR-based methods in 50 patients with irritable bowel syndrome and 100 healthy controls. Serotonin transporter polymorphisms were similar in patients and healthy controls. There were no significant differences in allele or genotype frequencies between the two groups. Our findings suggest that polymorphisms in the gene encoding for the serotonin transporter are not associated with irritable bowel syndrome. Interactions between environmental factors and predisposing genetic factors are important in the pathophysiology of irritable bowel syndrome, and further genetic and epigenetic research may provide novel insights into the mechanisms contributing to this disease. Copyright © 2013 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All rights reserved.

  8. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

    Science.gov (United States)

    Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

    2012-01-01

    Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

  9. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.

    Science.gov (United States)

    Patrick, Rhonda P; Ames, Bruce N

    2015-06-01

    Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. © FASEB.

  10. Does serotonin play a role in entrance into hibernation?

    Science.gov (United States)

    Canguilhem, B; Miro, J L; Kempf, E; Schmitt, P

    1986-10-01

    To study the role of brain serotonin in entrance into hibernation, intraventricular injections of 5,7-dihydroxytryptamine, electrolytic lesions of small parts of the median raphe nucleus, and chemical lesions of the same nucleus were undertaken on the European hamster in winter. All the lesions led to a variable decrease of serotonin levels in all parts of the brain areas examined. However, hibernation was suppressed only in those animals whose serotonergic neurons were destroyed in a small anterior part of the median raphe nucleus. Electrolytic lesions as well as chemical lesions in the other parts of the median raphe nucleus or the 5,7-dihydroxytryptamine injections into lateral ventricles do not prevent hibernation. These data suggest that in the European hamster only a specific group of serotonergic neurons of the median raphe nucleus are involved in the process of entrance into hibernation.

  11. Serotonin in the sudden infant death syndrome.

    Science.gov (United States)

    Waters, Karen

    2010-11-01

    It seems likely that some infants who die from sudden infant death syndrome (SIDS) have a brainstem abnormality of the serotonergic system. Evidence suggests that infants who died from SIDS had defective respiratory and/or autonomic responses that led to death instead of recovery after an acute insult. The serotonergic neuromodulator system has roles in the control of cardiac autonomic and respiratory function, as well as now being identified as abnormal in infants with SIDS. This manuscript reviews the multiple roles of serotonin with reference to the functional aspects of the relevant brain regions. Correlations with pre- or postnatal exposure to stressors, or an underlying genetic process are also reviewed. Together, these studies indicate that perturbed function of the serotonin system will have significant physiological impact during early development. Understanding the functional importance of these systems assists understanding of the pathogenesis of SIDS. In conclusion, whether an infant inherits serotonergic defects and is therefore "inherently vulnerable", or whether postnatal stressors can induce the abnormalities, any functional abnormalities of the serotonergic system that result are likely to be subclinical in the majority of cases and not easily detected with current medical tools. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  12. Molecular cloning, expression and characterization of a bovine serotonin transporter

    DEFF Research Database (Denmark)

    Mortensen, O V; Kristensen, A S; Rudnick, G

    1999-01-01

    The serotonin transporter (SERT) is a member of a highly homologous family of sodium/chloride dependent neurotransmitter transporters responsible for reuptake of biogenic amines from the extracellular fluid. SERT constitutes the pharmacological target of several clinically important antidepressan......-methylenedioxymethamphetamine (MDMA) was mainly unchanged. RT-PCR amplification of RNA from different tissues demonstrated expression of SERT in placenta, brain stem, bone marrow, kidney, lung, heart, adrenal gland, liver, parathyroid gland, thyroid gland, small intestine and pancreas....

  13. Association between serotonin transporter gene polymorphism and recurrent aphthous stomatitis.

    Science.gov (United States)

    Manchanda, Aastha; Iyengar, Asha R; Patil, Seema

    2016-01-01

    Anxiety-related traits have been attributed to sequence variability in the genes coding for serotonin transmission in  the brain. Two alleles, termed long (L) and short (S) differing by 44 base pairs, are found in a polymorphism identified in the promoter region of serotonin transporter gene. The presence of the short allele  and SS and LS genotypes is found to be associated with the reduced expression of this gene decreasing the uptake of serotonin in the brain leading to various anxiety-related traits. Recurrent aphthous stomatitis (RAS) is an oral mucosal disease with varied etiology including the presence of stress, anxiety, and genetic influences. The present study aimed to determine this serotonin transporter gene polymorphism in patients with RAS and compare it with normal individuals. This study included 20 subjects with various forms of RAS and 20 normal healthy age- and gender-matched individuals. Desquamated oral mucosal cells were collected for DNA extraction and subjected to polymerase chain reaction for studying insertion/deletion in the 5-HTT gene-linked polymorphic region. Cross tabulations followed by Chi-square tests were performed to compare the significance of findings, P aphthous stomatitis (60%) and controls (40%). The total percentage of LS and SS genotypes and the frequency of S allele were found to be higher in the subjects with aphthous stomatitis as compared to the control group although a statistically significant correlation could not be established, P = 0.144 and 0.371, respectively. Within the limitations of this study, occurrence of RAS was not found to be associated with polymorphic promoter region in serotonin transporter gene.

  14. Exercise and sleep in aging: emphasis on serotonin.

    Science.gov (United States)

    Melancon, M O; Lorrain, D; Dionne, I J

    2014-10-01

    Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Platelet serotonin transporter function predicts default-mode network activity.

    Directory of Open Access Journals (Sweden)

    Christian Scharinger

    Full Text Available The serotonin transporter (5-HTT is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence.A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD activity and platelet Vmax.The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity.This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

  16. Intra- and Interhemispheric Propagation of Electrophysiological Synchronous Activity and Its Modulation by Serotonin in the Cingulate Cortex of Juvenile Mice.

    Directory of Open Access Journals (Sweden)

    Víctor Rovira

    Full Text Available Disinhibition of the cortex (e.g., by GABA -receptor blockade generates synchronous and oscillatory electrophysiological activity that propagates along the cortex. We have studied, in brain slices of the cingulate cortex of mice (postnatal age 14-20 days, the propagation along layer 2/3 as well as the interhemispheric propagation through the corpus callosum of synchronous discharges recorded extracellularly and evoked in the presence of 10 μM bicuculline by electrical stimulation of layer 1. The latency of the responses obtained at the same distance from the stimulus electrode was longer in anterior cingulate cortex (ACC: 39.53 ± 2.83 ms, n = 7 than in retrosplenial cortex slices (RSC: 21.99 ± 2.75 ms, n = 5; p<0.05, which is equivalent to a lower propagation velocity in the dorso-ventral direction in ACC than in RSC slices (43.0 mm/s vs 72.9 mm/s. We studied the modulation of this propagation by serotonin. Serotonin significantly increased the latency of the intracortical synchronous discharges (18.9% in the ipsilateral hemisphere and 40.2% in the contralateral hemisphere, and also increased the interhemispheric propagation time by 86.4%. These actions of serotonin were mimicked by the activation of either 5-HT1B or 5-HT2A receptors, but not by the activation of the 5-HT1A subtype. These findings provide further knowledge about the propagation of synchronic electrical activity in the cerebral cortex, including its modulation by serotonin, and suggest the presence of deep differences between the ACC and RSC in the structure of the local cortical microcircuits underlying the propagation of synchronous discharges.

  17. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; de Bruin, A.

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

  18. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration.

    NARCIS (Netherlands)

    Matondo, R.B.; Punt, C.; Homberg, J.R.; Toussaint, M.J.; Kisjes, R.; Korporaal, S.J.; Akkerman, J.W.; Cuppen, E.; Bruin, A. de

    2009-01-01

    The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver

  19. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    ... Effexor XR) ― also approved to treat anxiety and panic disorder All SNRIs work in a similar way ... such as aspirin or warfarin (Coumadin, Jantoven). Serotonin syndrome. Rarely, serotonin syndrome can occur when you take ...

  20. Blood platelet serotonin following enterectomy in rats.

    Science.gov (United States)

    Osim, E E; Wyllie, J H

    1991-01-01

    The role of the intestine as a source of platelet serotonin was investigated. Radioactive serotonin precursor. 5-Hydroxytryptophan was injected into enterectomised and sham-operated rats. Blood samples were taken at time intervals and serotonin uptake was estimated by radioactive counting. Soon (1-2 hrs) after surgery and under sodium pentobarbital anaesthesia, platelet 5HT activity was higher in enterectomised rats than in controls. The intestine may not be the major source of platelet serotonin.

  1. Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

    Directory of Open Access Journals (Sweden)

    Marco Redaelli

    Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

  2. The Effects of Glycogen Synthase Kinase-3beta in Serotonin Neurons

    Science.gov (United States)

    Zhou, Wenjun; Chen, Ligong; Paul, Jodi; Yang, Sufen; Li, Fuzeng; Sampson, Karen; Woodgett, Jim R.; Beaulieu, Jean Martin; Gamble, Karen L.; Li, Xiaohua

    2012-01-01

    Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase in brain. Increasing evidence has shown that GSK3 acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B) receptors in a highly selective manner and prominent modulating effect on 5-HT1B receptor activity. In this study, we utilized the serotonin neuron-selective GSK3β knockout (snGSK3β-KO) mice to test if GSK3β in serotonin neurons selectively modulates 5-HT1B autoreceptor activity and function. The snGSK3β-KO mice were generated by crossbreeding GSK3β-floxed mice and ePet1-Cre mice. These mice had normal growth and physiological characteristics, similar numbers of tryptophan hydroxylase-2 (TpH2)-expressing serotonin neurons, and the same brain serotonin content as in littermate wild type mice. However, the expression of GSK3β in snGSK3β-KO mice was diminished in TpH2-expressing serotonin neurons. Compared to littermate wild type mice, snGSK3β-KO mice had a reduced response to the 5-HT1B receptor agonist anpirtoline in the regulation of serotonergic neuron firing, cAMP production, and serotonin release, whereas these animals displayed a normal response to the 5-HT1A receptor agonist 8-OH-DPAT. The effect of anpirtoline on the horizontal, center, and vertical activities in the open field test was differentially affected by GSK3β depletion in serotonin neurons, wherein vertical activity, but not horizontal activity, was significantly altered in snGSK3β-KO mice. In addition, there was an enhanced anti-immobility response to anpirtoline in the tail suspension test in snGSK3β-KO mice. Therefore, results of this study demonstrated a serotonin neuron-targeting function of GSK3β by regulating 5-HT1B autoreceptors, which impacts serotonergic neuron firing, serotonin release, and serotonin-regulated behaviors. PMID:22912839

  3. Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.

    Science.gov (United States)

    Helal, Christopher J; Arnold, Eric P; Boyden, Tracey L; Chang, Cheng; Chappie, Thomas A; Fennell, Kimberly F; Forman, Michael D; Hajos, Mihaly; Harms, John F; Hoffman, William E; Humphrey, John M; Kang, Zhijun; Kleiman, Robin J; Kormos, Bethany L; Lee, Che-Wah; Lu, Jiemin; Maklad, Noha; McDowell, Laura; Mente, Scot; O'Connor, Rebecca E; Pandit, Jayvardhan; Piotrowski, Mary; Schmidt, Anne W; Schmidt, Christopher J; Ueno, Hirokazu; Verhoest, Patrick R; Yang, Edward X

    2017-07-13

    Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

  4. Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

    Directory of Open Access Journals (Sweden)

    Susann Schröder

    2015-05-01

    Full Text Available Phosphodiesterase 2A (PDE2A is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET. Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2–4 and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4 and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.

  5. Pharmacogenetic workup of perioperative serotonin syndrome.

    Science.gov (United States)

    Beatty, Nicole C; Nicholson, Wayne T; Langman, Loralie J; Curry, Timothy B; Eisenach, John H

    2013-12-01

    Serotonin syndrome is gaining attention in perioperative and chronic pain settings due to the growing prevalence of multimodal therapies that increase serotonin levels and thereby heighten patient risk. A patient's genetic make-up may further increase the risk of serotonin syndrome. A case of serotonin syndrome on emergence after general anesthesia is presented. A subsequent cytochrome P4502D6 genetic test result suggested a potential alteration in metabolism. For this patient, who was taking combination antidepressant medications and receiving common perioperative medicines, additive pharmacodynamic effects converged with a pharmacogenetic predisposition, resulting in serotonin syndrome. © 2013 Elsevier Inc. All rights reserved.

  6. Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host

    Directory of Open Access Journals (Sweden)

    Leslie D. Knecht

    2016-07-01

    Full Text Available Bacteria in humans play an important role in health and disease. Considerable emphasis has been placed in understanding the role of bacteria in host-microbiome interkingdom communication. Here we show that serotonin, responsible for mood in the brain and motility in the gut, can also act as a bacterial signaling molecule for pathogenic bacteria. Specifically, we found that serotonin acts as an interkingdom signaling molecule via quorum sensing and that it stimulates the production of bacterial virulence factors and increases biofilm formation in vitro and in vivo in a novel mouse infection model. This discovery points out at roles of serotonin both in bacteria and humans, and at phenotypic implications not only manifested in mood behavior but also in infection processes in the host. Thus, regulating serotonin concentrations in the gut may provide with paradigm shifting therapeutic approaches.

  7. Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host.

    Science.gov (United States)

    Knecht, Leslie D; O'Connor, Gregory; Mittal, Rahul; Liu, Xue Z; Daftarian, Pirouz; Deo, Sapna K; Daunert, Sylvia

    2016-07-01

    Bacteria in humans play an important role in health and disease. Considerable emphasis has been placed in understanding the role of bacteria in host-microbiome interkingdom communication. Here we show that serotonin, responsible for mood in the brain and motility in the gut, can also act as a bacterial signaling molecule for pathogenic bacteria. Specifically, we found that serotonin acts as an interkingdom signaling molecule via quorum sensing and that it stimulates the production of bacterial virulence factors and increases biofilm formation in vitro and in vivo in a novel mouse infection model. This discovery points out at roles of serotonin both in bacteria and humans, and at phenotypic implications not only manifested in mood behavior but also in infection processes in the host. Thus, regulating serotonin concentrations in the gut may provide with paradigm shifting therapeutic approaches. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders.

    Science.gov (United States)

    Jaiswal, Preeti; Mohanakumar, Kochupurackal P; Rajamma, Usha

    2015-08-01

    Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. ROLE OF SEROTONIN IN FISH REPRODUCTION

    Directory of Open Access Journals (Sweden)

    Parvathy ePrasad

    2015-06-01

    Full Text Available The neuroendocrine mechanism regulates reproduction through the hypothalamo-pituitary-gonadal (HPG axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviours, gonadotropin release and gonadotropin-release hormone (GnRH secretion. However, the serotonin system in teleost may play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction.

  10. Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Jensen, Anders A.; Kehler, Jan

    2010-01-01

    Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular...

  11. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine.

    Science.gov (United States)

    Stahl, Stephen M

    2015-10-01

    Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. 5HT3 receptor antagonism is one of these actions, and this leads to increased release of norepinephrine (NE), acetylcholine (ACh), and serotonin (5HT) within various brain circuits.

  12. Serotonin 5-HT2A receptor binding in platelets from healthy subjects as studied by [3H]-lysergic acid diethylamide ([3H]-LSD): intra- and interindividual variability.

    Science.gov (United States)

    Spigset, O; Mjörndal, T

    1997-04-01

    In studies on platelet 5-HT2A receptor binding in patients with neuropsychiatric disorders, there has been a marked variability and a considerable overlap of values between patients and controls. The causes of the large variability in 5-HT2A receptor parameters is still unsettled. In the present study, we have quantified the intra- and interindividual variability of platelet 5-HT2A receptor binding in 112 healthy subjects and explored factors that may influence 5-HT2A receptor binding, using [3H]-lysergic acid diethylamide as radioligand. Age, gender, blood pressure, and metabolic capacity of the liver enzymes CYP2D6 and CYP2C19 did not influence Bmax and Kd values. Body weight and body mass index (BMI) showed a negative correlation with Kd (p = .04 and .03, respectively), but not with Bmax. Bmax was significantly lower in the light half of the year than in the dark half of the year (p = .001), and Kd was significantly lower in the fall than in the summer and winter (p < .001). In females, there was a significant increase in Bmax from week 1 to week 2 of the menstrual cycle (p = .03). Females taking contraceptive pills had significantly higher Kd than drug-free females in weeks 1 and 4 of the menstrual cycle (p = .04). This study shows that a number of factors should be taken into account when using platelet 5-HT2A receptor binding in studies of neuropsychiatric disorders.

  13. Neuroticism and serotonin 5-HT1A receptors in healthy subjects

    DEFF Research Database (Denmark)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell

    2015-01-01

    with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may......Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy...... subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples...

  14. BDNF val66met association with serotonin transporter binding in healthy humans

    DEFF Research Database (Denmark)

    Fisher, P. M.; Ozenne, B.; Svarer, C.

    2017-01-01

    The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted...... differences in 5-HTT levels in humans but with equivocal results, possibly due to limited sample sizes. Within the current study we evaluated these genetic predictors of 5-HTT binding with [11C]DASB positron emission tomography (PET) in a comparatively large cohort of 144 healthy individuals. We used a latent......-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT...

  15. Serotonin in fear conditioning processes.

    Science.gov (United States)

    Bauer, Elizabeth P

    2015-01-15

    This review describes the latest developments in our understanding of how the serotonergic system modulates Pavlovian fear conditioning, fear expression and fear extinction. These different phases of classical fear conditioning involve coordinated interactions between the extended amygdala, hippocampus and prefrontal cortices. Here, I first define the different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. The serotonergic system can be manipulated by administering serotonin receptor agonists and antagonists, as well as selective serotonin reuptake inhibitors (SSRIs), and these can have significant effects on emotional learning and memory. Moreover, variations in serotonergic genes can influence fear conditioning and extinction processes, and can underlie differential responses to pharmacological manipulations. This research has considerable translational significance as imbalances in the serotonergic system have been linked to anxiety and depression, while abnormalities in the mechanisms of conditioned fear contribute to anxiety disorders. Copyright © 2014. Published by Elsevier B.V.

  16. Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.

    Science.gov (United States)

    Oyamada, Yoshihiro; Horiguchi, Masakuni; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-05-15

    Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain.

    Directory of Open Access Journals (Sweden)

    Rick H. A. Van der Doelen

    2014-10-01

    Full Text Available The short allelic variant of the serotonin transporter (5-HTT promoter-linked polymorphic region (5-HTTLPR has been associated with the etiology of major depression by interaction with early life stress (ELS. A frequently observed endophenotype in depression is the abnormal regulation of levels of stress hormones such as glucocorticoids. It is hypothesized that altered central glucocorticoid influence on stress-related behavior and memory processes could underlie the depressogenic interaction of 5-HTTLPR and ELS. One possible mechanism could be the altered expression of the genes encoding the glucocorticoid and mineralocorticoid receptor (GR, MR and their inhibitory regulator FK506-binding protein 51 (FKBP5 in stress-related forebrain areas. To test this notion, we exposed heterozygous (5-HTT+/- and homozygous (5-HTT-/- serotonin transporter knockout rats and their wildtype littermates (5-HTT+/+ to daily 3 h maternal separations from postnatal day 2 to 14. In the medial prefrontal cortex (mPFC and hippocampus of the adult male offspring, we found that GR, MR and FKBP5 mRNA levels were affected by ELS x 5-HTT genotype interaction. Specifically, 5-HTT+/+ rats exposed to ELS showed decreased GR and FKBP5 mRNA in the dorsal and ventral mPFC, respectively. In contrast, 5-HTT+/- rats showed increased MR mRNA levels in the hippocampus and 5-HTT-/- rats showed increased FKBP5 mRNA in the ventral mPFC after ELS exposure. These findings indicate that 5-HTT genotype determines the specific adaptation of GR, MR and FKBP5 expression in response to early life adversity. Therefore, altered extra-hypothalamic glucocorticoid signaling should be considered to play a role in the depressogenic interaction of ELS and 5-HTTLPR.

  18. The relationship between the plasma concentration of blonanserin, and its plasma anti-serotonin 5-HT(2A) activity/anti-dopamine D₂ activity ratio and drug-induced extrapyramidal symptoms.

    Science.gov (United States)

    Suzuki, Hidenobu; Gen, Keishi

    2012-03-01

     Blonanserin is a second-generation antipsychotic that was developed in Japan. We investigated the relationships between plasma concentration, the plasma anti-5-HT(2A) activity/anti-D₂ activity (S/D) ratio and extrapyramidal symptoms (EPS) in blonanserin dosing.  The subjects were 29 outpatients with schizophrenia. We assessed EPS using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The plasma concentrations were measured by high performance liquid chromatography, and the plasma anti-D₂ and anti-5-HT(2A) activities were measured by [³H]-spiperone and [³H]-ketanserin radioreceptor assays. The results revealed that there were significant correlations between both the plasma concentration and the DIEPSS total score (Pblonanserin is mainly determined by plasma concentration, but the incidence of EPS may be inhibited when anti-5HT(2A) activity is predominant over anti-D₂ activity. © 2012 The Authors. Psychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology.

  19. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): modifying serotonin's downstream effects on glutamate and GABA (gamma amino butyric acid) release.

    Science.gov (United States)

    Stahl, Stephen M

    2015-08-01

    Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. These actions modify the release of both glutamate and GABA (gamma amino butyric acid) within various brain circuits.

  20. SEROTONIN METABOLISM FOLLOWING PLATINUM-BASED CHEMOTHERAPY COMBINED WITH THE SEROTONIN TYPE-3 ANTAGONIST TROPISETRON

    NARCIS (Netherlands)

    SCHRODER, CP; VANDERGRAAF, WTA; KEMA, IP; GROENEWEGEN, A; SLEIJFER, DT; DEVRIES, EGE

    1995-01-01

    The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3

  1. TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain.

    Science.gov (United States)

    Jang, Yongwoo; Lee, Sung Hoon; Lee, Byeongjun; Jung, Seungmoon; Khalid, Arshi; Uchida, Kunitoshi; Tominaga, Makoto; Jeon, Daejong; Oh, Uhtaek

    2015-08-26

    Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca(2+)-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2(-/-) mice. The brains of Trpm2(-/-) mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca(2+)-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD. Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium

  2. Serotonin manipulations and social behavior : Studies in individuals at familial risk for depression

    NARCIS (Netherlands)

    Hogenelst, Koen

    2016-01-01

    Interactions with others affect our mood, and vice versa. Unsurprisingly, people with a mood disorder such as depression often have difficulties in their social relationships. Depression is often thought to be associated with a decreased availability of serotonin, a signaling molecule in the brain

  3. Lack of differential serotonin biosynthesis capacity in genetically selected low and high aggressive mice

    NARCIS (Netherlands)

    Natarajan, Deepa; de Boer, Sietse F.; Koolhaas, Jaap M.

    2009-01-01

    Reduced brain serotonin (5-HT) activity has been linked to impulsive and violent forms of aggression for decades. Despite a vast accumulation of data pertinent to the above observation, information about the possible mechanisms underlying such a decreased 5-HT functioning is virtually absent.

  4. Effects of Early Serotonin Programming on Fear Response, Memory and Aggression

    Science.gov (United States)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter development of serotonergic circuitry, altering behaviors mediated by 5-HT signaling, including memory, fear and aggression. The present study was desi...

  5. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

    DEFF Research Database (Denmark)

    Lucas, Guillaume; Rymar, Vladimir V; Du, Jenny

    2007-01-01

    Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain p...

  6. Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users

    NARCIS (Netherlands)

    Reneman, Liesbeth; Schilt, T.; de Win, Maartje M.; Booij, Jan; Schmand, Ben; van den Brink, Wim; Bakker, Onno

    2006-01-01

    Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive

  7. Serotonin 6 receptor controls alzheimer’s disease and depression

    Science.gov (United States)

    Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

    2015-01-01

    Alzheimer’s disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression. PMID:26449188

  8. Protracted effects of chronic stress on serotonin-dependent thermoregulation.

    Science.gov (United States)

    Natarajan, Reka; Northrop, Nicole A; Yamamoto, Bryan K

    2015-01-01

    Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. The body temperature is controlled in part, by the medial preoptic area (mPOA) of the hypothalamus. To investigate the effect of chronic stress on 5HT and how it affects body temperature regulation, we examined whether exposure to a chronic unpredictable stress (CUS) paradigm produces long-term alterations in thermoregulatory function of the mPOA through decreased 5HT neurotransmission. Adult male Sprague-Dawley rats underwent 21 d of CUS. Four days after the last stress exposure, basal body temperature in the home cage and body temperature in a cold room maintained at 10 °C were recorded. The CUS rats had significantly higher subcutaneous basal body temperature at 13:00 h compared to unstressed (NoStress) rats. Whereas the NoStress rats were able to significantly elevate body temperature from basal levels at 30 and 60 min of exposure to the cold room, the CUS rats showed a hypothermic response to the cold. Treatment during CUS with metyrapone, a corticosterone synthesis inhibitor, blocked stress-induced decrease in body temperature in response to the cold challenge. CUS also decreased 5HT transporter protein immunoreactivity in the mPOA and 5HT2A/C agonist injection into the mPOA after CUS exposure caused stressed rats to exhibit a sensitized hyperthermic response to cold. These results indicate that the CUS induced changes to the 5HTergic system alter mPOA function in thermoregulation. These findings help us to explain the mechanisms underlying chronic stress-induced disorders such as chronic fatigue syndrome wherein long lasting thermoregulatory deficits are observed.

  9. Protracted effects of chronic stress on serotonin dependent thermoregulation

    Science.gov (United States)

    Natarajan, Reka; Northrop, Nicole A.; Yamamoto, Bryan K.

    2016-01-01

    Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. Body temperature is controlled in part, by the medial preoptic area of the hypothalamus (mPOA). To investigate the effect of chronic stress on 5HT and how it affects body temperature regulation, we examined whether exposure to a chronic unpredictable stress paradigm (CUS) produces long-term alterations in thermoregulatory function of the mPOA through decreased 5HT neurotransmission. Adult male Sprague-Dawley rats underwent 21 days of CUS. Four days after last stress exposure, basal body temperature in the home cage and body temperature in a cold room maintained at 10°C were recorded. CUS rats had significantly higher subcutaneous basal body temperature at 13:00 h compared to unstressed (NoStress) rats. Whereas the NoStress rats were able to significantly elevate body temperature from basal levels at 30 and 60 min of exposure to the cold room, the CUS rats showed a hypothermic response to the cold. Treatment during CUS with metyrapone, a corticosterone synthesis inhibitor, blocked stress-induced decrease in body temperature in response to the cold challenge. CUS also decreased 5HT transporter protein immunoreactivity in the mPOA and 5HT2A/C agonist injection into the mPOA after CUS exposure caused stressed rats to exhibit a sensitized hyperthermic response to cold. These results indicate that CUS induced changes to the 5HTergic system alters mPOA function in thermoregulation. These findings help explain mechanisms underlying chronic stress induced disorders such as chronic fatigue syndrome wherein long lasting thermoregulatory deficits are observed. PMID:26414686

  10. Mood, food, and cognition: role of tryptophan and serotonin.

    Science.gov (United States)

    Strasser, Barbara; Gostner, Johanna M; Fuchs, Dietmar

    2016-01-01

    Food is not only necessary as a metabolic fuel for the body, it becomes more and more evident that there exists an association between food and brain functions like mood and cognition. Tryptophan represents a key element for brain functioning, because of its role as a precursor for production of neurotransmitter serotonin (5-hydroxytryptamine). In clinical conditions, which involve chronic immune system activation or under cytokine therapy, lower tryptophan levels because of high catabolism of tryptophan as indicated by the kynurenine to tryptophan ratio are common and often associate with depressive mood. Studies in the in vitro model of mitogen-stimulated peripheral blood mononuclear cells revealed that several phytocompounds, mainly antioxidants like polyphenols and vitamins, can interfere with inflammatory signaling cascades including tryptophan breakdown. If extrapolated to the in vivo situation, such compounds could increase blood and brain tryptophan availability for serotonin production. Although there is some in vivo evidence for the effect of such compounds, outcomes are hardly predictable and most likely depend on the individual's immunological state. Not only a diet rich in tryptophan but also a diet rich in antioxidants can have a positive impact on mood and cognition. This could be of special relevance for individuals who present with low grade inflammation conditions.

  11. Evaluation of the brain 5-HT2A receptor binding index in dogs with anxiety disorders, measured with 123I-5I-R91150 and SPECT.

    Science.gov (United States)

    Vermeire, Simon T; Audenaert, Kurt R; Dobbeleir, André A; De Meester, Rudy H; De Vos, Filip J; Peremans, Kathelijne Y

    2009-02-01

    The serotonergic system has been implicated in emotional and cognitive functions since early work. In particular, an important role has been attributed to the 5-HT2A receptor in schizophrenia, depression, eating disorders, and anxiety. The aim of the study was to evaluate the involvement of the brain 5-HT2A receptor in dogs with severe anxiety disorder, using 123I-5I-R91150 and SPECT. SPECT was performed with the 5-HT2A receptor-specific radioligand 123I-5I-R91150 to determine the 5-HT2A receptor binding index (BI) in the brains of dogs. Sixteen dogs with pathologic anxiety problems were compared with 22 normal-behaving reference dogs. Lower 5-HT2A receptor BI was found in the left (P=0.001) and right (P=0.002) frontal cortices in the group of dogs with anxiety disorders than in the reference group. Right (P=0.022) and left (P=0.048) temporocortical BIs were also significantly lower in the dogs with anxiety disorders. Finally, the BI was significantly lower in the right occipital cortex (P=0.038) of dogs with anxiety disorders than in the reference dogs. After correction for multiple comparisons (Panxiety disorders in dogs. The affected brain regions are in concordance with the brain regions involved in human anxiety disorders. The acquired data confirm the potential of using the dog as a natural model for investigation of the different mechanisms of anxiety disorders. In this regard, the use of dogs may contribute to the development of novel treatment approaches and new drugs for veterinary and human use.

  12. Lineage tracing of dlx1a/2a and dlx5a/6a expressing cells in the developing zebrafish brain.

    Science.gov (United States)

    Solek, Cynthia M; Feng, Shengrui; Perin, Sofia; Weinschutz Mendes, Hellen; Ekker, Marc

    2017-07-01

    Lineage tracing of specific populations of progenitor cells provides crucial information about developmental programs. Four members of the Dlx homeobox gene family, Dlx1,2, 5 and 6, are involved in the specification of γ-aminobutyric acid (GABA)ergic neurons in the vertebrate forebrain. Orthologous genes in mammals and teleost show similarities in expression patterns and transcriptional regulation mechanisms. We have used lineage tracing to permanently label dlx-expressing cells in the zebrafish and have characterized the progeny of these cells in the larva and in the juvenile and adult brain. We have found that dlx1a/2a and dlx5a/6a expressing progenitors give rise, for the most part, to small populations of cells which constitute only a small proportion of GABAergic cells in the adult brain tissue. Moreover, some of the cells do not acquire a neuronal phenotype suggesting that, regardless of the time a cell expresses dlx genes in the brain, it can potentially give rise to cells other than neurons. In some instances, labeling larval dlx5a/6a-expressing cells, but not dlx1a/2a-expressing cells, results in massively expanding, widespread clonal expansion throughout the adult brain. Our data provide a detailed lineage analysis of the dlx1a/2a and dlx5a/6a expressing progenitors in the zebrafish brain and lays the foundation for further characterization of the role of these transcription factors beyond the specification of GABAergic neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. PET imaging of the brain serotonin transporters (SERT) with N,N-dimethyl-2-(2-amino-4-[{sup 18}F]fluorophenylthio)benzylamine (4-[{sup 18}F]-ADAM) in humans: a preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Wen-Sheng [PET Center, Tri-Service General Hospital, Department of Nuclear Medicine, Neihu, Taipei (China); Changhua Christian Hospital, Department of Nuclear Medicine, Changhua (China); Huang, San-Yuan; Ho, Pei-Shen; Yeh, Chin-Bin [Tri-Service General Hospital, Department of Psychiatry, Taipei (China); Ma, Kuo-Hsing [National Defense Medical Center, Department of Biology and Anatomy, Taipei (China); Huang, Ya-Yao; Shiue, Chyng-Yann [PET Center, Tri-Service General Hospital, Department of Nuclear Medicine, Neihu, Taipei (China); PET Center, National Taiwan University Hospital, Department of Nuclear Medicine, Taipei (China); Liu, Ren-Syuan [Taipei Veterans General Hospital, Department of Nuclear Medicine, Taipei (China); Cheng, Cheng-Yi [PET Center, Tri-Service General Hospital, Department of Nuclear Medicine, Neihu, Taipei (China)

    2013-01-15

    The aim of this study was to assess the feasibility of using 4-[{sup 18}F]-ADAM as a brain SERT imaging agent in humans. Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33 {+-} 9 years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[{sup 18}F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region. 4-[{sup 18}F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN) > TH > STR > PFC > CB. The DVR (n = 4, t* = 60 min) in the RN, TH, STR and PFC were 3.00 {+-} 0.50, 2.25 {+-} 0.45, 2.05 {+-} 0.31 and 1.40 {+-} 0.13, respectively. The optimal time for imaging brain SERT with 4-[{sup 18}F]-ADAM was 120-140 min after injection. At the optimal imaging time, the SURs (n = 15) in the MB, TH, STR, and PFC were 2.25 {+-} 0.20, 2.28 {+-} 0.20, 2.12 {+-} 0.18 and 1.47 {+-} 0.14, respectively. There were no significant differences in SERT availability between men and women (p < 0.05). The results of this study showed that 4-[{sup 18}F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[{sup 18}F]-ADAM may be feasible for assessing the status of brain SERT in humans. (orig.)

  14. Serotonin modulates insect hemocyte phagocytosis via two different serotonin receptors.

    Science.gov (United States)

    Qi, Yi-Xiang; Huang, Jia; Li, Meng-Qi; Wu, Ya-Su; Xia, Ren-Ying; Ye, Gong-Yin

    2016-03-14

    Serotonin (5-HT) modulates both neural and immune responses in vertebrates, but its role in insect immunity remains uncertain. We report that hemocytes in the caterpillar, Pieris rapae are able to synthesize 5-HT following activation by lipopolysaccharide. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or RNAi knock-down impaired hemocyte phagocytosis. Biochemical and functional experiments showed that naive hemocytes primarily express 5-HT1B and 5-HT2B receptors. The blockade of 5-HT1B significantly reduced phagocytic ability; however, the blockade of 5-HT2B increased hemocyte phagocytosis. The 5-HT1B-null Drosophila melanogaster mutants showed higher mortality than controls when infected with bacteria, due to their decreased phagocytotic ability. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. Combined, these data demonstrate that 5-HT mediates hemocyte phagocytosis through 5-HT1B and 5-HT2B receptors and serotonergic signaling performs critical modulatory functions in immune systems of animals separated by 500 million years of evolution.

  15. BLOOD CHEMISTRY AND PLATELET SEROTONIN UPTAKE As ...

    African Journals Online (AJOL)

    'AFRICAN JOURNAL OF CLINICAL AND EXPERIMENTAL MICROBIOLOGY MAY 2004 ISSN 1595-689X VOL.5 No.2 ... investigations by means of a questionnaire. .... platelet otomeh'ically. Protein concentration in platelet—rich plasma and in the discharged serotonin was determined serotonin, were determined by the ...

  16. Genetic polymorphism of serotonin transporter 5-HTTLPR ...

    Indian Academy of Sciences (India)

    genetic polymorphism of serotonin transporter in smoking behaviour is reviewed considering the interactive effect of genetic factors. ..... depression. Lancet 347, 731–733. Olausson P., Engel J. A. and Söderpalm B. 2002 Involvement of serotonin in nicotine dependence: processes relevant to positive and negative regulation ...

  17. The serotonin transporter knockout rat : A review

    NARCIS (Netherlands)

    Olivier, Jocelien; Cools, Alexander; Ellenbroek, Bart A.; Cuppen, E.; Homberg, Judith; Kalueff, Allan V.; LaPorte, Justin L.

    2010-01-01

    This chapter dicusses the most recent data on the serotonin transporter knock-out rat, a unique rat model that has been generated by target-selected N-ethyl-N-nitrosourea (ENU) driven mutagenesis. The knock-out rat is the result of a premature stopcodon in the serotonin transporter gene, and the

  18. Serotonin: Modulator of a Drive to Withdraw

    Science.gov (United States)

    Tops, Mattie; Russo, Sascha; Boksem, Maarten A. S.; Tucker, Don M.

    2009-01-01

    Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose…

  19. Serotonin and migraine: biology and clinical implications.

    Science.gov (United States)

    Hamel, E

    2007-11-01

    Migraine is the most frequent neurological disorder in the adult population worldwide, affecting up to 12% of the general population and more frequent in women ( approximately 25%). It has a high impact on our society due to its disabling nature and, therein, reduced quality of life and increased absenteeism from work. Headache is the primary clinical manifestation and it has been associated with 'a hereditary or predisposed sensitivity of neurovascular reactions to certain stimuli or to cyclic changes in the central nervous system' (1). Amongst the many neurotransmitters in the brain, the serotonergic (serotonin, 5-HT) system from the brainstem raphe nucleus has been most convincingly implicated in migraine pathophysiology. The documented changes in 5-HT metabolism and in the processing of central 5-HT-mediated responses during and in between migraine attacks have led to the suggestion that migraine is a consequence of a central neurochemical imbalance that involves a low serotonergic disposition. Although the exact cascade of events that link abnormal serotonergic neurotransmission to the manifestation of head pain and the accompanying symptoms has yet to be fully understood, recent evidence suggests that a low 5-HT state facilitates activation of the trigeminovascular nociceptive pathway, as induced by cortical spreading depression. In this short review, we present and discuss the original and most recent findings that support a role for altered serotonergic neurotransmission in the manifestation of migraine headache.

  20. Compositions and methods related to serotonin 5-HT1A receptors

    Science.gov (United States)

    Mukherjee, Jogeshwar; Saigal, Neil

    2010-06-08

    Contemplated substituted arylpiperazinyl compounds, and most preferably 18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with 18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

  1. Compositions and methods related to serotonin 5-HT1A receptors

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar; Saigal, Neil; Saigal, legal representative, Harsh

    2012-09-25

    Contemplated substituted arylpiperazinyl compounds, and most preferably 18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with 18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

  2. Compositions and methods related to serotonin 5-HT1A receptors

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar [Irvine, CA; Saigal, Neil [Fresno, CA; Saigal, legal representative, Harsh (Fresno, CA)

    2012-09-25

    Contemplated substituted arylpiperazinyl compounds, and most preferably .sup.18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with .sup.18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

  3. Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans

    DEFF Research Database (Denmark)

    Frokjaer, V.G.; Pinborg, Lars Hageman; Madsen, J.

    2008-01-01

    Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin......; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated...

  4. Development and application of assays for serotonin

    Energy Technology Data Exchange (ETDEWEB)

    Gow, I.F.

    1987-01-01

    In this thesis, two assays for serotonin were developed, validated, and used to investigate the relationship between platelet aggregation, serotonin levels and sodium status and serotonin levels and platelet function in patients with cardiovascular disease. A radioimmunoassay (RIA) using an (/sup 125/I)-labelled tracer was developed and validated for the measurement of serotonin in human platelet-rich plasma (PRP) and rat serum. Antisera were raised against N-succinamylserotonin conjugated to bovine albumin and, to improve assay sensitivity, the analyte was made chemically similar to the immunogen by conversion to N-acetylserotonin prior to assay, using the specific amino reagent N-acetoxysuccinimide. An assay for serotonin using high-pressure liquid chromatography with electrochemical detection (HPLC-ECD) was developed, and used to validate the RIA. The RIA can be used to assay up to 100 samples/day compared with 10-20/day by the HPLC-ECD assay.

  5. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    Energy Technology Data Exchange (ETDEWEB)

    Eum, Sung Yong, E-mail: seum@miami.edu; Jaraki, Dima; András, Ibolya E.; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP

  6. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue

    2009-01-01

    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

  7. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H

    OpenAIRE

    Bahri, Mohamed Ali; Plenevaux, Alain; Aerts, Joël; Bastin, Christine; Becker, Guillaume; Mercier, Joël; Valade, Anne; Buchanan, Tim; Mestdagh, Nathalie; Ledoux, Didier; Seret, Alain; Luxen, André; Salmon, Eric

    2017-01-01

    Introduction: Brain distribution of synaptic vesicle protein 2Awas measured with fluorine-18 UCBH ([18F]UCB-H) and positron emission tomography (PET). Methods: Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic v...

  8. Whole genome sequencing of a dizygotic twin suggests a role for the serotonin receptor HTR7 in autism spectrum disorder.

    Science.gov (United States)

    Helsmoortel, Céline; Swagemakers, Sigrid M A; Vandeweyer, Geert; Stubbs, Andrew P; Palli, Ivo; Mortier, Geert; Kooy, R Frank; van der Spek, Peter J

    2016-12-01

    Whole genome sequencing of a severely affected dizygotic twin with an autism spectrum disorder and intellectual disability revealed a compound heterozygous mutation in the HTR7 gene as the only variation not detected in control databases. Each parent carries one allele of the mutation, which is not present in an unaffected stepsister. The HTR7 gene encodes the 5-HT7 serotonin receptor that is involved in brain development, synaptic transmission, and plasticity. The paternally inherited p.W60C variant is situated at an evolutionary conserved nucleotide and predicted damaging by Polyphen2. A mutation akin to the maternally inherited pV286I mutation has been reported to significantly affect the binding characteristics of the receptor. Therefore, the observed sequence alterations provide a first suggestive link between a genetic abnormality in the HTR7 gene and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Serotonin, neural markers and memory

    Directory of Open Access Journals (Sweden)

    Alfredo eMeneses

    2015-07-01

    Full Text Available Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals’ species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors as well as SERT (serotonin transporter seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence

  10. Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation

    Directory of Open Access Journals (Sweden)

    Nakayama H

    2014-02-01

    Full Text Available Hiroto Nakayama,1,* Sumiyo Umeda,2,* Masashi Nibuya,3 Takeshi Terao,4 Koichi Nisijima,5 Soichiro Nomura3 1Yamaguchi Prefecture Mental Health Medical Center, Yamaguchi, Japan; 2Department of Psychiatry, NTT West Osaka Hospital, Osaka, Japan; 3Department of Psychiatry, National Defense Medical College, Saitama, Japan; 4Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan; 5Department of Psychiatry, Jichi University School of Medicine, Tochigi, Japan  *These authors contributed equally to this work Abstract: We propose the possibility of 5-hydroxytryptamine (5-HT1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day. She also complained of depressed mood and was prescribed paroxetine (10 mg/day. She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day. Depressive symptoms appeared and paroxetine (10 mg/day was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin–dopamine antagonist and agonistic on the 5-HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects

  11. Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals.

    Science.gov (United States)

    Dickinson, Dwight; Straub, Richard E; Trampush, Joey W; Gao, Yuan; Feng, Ningping; Xie, Bin; Shin, Joo Heon; Lim, Hun Ki; Ursini, Gianluca; Bigos, Kristin L; Kolachana, Bhaskar; Hashimoto, Ryota; Takeda, Masatoshi; Baum, Graham L; Rujescu, Dan; Callicott, Joseph H; Hyde, Thomas M; Berman, Karen F; Kleinman, Joel E; Weinberger, Daniel R

    2014-06-01

    One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation. To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide

  12. High familial risk for mood disorder is associated with low dorsolateral prefrontal cortex serotonin transporter binding

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G; Vinberg, Maj; Erritzoe, David

    2009-01-01

    Mood disorders are elicited through a combination of genetic and environmental stress factors, and treatment with selective serotonin reuptake inhibitors ameliorates depressive symptoms. Changes in the serotonin transporter (SERT) binding may therefore occur in depressive patients and in subjects...... at risk for developing depression. The aim of this study was to explore whether abnormalities in SERT might be present in healthy individuals with familial predisposition to mood disorder. Nine individuals at high familial risk (mean age 32.2+/-4.2 years) and 11 individuals at low risk (mean age 32.......4+/-5.0 years) for developing mood disorder were included. The subjects were healthy twins with or without a co-twin history of mood disorder identified by linking information from the Danish Twin Register and the Danish Psychiatric Central Register. Regional in vivo brain serotonin transporter binding...

  13. Organization of dopamine and serotonin system: Anatomical and functional mapping of monosynaptic inputs using rabies virus.

    Science.gov (United States)

    Ogawa, Sachie K; Watabe-Uchida, Mitsuko

    2017-05-02

    Dopamine and serotonin play critical roles in flexible behaviors and are related to various psychiatric and motor disorders. This paper reviews the global organization of dopamine and serotonin systems through recent findings using a modified rabies virus. We first introduce methods for comprehensive mapping of monosynaptic inputs. We then describe quantitative comparisons across the data regarding monosynaptic inputs to dopamine neurons versus serotonin neurons. There is surprising similarity between the input to dopamine neurons in the ventral tegmental area (VTA) and the input to serotonin neurons in the dorsal raphe (DR), suggesting functional interactions between these systems. We next introduce studies of mapping monosynaptic inputs to subpopulations of dopamine neurons specified by their projection targets. It was found that the population of dopamine neurons that project to the tail of the striatum (TS) forms an anatomically distinct outlier, suggesting a unique function. From these series of anatomical studies, we propose that there are three information flows that regulate these neuromodulatory systems: the midline stream to serotonin neurons in median raphe (MR) and B6, the central stream to value-coding dopamine neurons and serotonin neurons in rostral DR, and the lateral stream to TS-projecting dopamine neurons. Finally we introduce a new approach to investigate firing patterns of monosynaptic inputs to dopamine neurons in behaving animals. Combining anatomical and physiological findings, we propose that within the central stream, dopamine neurons broadcast a central teaching signal rather than personal teaching signals to multiple brain areas, which are computed in a redundant way in multi-layered neural circuits. Examination of global organization of the dopamine and serotonin circuits not only revealed the complexity of the systems but also revealed some principles of their organization. We will also discuss limitations, practical issues and the

  14. Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin

    Science.gov (United States)

    Leu-Semenescu, Smaranda; Arnulf, Isabelle; Decaix, Caroline; Moussa, Fathi; Clot, Fabienne; Boniol, Camille; Touitou, Yvan; Levy, Richard; Vidailhet, Marie; Roze, Emmanuel

    2010-01-01

    Background: A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa–responsive fluctuating generalized dystonia–parkinsonism. The non–motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. Objective: We examine the sleep, sleep–wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. Patient: The patient was a 28–year–old man with fluctuating generalized dystonia–parkinsonism caused by sepiapterin reductase deficiency. Methods: A sleep interview, wrist actigraphy, sleep log over 14 days, 48–h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5–hydroxytryptophan (the precursor of serotonin) and levodopa were performed. Results: Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep–wake rhythm (sleep occurred every 11.8 ± 5.3 h), organic hyperphagia, attention/executive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5–hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep–wake rhythm (sleep occurred every 24±1.7 h, P melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep–wake rhythm. Citation: Leu–Semenescu S; Arnulf I; Dicaix C; Moussa F; Clot F; Boniol C; Touitou Y; Levy R; Vidailhet M; Roze E. Sleep and rhythm consequences of a genetically induced loss of serotonin. SLEEP 2010;33(3):307–314. PMID:20337188

  15. Role of serotonin in pathogenesis of analgesic induced headache

    Energy Technology Data Exchange (ETDEWEB)

    Srikiatkhachorn, A.

    1999-12-16

    Analgesic abuse has recently been recognized as a cause of deterioration in primary headache patients. Although the pathogenesis of this headache transformation is still obscure, and alteration of central pain control system is one possible mechanism. A number of recent studies indicated that simple analgesics exert their effect by modulating the endogenous pain control system rather than the effect at the peripheral tissue, as previously suggested. Serotonin (5-hydroxytryptamine ; 5-HT) has long been known to play a pivotal role in the pain modulatory system in the brainstem. In the present study, we investigated the changes in 5-HT system in platelets and brain tissue. A significant decrease in platelet 5-HT concentration (221.8{+-}30.7, 445.3{+-}37.4 and 467.2{+-}38.5 ng/10{sup 9} platelets, for patients with analgesic-induced headache and migraine patients, respectively, p<0.02) were evident in patients with analgesic induced headache. Chronic paracetamol administration induced a decrease in 5-HT{sub 2} serotonin receptor in cortical and brain stem tissue in experimental animals (B{sub max}=0.93{+-}0.04 and 1.79{+-}0.61 pmol/mg protein for paracetamol treated rat and controls, respectively, p<0.05). Our preliminary results suggested that chronic administration of analgesics interferes with central and peripheral 5-HT system and therefore possibly alters the 5-HT dependent antinociceptive system. (author)

  16. Emotional voice processing: investigating the role of genetic variation in the serotonin transporter across development.

    Directory of Open Access Journals (Sweden)

    Tobias Grossmann

    Full Text Available The ability to effectively respond to emotional information carried in the human voice plays a pivotal role for social interactions. We examined how genetic factors, especially the serotonin transporter genetic variation (5-HTTLPR, affect the neurodynamics of emotional voice processing in infants and adults by measuring event-related brain potentials (ERPs. The results revealed that infants distinguish between emotions during an early perceptual processing stage, whereas adults recognize and evaluate the meaning of emotions during later semantic processing stages. While infants do discriminate between emotions, only in adults was genetic variation associated with neurophysiological differences in how positive and negative emotions are processed in the brain. This suggests that genetic association with neurocognitive functions emerges during development, emphasizing the role that variation in serotonin plays in the maturation of brain systems involved in emotion recognition.

  17. Characterization, solubilization and partial purification of serotonin 5-HT1C receptors

    Energy Technology Data Exchange (ETDEWEB)

    Yagaloff, K.A.

    1986-01-01

    /sup 125/I-Lysergic acid diethylamide (/sup 125/I-LSD) binds with high affinity to a unique serotonergic site on rat choroid plexus. These sites were localized to choroid plexus epithelial cells using a novel high resolution autoradiographic technique. In membrane preparations, the serotonergic site density was 3100 fmol/mg protein, which is 10 fold higher than the density of any other serotonergic site in brain homogenates. The pharmacology of this site, termed the 5-HT1c site, does not match that of 5-Ht1a, 5-HT1b or 5HT2 serotonergic sites. 5-Ht1c sites were solubilized from pig choroid plexus using the zwitterionic detergent, CHAPS. High affinity labelling of the solubilized site was obtained using the serotonergic radioligand, N1-methyl-2-(/sup 125/I)lysergic acid diethylamide (/sup 125/I-MIL). Choroid plexus tumors obtained from transgenic mice were examined for the presence of serotonin 5-HT1c receptors. /sup 125/I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT1c receptors in normal choroid plexus. The tumor exhibits the highest site density of serotonin receptors (6600 fmol/mg protein) found in any tissue. /sup 125/I-LSD autoradiography of brain sections from transgenic mice shows high levels of specific labelling over the tumor. The affinities of various indolealkyl, phenlakyl and beta-carboline derivatives for the serotonin 5-HT1c receptor were measured in pig choroid plexus using /sup 125/I-MIL. Serotonin precursors and metabolites were all very weak inhibitors of specific /sup 125/I-MIL binding. Structure-affinity relationships were determined for a number of indolealkylamine analogues. Only serotonin is present in cerebrospinal fluid at concentrations near its 5-HT1c inhibition constant, suggesting that serotonin is the natural 5-HT1c agonist.

  18. Temporal Profile of Microtubule-Associated Protein 2: A Novel Indicator of Diffuse Brain Injury Severity and Early Mortality after Brain Trauma.

    Science.gov (United States)

    Papa, Linda; Robicsek, Steven A; Brophy, Gretchen M; Wang, Kevin K W; Hannay, H Julia; Heaton, Shelley; Schmalfuss, Ilona; Gabrielli, Andrea; Hayes, Ronald L; Robertson, Claudia S

    2018-01-01

    This study compared cerebrospinal fluid (CSF) levels of microtubule-associated protein 2 (MAP-2) from adult patients with severe traumatic brain injury (TBI) with uninjured controls over 10 days, and examined the relationship between MAP-2 concentrations and acute clinical and radiologic measures of injury severity along with mortality at 2 weeks and over 6 months. This prospective study, conducted at two Level 1 trauma centers, enrolled adults with severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring a ventriculostomy, as well as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 h following TBI and analyzed via enzyme-linked immunosorbent assay for MAP-2 (ng/mL). Injury severity was assessed by the GCS score, Marshall Classification on computed tomography (CT), Rotterdam CT score, and mortality. There were 151 patients enrolled-130 TBI and 21 control patients. MAP-2 was detectable within 6 h of injury and was significantly elevated compared with controls (p < 0.001) at each time-point. MAP-2 was highest within 72 h of injury and decreased gradually over 10 days. The area under the receiver operating characteristic curve for deciphering TBI versus controls at the earliest time-point CSF was obtained was 0.96 (95% CI 0.93-0.99) and for the maximal 24-h level was 0.98 (95% CI 0.97-1.00). The area under the curve for initial MAP-2 levels predicting 2-week mortality was 0.80 at 6 h, 0.81 at 12 h, 0.75 at 18 h, 0.75 at 24 h, and 0.80 at 48 h. Those with Diffuse Injury III-IV had much higher initial (p = 0.033) and maximal (p = 0.003) MAP-2 levels than those with Diffuse Injury I-II. There was a graded increase in the overall levels and peaks of MAP-2 as the degree of diffuse injury increased within the first 120 h post-injury. These data suggest that early levels of MAP-2 reflect severity of diffuse brain injury and predict 2-week mortality in TBI patients. These

  19. Serotonin synthesis studied with positron emission tomography, (PET)

    DEFF Research Database (Denmark)

    Honoré, Per Gustaf Hartvig; Lundquist, Pinelopi

    Positron emission tomography (PET) has the potential to study the biosynthesis and release of serotonin (5HT) at brain serotonergic neurons. PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes. This section focuses on probes to measure...... seroonin synthesis rate. Knowledge of altered 5HT synthesis and release in disease states may furnish basis for effective pharmacotherapy that may improve the care of psychiatric and neurological disease. Validation of PET measurements of the two PET tracers using perturbation showed that 5-hydroxy......-L-(beta-11C tryptophan) (5HTP) quantifies the activity of amino acid decarboxylase in the conversion to 5HT. On the other hand, alpha-methyl-tryptophan (AMT) measures the conversion to the corresponding 5-hydroxytryptophan analogue. The irreversible binding of the PET probe 5HTP in the monkey brain was lower...

  20. Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development

    Directory of Open Access Journals (Sweden)

    Xiaoning Chen

    2015-01-01

    Full Text Available Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluΔ mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

  1. Peripheral Serotonin 1B Receptor Transcription Predicts the Effect of Acute Tryptophan Depletion on Risky Decision-Making

    Science.gov (United States)

    Mancinelli, Federico; Lockwood, Patricia L; Matarin, Mar; Dolan, Raymond J; Wood, Nick W; Dayan, Peter; Roiser, Jonathan P

    2017-01-01

    Abstract Background The effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible. Methods Using a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1. Results Acute tryptophan depletion did not significantly influence participants’ sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings. Conclusions These results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors. PMID:27638901

  2. Who's flying the plane: Serotonin levels, aggression and free will

    Science.gov (United States)

    Siegel, Allan; Douard, John

    2010-01-01

    The present paper addresses the philosophical problem raised by current causal neurochemical models of impulsive violence and aggression: to what extent can we hold violent criminal offenders responsible for their conduct if that conduct is the result of deterministic biochemical processes in the brain. This question is currently receiving a great deal of attention among neuroscientists, legal scholars and philosophers. We examine our current knowledge of neuroscience to assess the possible roles of deterministic factors which induce impulsive aggression, and the extent to which this behavior can be controlled by neural conditioning mechanisms. Neural conditioning mechanisms, we suggest, may underlie what we consider the basis of responsible (though not necessarily moral) behavior: the capacity to give and take reasons. The models we first examine are based in part upon the role played by the neurotransmitter, serotonin, in the regulation of violence and aggression. Collectively, these results would appear to argue in favor of the view that low brain serotonin levels induce impulsive aggression which overrides mechanisms related to rational decision making processes. We next present an account of responsibility as based on the capacity to exercise a certain kind of reason-responsive control over one's conduct. The problem with such accounts of responsibility, however, is that they fail to specify a neurobiological realization of such mechanisms of control. We present a neurobiological, and weakly determinist, framework for understanding how persons can exercise guidance control over their conduct. This framework is based upon classical conditioning of neurons in the prefrontal cortex that allow for a decision making mechanism that provides for prefrontal cortical control of the sites in the brain which express aggressive behavior that include the hypothalamus and midbrain periaqueductal gray. The authors support the view that, in many circumstances, neural

  3. Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.

    Science.gov (United States)

    Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2007-01-01

    The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies.

  4. Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

    Science.gov (United States)

    Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

    2016-01-01

    Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Transient Serotonin Syndrome by Concurrent Use of Electroconvulsive Therapy and Selective Serotonin Reuptake Inhibitor: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nagahisa Okamoto

    2012-01-01

    Full Text Available The serotonin syndrome, which is characterized by psychiatric, autonomic nervous and neurological symptoms, is considered to be caused by excessive stimulation of the 5-HT1A and 5-HT2 receptors in the gray matter and spinal cord of the central nervous system, after the start of dosing or increase of the dose of a serotoninergic drug. There have been hardly any reports of induction of serotonin syndrome by electroconvulsive therapy (ECT in combination with antidepressant. We present the case of a female patient with major depressive disorder (MDD who developed transient serotonin syndrome soon after the first session of ECT in combination with paroxetine. Paroxetine was discontinued, and her psychiatric, autonomic nervous and neurological symptoms were gradually relieved and disappeared within 2 days. We performed the second ECT session 5 days after the initial session and performed 12 sessions of ECT without any changes in the procedure of ECT and anesthesia, but no symptoms of SS were observed. Finally, her MDD remitted. ECT might cause transiently increased blood-brain barrier (BBB permeability and enhance the transmissivity of the antidepressant in BBB. Therefore, it is necessary to pay attention to rare side effect of serotonin syndrome by ECT in combination with antidepressant.

  6. Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

    DEFF Research Database (Denmark)

    Hasselbalch, S G; Madsen, K; Svarer, C

    2008-01-01

    Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed...... cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F......]altanserin PET in a bolus-infusion approach. A significant global reduction of 20-30% in 5-HT(2A) binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT(2A) binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude...

  7. Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness

    DEFF Research Database (Denmark)

    Aznar, Susana; Klein, Anders B; Santini, Martin A

    2010-01-01

    Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging....... Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber...... density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls...

  8. An Exploration of the Serotonin System in Antisocial Boys with High Levels of Callous-Unemotional Traits

    Science.gov (United States)

    Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David; Dadds, Mark

    2013-01-01

    Background The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations – those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. Method Participants were boys with antisocial behaviour problems aged 3–16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed. Results Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. Conclusion Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required. PMID:23457595

  9. An exploration of the serotonin system in antisocial boys with high levels of callous-unemotional traits.

    Directory of Open Access Journals (Sweden)

    Caroline Moul

    Full Text Available BACKGROUND: The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations - those with psychopathic (callous-unemotional personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. METHOD: Participants were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66 and/or serotonin-system single nucleotide polymorphisms (N = 157 were assayed. RESULTS: Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B and 2a receptor gene (HTR2A were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. CONCLUSION: Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required.

  10. Location of the Antidepressant Binding Site in the Serotonin Transporter IMPORTANCE OF SER-438 IN RECOGNITION OF CITALOPRAM AND TRICYCLIC ANTIDEPRESSANTS

    DEFF Research Database (Denmark)

    Andersen, Jacob; Taboureau, Olivier; Hansen, Kasper B.

    2009-01-01

    The serotonin transporter (SERT) regulates extracellular levels of serotonin (5-hydroxytryptamine, 5HT) in the brain by transporting 5HT into neurons and glial cells. The human SERT (hSERT) is the primary target for drugs used in the treatment of emotional disorders, including depression. h...... antidepressants, including the selective serotonin reuptake inhibitor citalopram and the tricyclic antidepressants imipramine, clomipramine, and amitriptyline. A conservative mutation of Ser-438 to threonine (S438T) selectively increased the K-i values for these antidepressants up to 175-fold. The effects...

  11. Metopic suture and RUNX2, a key transcription factor in osseous morphogenesis with possible important implications for human brain evolution.

    Science.gov (United States)

    Magherini, Stefano; Fiore, Maria Giulia; Chiarelli, Brunetto; Serrao, Antonio; Paternostro, Ferdinando; Morucci, Gabriele; Branca, Jacopo J V; Ruggiero, Marco; Pacini, Stefania

    2015-01-01

    Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates. We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure. Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution.

  12. Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin?

    NARCIS (Netherlands)

    Beyer, Chad E.; Cremers, Thomas I. F. H.

    2008-01-01

    Selective serotonin uptake inhibitors (SSRIs) exert their effects by inhibiting serotonin (5-HT) re-uptake. Although blockade occurs almost immediately, the neurochemical effects on 5-HT, as measured by in vivo microdialysis, have been a matter of considerable debate. In particular, literature

  13. Immunomodulatory Effects Mediated by Serotonin

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2015-01-01

    Full Text Available Serotonin (5-HT induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b downstream signaling transduction proteins; and (c enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

  14. Immunomodulatory Effects Mediated by Serotonin

    Science.gov (United States)

    Arreola, Rodrigo; Becerril-Villanueva, Enrique; Cruz-Fuentes, Carlos; Velasco-Velázquez, Marco Antonio; Garcés-Alvarez, María Eugenia; Hurtado-Alvarado, Gabriela; Quintero-Fabian, Saray; Pavón, Lenin

    2015-01-01

    Serotonin (5-HT) induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a) membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b) downstream signaling transduction proteins; and (c) enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases. PMID:25961058

  15. Sleep and rhythm consequences of a genetically induced loss of serotonin.

    Science.gov (United States)

    Leu-Semenescu, Smaranda; Arnulf, Isabelle; Decaix, Caroline; Moussa, Fathi; Clot, Fabienne; Boniol, Camille; Touitou, Yvan; Levy, Richard; Vidailhet, Marie; Roze, Emmanuel

    2010-03-01

    A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

  16. Effect of serotonin on paired associative stimulation-induced plasticity in the human motor cortex.

    Science.gov (United States)

    Batsikadze, Giorgi; Paulus, Walter; Kuo, Min-Fang; Nitsche, Michael A

    2013-10-01

    Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo-controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory- and excitability-diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation-elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke.

  17. Serotonin receptors in platelets of bipolar and schizoaffective patients: effect of lithium treatment.

    Science.gov (United States)

    Pandey, Ghanshyam N; Pandey, Subhash C; Ren, Xinguo; Dwivedi, Yogesh; Janicak, Philip G

    2003-11-01

    Abnormalities of serotonin (5HT) function have been implicated in mood disorders, and lithium treatment may produce its beneficial effects by modifying serotonergic mechanisms. It has also been observed that 5HT2A receptors are upregulated both in the postmortem brain and platelets of patients with depression and suicidal behavior. However, the role of 5HT2A receptors in bipolar disorders and in the mechanism of action of lithium is unclear. The major objective of this study was to examine if abnormalities of 5HT2A receptors are associated with bipolar or schizoaffective disorders and if treatment with lithium would cause changes in the 5HT2A receptors. 5HT2A receptors were studied in the platelets obtained from drug-free normal control subjects and patients with bipolar ( n=41) or schizoaffective ( n=20) disorders during a drug-free washout period and after treatment (4.0+/-0.44 weeks) with lithium ( n=16). The Bmax and K(D) of 5HT2A receptors were quantitated by binding techniques using [125I]lysergic acid diethylamide (LSD) as a ligand. We observed that the 5HT2A receptor Bmax was increased in platelets obtained from drug-free bipolar or schizoaffective patients as compared with normal control subjects. The 5HT2A receptor density was even more increased in bipolar or schizoaffective suicidal patients, and the 5HT2A receptor Bmax in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control subjects. Treatment with lithium caused a significant increase in the B(max) of platelet 5HT2A receptors in bipolar or schizoaffective patients. Our studies indicate that increased 5HT2A receptors may be associated with the pathophysiology of bipolar illness and that treatment with lithium further increases the density of 5HT2A receptors. Whether this increase in 5HT2A receptors caused by lithium is associated with its therapeutic mechanism of action is unclear. It is also not clear whether the increase in 5HT2A receptors in

  18. APHRODISIAC DRUGS FOR WOMEN AND ITS CORRELATION WITH SEROTONIN

    Directory of Open Access Journals (Sweden)

    P.K. Debnath

    2012-12-01

    Full Text Available Effect of PGE1 (0.4 mg/kg i p and Drugs affecting serotonin and Prostaglandin metabolism including aphrodisiac plants on the serotonin level in rat uterus in estrus, and pregnant state were taken up in the present study. Female aphrodisiac an upcoming branch became a thrust area after the discovery of Sildenfil. Some known aphrodisiac plants and natural products showed to increase uterine 5-HT level. The 5-HT response in rat's uterus is different in estrus and non-estrus state .The uterine 5-HT content increase three fold in estrus in comparison to non-estrus state. Drugs like l-tryptophan increase 5-HT synthesis and projected 5-HT concentration in uterine tissue. Monoamine oxidase inhibitor (MAOI pargyline also increased uterine tissue 5-HT. PGE1 like brain and intestine increased in uterine 5-HT. Indomethacin and diclofenac sodium known to block prostaglandin synthesis by inhibiting prostaglandin synthetase like pCPA reduced the 5-HT content. In pregnant uterus 5-HT content increased while Prostaglandin treatment both in estrus and nonestrus condition also increased 5-HT content more than three fold. Herbs with known aphrodisiac activity contain 5-HT showed significant increase in uterine 5-HT content significantly. The results such obtained show a silvelining in future study of these drugs for therapeutic use.

  19. Increased plasma serotonin in complex regional pain syndrome type 1

    OpenAIRE

    Wesseldijk, Feikje; Fekkes, Durk; Huygen, Frank; Bogaerts-Taal, Elly; Zijlstra, Freek

    2008-01-01

    textabstractBACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT2A receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics. METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls. RESULTS: The plasma 5-HT levels were 411 ± 263 nmol/L and 29 ± 18 nmo...

  20. Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.

    Science.gov (United States)

    Bosker, Fokko J; Tanke, Marit A C; Jongsma, Minke E; Cremers, Thomas I F H; Jagtman, Evelien; Pietersen, Charmaine Y; van der Hart, Marieke G C; Gladkevich, Anatoliy V; Kema, Ido P; Westerink, Ben H C; Korf, Jakob; den Boer, Johan A

    2010-12-01

    We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation.

    Science.gov (United States)

    Kung, Ling-Hsuan; Scrogin, Karie E

    2011-11-01

    Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ∼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.

  2. Detailed mapping of serotonin 5-HT{sub 1B} and 5-HT{sub 1D} receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function

    Energy Technology Data Exchange (ETDEWEB)

    Leysen, J.E. [Graduate School Neurosciences, Amsterdam (Netherlands); Schotte, A.; Jurzak, M.; Luyten, W.H.M.L. [Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse (Belgium); Voorn, P.; Bonaventure, P. [Graduate School Neurosciences, Amsterdam (Netherlands)

    1997-10-17

    The similar pharmacology of the 5-HT{sub 1B} and 5-HT{sub 1D} receptors, and the lack of selective compounds sufficiently distinguishing between the two receptor subtypes, have hampered functional studies on these receptors. In order to provide clues for differential functional roles of the two subtypes, we performed a parallel localization study throughout the guinea-pig brain and the trigeminal ganglia by means of quantitative in situ hybridization histochemistry (using [{sup 35}S]-labelled riboprobes probes for receptor messenger RNA) and receptor autoradiography (using a new radioligand [{sup 3}H]alniditan).The anatomical patterns of 5-HT{sub 1B} and 5-HT{sub 1D} receptor messenger RNA were quite different. While 5-HT{sub 1B} receptor messenger RNA was abundant throughout the brain (with highest levels in the striatum, nucleus accumbens, olfactory tubercle, cortex, hypothalamus, hippocampal formation, amygdala, thalamus, dorsal raphe and cerebellum), 5-HT{sub 1D} receptor messenger RNA exhibited a more restricted pattern; it was found mainly in the olfactory tubercle, entorhinal cortex, dorsal raphe, cerebellum, mesencephalic trigeminal nucleus and in the trigeminal ganglion. The density of 5-HT{sub 1B/1D} binding sites (combined) obtained with [{sup 3}H]alniditan autoradiography was high in the substantia nigra, superior colliculus and globus pallidus, whereas lower levels were detected in the caudate-putamen, hypothalamus, hippocampal formation, amygdala, thalamus and central gray. This distribution pattern was indistinguishable from specific 5-HT{sub 1B} receptor labelling in the presence of ketanserin under conditions to occlude 5-HT{sub 1D} receptor labelling; hence the latter were below detection level. Relationships between the regional distributions of the receptor messenger RNAs and binding sites and particular neuroanatomical pathways are discussed with respect to possible functional roles of the 5-HT{sub 1B} and 5-HT{sub 1D} receptors. (Copyright (c

  3. Effects of sleep deprivation on extracellular serotonin in hippocampus and frontal cortex of the rat

    OpenAIRE

    Bjorvatn, B; Grønli, J; Hamre, F; Sørensen, E; Fiske, E; Bjorkum, Alvhild Alette; Portas, CM; Ursin, R.

    2002-01-01

    Sleep deprivation improves the mood of depressed patients, but the exact mechanism behind this effect is unclear. An enhancement of serotonergic neurotransmission has been suggested. In this study, we used in vivo microdialysis to monitor extracellular serotonin in the hippocampus and the frontal cortex of rats during an 8 h sleep deprivation period. These brain regions were selected since both have been implicated in depression. The behavioral state of the animal was continuously monitored b...

  4. Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Visser, Anniek K.D.; Waarde, Aren van; Willemsen, Antoon T.M. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Bosker, Fokko J. [University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Luiten, Paul G.M. [University of Groningen, Center for Behavior and Neurosciences, Department of Molecular Neurobiology, Haren (Netherlands); Boer, Johan A. den [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Kema, Ido P. [University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Dierckx, Rudi A.J.O. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University Hospital Ghent, Department of Nuclear Medicine, Ghent (Belgium)

    2011-03-15

    The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are {alpha}-[{sup 11}C]methyltryptophan ([{sup 11}C]AMT) and 5-hydroxy-L-[{beta}-{sup 11}C]tryptophan ([{sup 11}C]5-HTP). Both tracers have advantages and disadvantages. [{sup 11}C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [{sup 11}C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain. (orig.)

  5. Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

    Science.gov (United States)

    Baasch, Anna-Lena; Hüning, Irina; Gilissen, Christian; Klepper, Joerg; Veltman, Joris A; Gillessen-Kaesbach, Gabriele; Hoischen, Alexander; Lohmann, Katja

    2014-04-01

    Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

  6. Role of Adenosine A2A Receptors in Modulating Synaptic Functions and Brain Levels of BDNF: a Possible Key Mechanism in the Pathophysiology of Huntington's Disease

    Directory of Open Access Journals (Sweden)

    Maria Teresa Tebano

    2010-01-01

    Full Text Available In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A2A receptors (A2ARs and brain-derived neurotrophic factor (BDNF. Not only are A2ARs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A2ARs, is involved in such effects. Furthermore, a basal tonus of A2ARs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A2ARs KO mice. The crucial role of adenosine A2ARs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A2ARs seems to play a pathogenetic role.

  7. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.

    Science.gov (United States)

    Howell, Leonard L; Cunningham, Kathryn A

    2015-01-01

    Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  8. alpha 1-Adrenoceptors modulate citalopram-induced serotonin release

    NARCIS (Netherlands)

    Rea, Kieran; Folgering, Joost; Westerink, Ben H. C.; Cremers, Thomas I. F. H.

    Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of alpha 1-adrenoceptor manipulation on extracellular serotonin levels in the

  9. Serotonin 5-HT(3) receptors in the central nervous system.

    Science.gov (United States)

    Chameau, Pascal; van Hooft, Johannes A

    2006-11-01

    The 5-HT(3) receptor is a ligand-gated ion channel activated by serotonin (5-HT). Although originally identified in the peripheral nervous system, the 5-HT(3) receptor is also ubiquitously expressed in the central nervous system. Sites of expression include several brain stem nuclei and higher cortical areas such as the amygdala, hippocampus, and cortex. On the subcellular level, both presynaptic and postsynaptic 5-HT(3) receptors can be found. Presynaptic 5-HT(3) receptors are involved in mediating or modulating neurotransmitter release. Postsynaptic 5-HT(3) receptors are preferentially expressed on interneurons. In view of this specific expression pattern and of the well-established role of 5-HT as a neurotransmitter shaping development, we speculate that 5-HT(3) receptors play a role in the formation and function of cortical circuits.

  10. The serotonin transporter in psychiatric disorders

    DEFF Research Database (Denmark)

    Spies, Marie; Knudsen, Karen Birgitte Moos; Lanzenberger, Rupert

    2015-01-01

    of various psychiatric disorders and their treatment. We review studies that use PET to measure cerebral serotonin transporter activity in psychiatric disorders, focusing on major depressive disorder and antidepressant treatment. We also discuss opportunities and limitations in the application...... of this neuroimaging method in clinical practice. Although results from individual studies diverge, meta-analysis indicates a trend towards reduced serotonin transporter availability in patients with major depressive disorder. Inconsistencies in results might suggest symptom heterogeneity in major depressive disorder...... and might therefore be relevant for stratification of patients into clinical subsets. PET has enabled the elucidation of mechanisms of response to selective serotonin reuptake inhibitors (SSRIs) and hence provides a basis for rational pharmacological treatment of major depressive disorder. Such imaging...

  11. Effects of the diet on brain function

    Science.gov (United States)

    Fernstrom, J. D.

    1981-01-01

    The rates of synthesis by brain neurons of the neurotransmitters serotonin, acetylcholine, and the catecholamines depend on the brain levels of the respective precursor molecules. Brain levels of each precursor are influenced by their blood concentration, and for the amino acid precursors, by the blood levels of other amino acids as well. Since diet readily alters blood concentrations of each of these precursors, it thereby also influences the brain formation of their neutrotransmitter products.

  12. Altered dopamine and serotonin metabolism in motorically asymptomatic R6/2 mice.

    Directory of Open Access Journals (Sweden)

    Fanny Mochel

    Full Text Available The pattern of cerebral dopamine (DA abnormalities in Huntington disease (HD is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD.

  13. Serotonin in the control of the sleep-like states in frogs.

    Science.gov (United States)

    Popova, N K; Lobacheva, I I; Karmanova, I G; Shilling, N V

    1984-05-01

    It has been established that brain serotonin (5-HT) is involved in the control of behavioral phenomena in amphibians. The transition of frogs from active wakefulness to sleep-like states was accompanied by alteration of brain 5-HT metabolism, i.e., in sleep-like state with plastic muscle tone 5-hydroxyindoleacetic acid (5-HIAA) level was reduced and in sleep-like state with rigid muscle tone both brain 5-HIAA and 5-HT were decreased. An experimental decrease of brain 5-HT level by inhibition of its biosynthesis by p-chlorophenylalanine (200 mg/kg) induced the sleep-like state of catatonic type, i.e., the state which was characterized by lowered brain 5-HT.

  14. The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Chan, J.Y.; Snoeren, E.; Cuppen, E.; Waldinger, M.; Olivier, B.; Oosting, R.

    2011-01-01

    INTRODUCTION: Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with s