Affective spectrum disorders and role of serotonergic system of the brain

Directory of Open Access Journals (Sweden)

Timotijević Ivana P.

2014-01-01

Full Text Available Affective spectrum disorders include mood and anxiety disorders, whereas the term functional somatic syndromes describes disorders in which the main symptom is chronic pain, with no pathognomonic tissue damage, such as fibromyalgia, irritable colon, tension headache. Pain as a symptom is often present in patients with depression and anxiety, and similarly, depressed mood, anxiety and other psychiatric symptoms are common in patients with functional somatic syndromes. This explains attitudes that affective disorders and functional somatic syndromes should be found along the same spectrum, due to a similar neurobiochemicalmehanism and dysfunction of these CNS structures and neurotransmitter systems, which lead to similar symptoms in both groups. The symptoms of affective disorders, including somatic are associated with serotonin and serotonergic transmission in the CNS. The existence of depressive and anxiety disorders, such as fatigue, sleep disorders, cognitive disorders, depressed mood, anxiety, and functional somatic syndromes code indicate a similar mechanism of origin. Hypothesis of central neuropathic pain explains the possibility of the descending inhibitory pain mechanisms, including serotonergic and noradrenergic projections and their receptors. Central suprasegmental senzitization in nociceptive pathways, also at the level of the thalamus and the sensory cortex, trigered by an emotional stressors can cause painful symptoms in both groups of disorders. Serotonergic and noradrenergic pathways and voltage sensitive channels of their receptors are included in the mechanism. Modern psychopharmacology can no longer ignore the existence of painful symptoms in affective disorder or depressive and anxiety symptoms in functional somatic syndromes and their treatment can improve. Therapeutic effects of SSRI and SNRI antidepressants and alpha 2 delta ligands for all kinds of painful symptoms in affective disorders - serotonergic spectrum is

The role of the serotonergic system in suicidal behavior

Science.gov (United States)

Sadkowski, Marta; Dennis, Brittany; Clayden, Robert C; ElSheikh, Wala; Rangarajan, Sumathy; DeJesus, Jane; Samaan, Zainab

2013-01-01

Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB); however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. PMID:24235834

Serotonergic mechanisms in the migraine brain

DEFF Research Database (Denmark)

Christensen, Marie Deen; Christensen, Casper Emil; Hougaard, Anders

2017-01-01

role of brain serotonergic mechanisms remains a matter of controversy. Methods We systematically searched PubMed for studies investigating the serotonergic system in the migraine brain by either molecular neuroimaging or electrophysiological methods. Results The literature search resulted in 59 papers......, of which 13 were eligible for review. The reviewed papers collectively support the notion that migraine patients have alterations in serotonergic neurotransmission. Most likely, migraine patients have a low cerebral serotonin level between attacks, which elevates during a migraine attack. Conclusion...... This review suggests that novel methods of investigating the serotonergic system in the migraine brain are warranted. Uncovering the serotonergic mechanisms in migraine pathophysiology could prove useful for the development of future migraine drugs....

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex

Directory of Open Access Journals (Sweden)

Emily K. Stephens

2018-01-01

Full Text Available Serotonin (5-HT selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current, or activation of non-specific cation conductances that underlie calcium-dependent afterdepolarizations (ADPs. However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s involved. In layer 5 of the mouse medial prefrontal cortex, we tested potential mechanisms of serotonergic excitation in commissural/callosal (COM projection neurons, a subpopulation of pyramidal neurons that exhibits 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%, rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances gated by 2A receptors. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50%, when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a non-specific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

DEFF Research Database (Denmark)

Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.

2012-01-01

Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist...... [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L......-DOPA and the 5-HT(1A) agonist, 8-OHDPAT, with microdialysis, and determined [(11) C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [(11) C...

Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat

Science.gov (United States)

Asante, Curtis O.; Dickenson, Anthony H.

2010-01-01

We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states. PMID:20709148

Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders.

Science.gov (United States)

Borrow, Amanda P; Cameron, Nicole M

2014-10-03

Clinical research has demonstrated a significant sex difference in the occurrence of depressive disorders. Beginning at pubertal onset, women report a higher incidence of depression than men. Women are also vulnerable to the development of depressive disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. These disorders are associated with reproductive stages involving changes in gonadal hormone levels. Specifically, female depression and female affective behaviors are influenced by estradiol levels. This review argues two major mechanisms by which estrogens influence depression and depressive-like behavior: through interactions with neurotrophic factors and through an influence on the serotonergic system. In particular, estradiol increases brain derived neurotrophic factor (BDNF) levels within the brain, and alters serotonergic expression in a receptor subtype-specific manner. We will take a regional approach, examining these effects of estrogens in the major brain areas implicated in depression. Finally, we will discuss the gaps in our current knowledge of the effects of estrogens on female depression, and the potential utility for estrogen receptor modulators in treatment for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

The use of serotonergic drugs to treat obesity – is there any hope?

Directory of Open Access Journals (Sweden)

Nicholas T Bello

2011-02-01

Full Text Available Nicholas T Bello1, Nu-Chu Liang21Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USAAbstract: Surgical interventional strategies for the treatment of obesity are being implemented at an increasing rate. The safety and feasibility of these procedures are questionable for most overweight or obese individuals. The use of long-term pharmacotherapy options, on the other hand, can target a greater portion of the obese population and provide early intervention to help individuals maintain a healthy lifestyle to promote weight loss. Medications that act on the central serotonergic pathways have been a relative mainstay for the treatment of obesity for the last 35 years. The clinical efficacy of these drugs, however, has been encumbered by the potential for drug-associated complications. Two drugs that act, albeit by different mechanisms, on the central serotonergic system to reduce food intake and decrease body weight are sibutramine and lorcaserin. Sibutramine is a serotonin and norepinephrine reuptake inhibitor, whereas lorcaserin is a selective 5HT2C receptor agonist. The recent worldwide withdrawal of sibutramine and FDA rejection of lorcaserin has changed the landscape not only for serotonin-based therapeutics specifically, but for obesity pharmacotherapy in general. The purpose of this review is to focus on the importance of the serotonergic system in the control of feeding and its potential as a target for obesity pharmacotherapy. Advances in refining and screening more selective receptor agonists and a better understanding of the potential off-target effects of serotonergic drugs are needed to produce beneficial pharmacotherapy.Keywords: 5-hydroxytryptamine, serotonin 1B, fenfluramine, dexfenfluramine, satiety, dorsal raphe

Cholinergic and serotonergic modulation of visual information processing in monkey V1.

Science.gov (United States)

Shimegi, Satoshi; Kimura, Akihiro; Sato, Akinori; Aoyama, Chisa; Mizuyama, Ryo; Tsunoda, Keisuke; Ueda, Fuyuki; Araki, Sera; Goya, Ryoma; Sato, Hiromichi

2016-09-01

The brain dynamically changes its input-output relationship depending on the behavioral state and context in order to optimize information processing. At the molecular level, cholinergic/monoaminergic transmitters have been extensively studied as key players for the state/context-dependent modulation of brain function. In this paper, we review how cortical visual information processing in the primary visual cortex (V1) of macaque monkey, which has a highly differentiated laminar structure, is optimized by serotonergic and cholinergic systems by examining anatomical and in vivo electrophysiological aspects to highlight their similarities and distinctions. We show that these two systems have a similar layer bias for axonal fiber innervation and receptor distribution. The common target sites are the geniculorecipient layers and geniculocortical fibers, where the appropriate gain control is established through a geniculocortical signal transformation. Both systems exert activity-dependent response gain control across layers, but in a manner consistent with the receptor subtype. The serotonergic receptors 5-HT1B and 5HT2A modulate the contrast-response curve in a manner consistent with bi-directional response gain control, where the sign (facilitation/suppression) is switched according to the firing rate and is complementary to the other. On the other hand, cholinergic nicotinic/muscarinic receptors exert mono-directional response gain control without a sign reversal. Nicotinic receptors increase the response magnitude in a multiplicative manner, while muscarinic receptors exert both suppressive and facilitative effects. We discuss the implications of the two neuromodulator systems in hierarchical visual signal processing in V1 on the basis of the developed laminar structure. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetic and biochemical changes of the serotonergic system in migraine pathobiology.

Science.gov (United States)

Gasparini, Claudia Francesca; Smith, Robert Anthony; Griffiths, Lyn Robyn

2017-12-01

Migraine is a brain disorder characterized by a piercing headache which affects one side of the head, located mainly at the temples and in the area around the eye. Migraine imparts substantial suffering to the family in addition to the sufferer, particularly as it affects three times more women than men and is most prevalent between the ages of 25 and 45, the years of child rearing. Migraine typically occurs in individuals with a genetic predisposition and is aggravated by specific environmental triggers. Attempts to study the biochemistry of migraine began as early as the 1960s and were primarily directed at serotonin metabolism after an increase of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin was observed in urine of migraineurs. Genetic and biochemical studies have primarily focused on the neurotransmitter serotonin, considering receptor binding, transport and synthesis of serotonin and have investigated serotonergic mediators including enzymes, receptors as well as intermediary metabolites. These studies have been mainly assayed in blood, CSF and urine as the most accessible fluids. More recently PET imaging technology integrated with a metabolomics and a systems biology platform are being applied to study serotonergic biology. The general trend observed is that migraine patients have alterations of neurotransmitter metabolism detected in biological fluids with different biochemistry from controls, however the interpretation of the biological significance of these peripheral changes is unresolved. In this review we present the biology of the serotonergic system and metabolic routes for serotonin and discuss results of biochemical studies with regard to alterations in serotonin in brain, cerebrospinal fluid, saliva, platelets, plasma and urine of migraine patients.

Frameworking memory and serotonergic markers.

Science.gov (United States)

Meneses, Alfredo

2017-07-26

The evidence for neural markers and memory is continuously being revised, and as evidence continues to accumulate, herein, we frame earlier and new evidence. Hence, in this work, the aim is to provide an appropriate conceptual framework of serotonergic markers associated with neural activity and memory. Serotonin (5-hydroxytryptamine [5-HT]) has multiple pharmacological tools, well-characterized downstream signaling in mammals' species, and established 5-HT neural markers showing new insights about memory functions and dysfunctions, including receptors (5-HT1A/1B/1D, 5-HT2A/2B/2C, and 5-HT3-7), transporter (serotonin transporter [SERT]) and volume transmission present in brain areas involved in memory. Bidirectional influence occurs between 5-HT markers and memory/amnesia. A growing number of researchers report that memory, amnesia, or forgetting modifies neural markers. Diverse approaches support the translatability of using neural markers and cerebral functions/dysfunctions, including memory formation and amnesia. At least, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors and SERT seem to be useful neural markers and therapeutic targets. Hence, several mechanisms cooperate to achieve synaptic plasticity or memory, including changes in the expression of neurotransmitter receptors and transporters.

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems.

Science.gov (United States)

Brüning, César Augusto; Souza, Ana Cristina Guerra; Gai, Bibiana Mozzaquatro; Zeni, Gilson; Nogueira, Cristina Wayne

2011-05-11

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems. Copyright © 2011 Elsevier B.V. All rights reserved.

Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors

Directory of Open Access Journals (Sweden)

Anne Teissier

2015-12-01

Full Text Available Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.

The evolution of the serotonergic nervous system

DEFF Research Database (Denmark)

Hay-Schmidt, Anders

2000-01-01

Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion......Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion...

Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors.

Science.gov (United States)

Teissier, Anne; Chemiakine, Alexei; Inbar, Benjamin; Bagchi, Sneha; Ray, Russell S; Palmiter, Richard D; Dymecki, Susan M; Moore, Holly; Ansorge, Mark S

2015-12-01

Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

5-HT1A receptor blockade reverses GABA(A) receptor alpha(3) subunit-mediated anxiolytic effects on stress-induced hyperthermia

NARCIS (Netherlands)

Vinkers, Christiaan H.; van Oorschot, Ruud; Korte, S. Mechiel; Olivier, Berend; Groenink, Lucianne

Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the

Serotonergic control of the developing cerebellum

NARCIS (Netherlands)

Oostland, M.

2013-01-01

The work described in this thesis gives insights in the mechanism behind the serotonergic control of the cerebellum during postnatal development. The findings present a powerful role for serotonin in the physiology of the developing cerebellum. The effects of the serotonergic control extend both

Harmane inhibits serotonergic dorsal raphe neurons in the rat.

Science.gov (United States)

Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

2005-11-01

Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

Modulation of anxiety circuits by serotonergic systems

DEFF Research Database (Denmark)

Lowry, Christopher A; Johnson, Philip L; Hay-Schmidt, Anders

2005-01-01

of emotionally salient events, often when both rewarding and aversive outcomes are possible. In this review, we highlight recent advances in our understanding of the neural circuits regulating anxiety states and anxiety-related behavior with an emphasis on the role of brainstem serotonergic systems in modulating...... anxiety-related circuits. In particular, we explore the possibility that the regulation of anxiety states and anxiety-related behavior by serotonergic systems is dependent on a specific, topographically organized mesolimbocortical serotonergic system that originates in the mid-rostrocaudal and caudal...

Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding

DEFF Research Database (Denmark)

Perfalk, Erik; Cunha-Bang, Sofi da; Holst, Klaus K.

2017-01-01

The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4...... receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [11C]SB207145...... findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment....

Influence of early stress on social abilities and serotonergic functions across generations in mice.

Directory of Open Access Journals (Sweden)

Tamara B Franklin

Full Text Available Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila.

Science.gov (United States)

Xu, Li; He, Jianzheng; Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

2016-01-01

Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.

Mediation by the serotonergic system of U-50,488H-induced antinociception and tolerance

Energy Technology Data Exchange (ETDEWEB)

Ho, Begonia Yeeman.

1989-01-01

The antinociceptive action of U-50,488H, a selective {kappa}-opioid receptor agonist, was attenuated by serotonergic but not by noradrenergic receptor antagonists. Intracerebroventricularly (i.c.v.) administered U-50,488H was antagonized by more than two fold by i.c.v. administered pindolol, methysergide, mianserin, ketanserin, pirenperone or ICS-205,930. A similar degree of antagonism of U-50,488H (i.c.v.) was found after intrathecal (i.t.) treatments with pindolol, methysergide or ICS-205,930 but not with mianserin, ketanserin or pirenperone. When U-50,488H and the antagonists were both given i.t., its antinociceptive action was attenuated by pindolol or methysergide, potentiated by mianserin, ketanserin or pirenperone and not affected by ICS-205,930. The release of serotonin was further studied directly by using a superfusion system. A naloxone reversible, concentration- and Ca{sup 2+}- dependent enhancement of release of ({sup 3}H)serotonin by U-50,488H was observed in spinal and brain tissues. Tolerance to the antinociceptive action of U-50,488H was induced in mice using slow release preparations of U-50,488H. Serotonergic receptor antagonists (pindolol or ketanserin) were co-administered with U-50,488H to test for their effects on the development of tolerance to U-50,488H.

Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

Science.gov (United States)

Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2016-09-01

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. © The Author(s) 2016.

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

and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C...

Up-regulation of serotonergic binding sites labeled by (3H) WB4101 following fimbrial transection and 5,7-dihydroxytryptamine-induced lesions

International Nuclear Information System (INIS)

Morrow, A.L.; Norman, A.B.; Battaglia, G.; Loy, R.; Creese, I.

1985-01-01

Lesions of the serotonergic afferents to the hippocampus, by fimbrial transection or by 5,7-dihydroxytryptamine treatment, produce an increase in the Bmax of ( 3 H)WB4101 to its nanomolar affinity binding site, with no effect on its picomolar affinity binding site or on ( 3 H)prazosin binding. The nanomolar site is serotonergic as the serotonergic agonists, serotonin and 8-hydroxy-dipropylaminotetraline (8-OH-DPAT) have nanomolar affinity for ( 3 H)WB4101 binding when studied in the presence of a prazosin mask (30nM) of the alpha-1 component of ( 3 H)WB4101 binding. The serotonin receptor antagonists metergoline, lysergic acid diethylamide and lisuride also have high nanomolar affinities while ketanserin, yohimbine, prazosin and noradrenergic agonists have affinities in the micromolar range. Fimbrial transection or 5,7-dihydroxytryptamine injections produced 32% and 44% increases in the Bmax of ( 3 H)WB4101 binding in the presence of a prazosin mask. Serotonin competition for ( 3 H)WB4101 binding was identical in control and experimental tissues from each lesion experiment. Although specific binding of ( 3 H)WB4101 was increased, there was no change in the affinities or the percentages of the two binding components for serotonin competition with ( 3 H)WB4101. These data suggest that removal of the serotonergic input to the hippocampus produces an increase in the Bmax of serotonin receptor binding sites labeled by ( 3 H)WB4101. 33 references, 3 figures, 3 tables

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens.

Science.gov (United States)

Halberstadt, Adam L

2015-01-15

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. Copyright © 2014 Elsevier B.V. All rights reserved.

Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.

Science.gov (United States)

Johnson, M D

1994-02-01

Serotonergic neurons are thought to play a role in depression and obsessive compulsive disorder. However, their functional transmitter repertoire is incompletely known. To investigate this repertoire, intracellular recordings were obtained from 132 cytochemically identified rat mesopontine serotonergic neurons that had re-established synapses in microcultures. Approximately 60% of the neurons evoked excitatory glutamatergic potentials in themselves or in target neurons. Glutamatergic transmission was frequently observed in microcultures containing a solitary serotonergic neuron. Evidence for co-release of serotonin and glutamate from single raphe neurons was also obtained. However, evidence for gamma-aminobutyric acid release by serotonergic neurons was observed in only two cases. These findings indicate that many cultured serotonergic neurons form glutamatergic synapses and may explain several observations in slices and in vivo.

Serotonergic neurons signal reward and punishment on multiple timescales

Science.gov (United States)

Cohen, Jeremiah Y; Amoroso, Mackenzie W; Uchida, Naoshige

2015-01-01

Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We ‘tagged’ serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales. DOI: http://dx.doi.org/10.7554/eLife.06346.001 PMID:25714923

An overview on benzylisoquinoline derivatives with dopaminergic and serotonergic activities.

Science.gov (United States)

Cabedo, N; Berenguer, I; Figadère, B; Cortes, D

2009-01-01

Dopamine and serotonin are important neurotransmitters in the mammalian central nervous system (CNS) involved in numerous physiological and behavioural disorders such as schizophrenia, major depression, anxiety, Parkinson's and Huntington's diseases, and attention deficit hyperactivity disorder. Several natural and synthetic benzylisoquinoline derivatives have displayed affinity for dopamine and serotonin receptors in nanomolar or micromolar ranges. This review covers the last three decades of dopaminergic and serotonergic activities, and especially focuses on structure-activity relationships of natural and synthetic benzylisoquinoline derivatives. We have included aporphines, 1-benzyltetrahydroisoquinolines, bis-benzylisoquinolines, protoberberines, cularines and other structural analogues. Further molecular modelling calculations have been considered as important tools to not only obtain structural information of both neurotransmitter receptors, but to also identify their pharmacophore features. The development of selective potential ligands like benzylisoquinoline derivatives may help in the therapy of diseases related to CNS dysfunction.

Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

OpenAIRE

Chowdhury, Srikanta; Yamanaka, Akihiro

2016-01-01

Orexin/hypocretin neurons play a crucial role in the regulation of sleep/wakefulness, primarily in the maintenance of wakefulness. These neurons innervate wide areas of the brain and receive diverse synaptic inputs including those from serotonergic (5-HT) neurons in the raphe nucleus. Previously we showed that pharmacological application of 5-HT directly inhibited orexin neurons via 5-HT1A receptors. However, it was still unclear how 5-HT neurons regulated orexin neurons since 5-HT neurons co...

Assessment of serotonergic system in formation of memory and learning

Directory of Open Access Journals (Sweden)

J. C. da Silva

2017-11-01

Full Text Available Abstract We evaluated the involvement of the serotonergic system on memory formation and learning processes in healthy adults Wistar rats. Fifty-seven rats of 5 groups had one serotonergic nuclei damaged by an electric current. Electrolytic lesion was carried out using a continuous current of 2mA during two seconds by stereotactic surgery. Animals were submitted to learning and memory tests. Rats presented different responses in the memory tests depending on the serotonergic nucleus involved. Both explicit and implicit memory may be affected after lesion although some groups showed significant difference and others did not. A damage in the serotonergic nucleus was able to cause impairment in the memory of Wistar. The formation of implicit and explicit memory is impaired after injury in some serotonergic nuclei.

Serotonergic Drugs and Valvular Heart Disease

Science.gov (United States)

Rothman, Richard B.; Baumann, Michael H.

2009-01-01

Background The serotonin (5-HT) releasers (±)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use due to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the “5-HT hypothesis”) suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease. Objective Here we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease. Methods Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations. Conclusions The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT2B receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT2B agonist activity. PMID:19505264

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

Directory of Open Access Journals (Sweden)

Xi-Ling Jiang

2016-09-01

Full Text Available We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI, potentiates serotonin (5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88–0.496 µmol/L for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT–induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

Characterization of Induced Pluripotent Stem Cell-derived Human Serotonergic Neurons

Directory of Open Access Journals (Sweden)

Lining Cao

2017-05-01

Full Text Available In the brain, the serotonergic neurons located in the raphe nucleus are the unique resource of the neurotransmitter serotonin, which plays a pivotal role in the regulation of brain development and functions. Dysfunction of the serotonin system is present in many psychiatric disorders. Lack of in vitro functional human model limits the understanding of human central serotonergic system and its related diseases and clinical applications. Previously, we have developed a method generating human serotonergic neurons from induced pluripotent stem cells (iPSCs. In this study, we analyzed the features of these human iPSCs-derived serotonergic neurons both in vitro and in vivo. We found that these human serotonergic neurons are sensitive to the selective neurotoxin 5, 7-Dihydroxytryptamine (5,7-DHT in vitro. After being transplanted into newborn mice, the cells not only expressed their typical molecular markers, but also showed the migration and projection to the host’s cerebellum, hindbrain and spinal cord. The data demonstrate that these human iPSCs-derived neurons exhibit the typical features as the serotonergic neurons in the brain, which provides a solid foundation for studying on human serotonin system and its related disorders.

The Integrin Receptor in Biologically Relevant Bilayers

DEFF Research Database (Denmark)

Kalli, Antreas C.; Róg, Tomasz; Vattulainen, Ilpo

2017-01-01

/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics. The results of this study...... demonstrate the dynamic nature of the integrin receptor and suggest that the presence of the integrin receptor alters the lipid organization between the two leaflets of the bilayer. In particular, our results suggest elevated density of cholesterol and of phosphatidylserine lipids around the integrin....../talin complex and a slowing down of lipids in an annulus of ~30 Å around the protein due to interactions between the lipids and the integrin/talin F2–F3 complex. This may in part regulate the interactions of integrins with other related proteins or integrin clustering thus facilitating signal transduction...

The role of the serotonergic system in suicidal behavior

Directory of Open Access Journals (Sweden)

Sadkowski M

2013-11-01

Full Text Available Marta Sadkowski,1,* Brittany Dennis,2–4,* Robert C Clayden,2 Wala ElSheikh,5 Sumathy Rangarajan,5 Jane DeJesus,5 Zainab Samaan3–6 1Arts and Sciences Program, 2Faculty of Health Sciences, 3Department of Clinical Epidemiology and Biostatistics, 4Population Genomics Program, McMaster University, Hamilton, ON, Canada; 5Population Health Research Institute, Hamilton, ON, Canada; 6Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada *These authors contributed equally to this work Abstract: Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB; however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. Keywords: serotonin, suicide, genetic

Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats.

Science.gov (United States)

Lee, Ji-Hye; Li, Dong Xing; Yoon, Heera; Go, Donghyun; Quan, Fu Shi; Min, Byung-Il; Kim, Sun Kwang

2014-12-06

Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats. The behavioral signs of cold allodynia in Sprague-Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat's tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment. The serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 μg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 μg, i.t.) or

Effects of hypergravic fields on serotonergic neuromodulation in the rat hippocampus.

Science.gov (United States)

Horrigan, D J; Fuller, C A; Horowitz, J M

1997-10-01

The effects of 7 day exposure to 2G fields on serotonergic modulation at two synapses on a hippocampal pathway were examined by recording dentate gyrus and CA1 pyramidal cell layer electrical activity. Serotonin decreased the amplitude of the population spike (synchronous action potentials in hundreds of neurons) in both the dentate gyrus and CA1 regions of rats exposed to 2G fields for 7 days. The inhibition, averaging 26 +/- 4% (mean +/- SEM) in the dentate gyrus and 80 +/- 5% in the CA1 region, was not significantly different from inhibitory responses observed in 1G controls. The 5-HT1A agonist 8-OH-DPAT mimicked this inhibition in the dentate and CA1 regions of 1G rats. 8-OH-DPAT responses were not affected by exposure to 2G fields. We conclude that the hippocampus contains surplus 5-HT receptors so that decreases in receptor density reported in receptor binding studies do not result in a decrease in modulatory capability. A model to account for the physiological pathway that relates gravitational field strength to 5-HT receptor density without changing the effectiveness of 5-HT neuromodulation is discussed.

Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents.

Science.gov (United States)

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; Gu, Jianguo G

2017-05-01

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In this study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, γ-aminobutyric acid (GABA), and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (I h ), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of I h currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. © 2017 International Society for Neurochemistry.

Tetracycline inducible gene manipulation in serotonergic neurons.

Directory of Open Access Journals (Sweden)

Tillmann Weber

Full Text Available The serotonergic (5-HT neuronal system has important and diverse physiological functions throughout development and adulthood. Its dysregulation during development or later in adulthood has been implicated in many neuropsychiatric disorders. Transgenic animal models designed to study the contribution of serotonergic susceptibility genes to a pathological phenotype should ideally allow to study candidate gene overexpression or gene knockout selectively in serotonergic neurons at any desired time during life. For this purpose, conditional expression systems such as the tet-system are preferable. Here, we generated a transactivator (tTA mouse line (TPH2-tTA that allows temporal and spatial control of tetracycline (Ptet controlled transgene expression as well as gene deletion in 5-HT neurons. The tTA cDNA was inserted into a 196 kb PAC containing a genomic mouse Tph2 fragment (177 kb by homologous recombination in E. coli. For functional analysis of Ptet-controlled transgene expression, TPH2-tTA mice were crossed to a Ptet-regulated lacZ reporter line (Ptet-nLacZ. In adult double-transgenic TPH2-tTA/Ptet-nLacZ mice, TPH2-tTA founder line L62-20 showed strong serotonergic β-galactosidase expression which could be completely suppressed with doxycycline (Dox. Furthermore, Ptet-regulated gene expression could be reversibly activated or inactivated when Dox was either withdrawn or added to the system. For functional analysis of Ptet-controlled, Cre-mediated gene deletion, TPH2-tTA mice (L62-20 were crossed to double transgenic Ptet-Cre/R26R reporter mice to generate TPH2-tTA/Ptet-Cre/R26R mice. Without Dox, 5-HT specific recombination started at E12.5. With permanent Dox administration, Ptet-controlled Cre-mediated recombination was absent. Dox withdrawal either postnatally or during adulthood induced efficient recombination in serotonergic neurons of all raphe nuclei, respectively. In the enteric nervous system, recombination could not be detected. We

Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB. 20

Energy Technology Data Exchange (ETDEWEB)

Conner, D.A.

1988-01-01

Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT{sub 1C} receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing ({sup 3}H)serotonin, ({sup 3}H)lysergic acid diethylamide or ({sup 3}H)dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor.

Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB.20

International Nuclear Information System (INIS)

Conner, D.A.

1988-01-01

Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT 1C receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing [ 3 H]serotonin, [ 3 H]lysergic acid diethylamide or [ 3 H]dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor

Involvement of autophagy upregulation in 3,4-methylenedioxymethamphetamine ('ecstasy')-induced serotonergic neurotoxicity.

Science.gov (United States)

Li, I-Hsun; Ma, Kuo-Hsing; Kao, Tzu-Jen; Lin, Yang-Yi; Weng, Shao-Ju; Yen, Ting-Yin; Chen, Lih-Chi; Huang, Yuahn-Sieh

2016-01-01

It has been suggested that autophagy plays pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug that causes long-term serotonergic neurotoxicity in the brain. Apoptosis and necrosis have been implicated in MDMA-induced neurotoxicity, but the role of autophagy in MDMA-elicited serotonergic toxicity has not been investigated. The present study aimed to examine the contribution of autophagy to neurotoxicity in serotonergic neurons in in vitro and in vivo animal models challenged with MDMA. Here, we demonstrated that in cultured rat serotonergic neurons, MDMA exposure induced LC3B-densely stained autophagosome formation, accompanying by a decrease in neurite outgrowth. Autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated MDMA-induced autophagosome accumulation, and ameliorated MDMA-triggered serotonergic neurite damage and neuron death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in serotonergic neurons and aggravated neurite degeneration. In addition, MDMA-induced autophagy activation in cultured serotonergic neurons might be mediated by serotonin transporter (SERT). In an in vivo animal model administered MDMA, neuroimaging showed that 3-MA protected the serotonin system against MDMA-induced downregulation of SERT evaluated by animal-PET with 4-[(18)F]-ADAM, a SERT radioligand. Taken together, our results demonstrated that MDMA triggers upregulation of autophagy in serotonergic neurons, which appears to be detrimental to neuronal growth. Copyright © 2015 Elsevier Inc. All rights reserved.

Serotonergic drugs in the treatment of depressive and anxiety disorders

NARCIS (Netherlands)

Den Boer, JA; Bosker, FJ; Slaap, BR

Serotonergic dysfunction has been implicated in the aetiology of several psychiatric conditions, including depressive and anxiety disorders. Much of the evidence for the role of serotonin (5-HT) in these disorders comes from treatment studies with serotonergic drugs, including selective serotonin

Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation : the involvement of the serotonergic system

NARCIS (Netherlands)

Waldinger, MD; Berendsen, HHG; Blok, BFM; Olivier, B; Holstege, G

Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying

Pharmacodynamic Study of Interaction of Aqueous Leaf Extract of Psidium Guajava Linn. (Myrtaceae) with Receptor Systems Using Isolated Tissue Preparations.

Science.gov (United States)

Mahaseth, R K; Kumar, S; Dutta, Shagun; Sehgal, Ratika; Rajora, Preety; Mathur, Rajani

2015-01-01

The present study investigates the interaction of aqueous leaf extract of Psidium guajava with muscarinic, serotonergic and adrenergic receptor system using isolated rat ileum, gastric fundus and trachea, respectively. The concentration-dependent contractile response of aqueous leaf extract of Psidium guajava was parallel and rightward of standard agonists, ACh and 5-HT indicating agonistic activity on muscarinic and serotonergic receptor systems. The inhibition of aqueous leaf extract of Psidium guajava mediated contractions in presence of atropine (10(-7) M) and ketanserin (10(-6) M) confirmed the activity. Relaxant effect of PG (0.2 mg/ml) on carbachol induced pre-contracted rat tracheal chain indicated its agonistic action on adrenergic receptor system. Inhibition (P<0.05) of the action in the presence of propranolol (1 ng/ml) confirmed the activity. It may be concluded that PG possesses agonistic action on muscarinic, serotonergic and adrenergic receptor systems.

Serotonergic synaptic input to facial motoneurons: localization by electron-microscopic autoradiography

Energy Technology Data Exchange (ETDEWEB)

Aghajanian, G K; McCall, R B [Yale Univ., New Haven, CT (USA). School of Medicine

1980-12-01

Serotonergic nerve terminals in the facial motor nucleus were labelled with (/sup 3/H)5-hydroxytryptamine. When serotonergic nerve terminals were destroyed (by the selective neurotoxin 5,7-dihydroxytryptamine) the labelling was lost. By electron-microscopic autoradiography, labelled serotonergic terminals were found to make axo-dendritic or axo-somatic junctions with facial motor neurons. No axo-axonic junctions were observed. These morphological findings are consistent with physiological studies which indicate that 5-hydroxytryptamine facilitates the excitation of facial motoneurons through a direct postsynaptic action.

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...... remained significant after correction for multiple comparisons (r = .35, p = .009). Conclusions: In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point...

Transient electromyographic findings in serotonergic toxicity due to combination of essitalopram and isoniazid

Directory of Open Access Journals (Sweden)

Çagdas Erdogan

2013-01-01

Full Text Available Here, we report a case of serotonergic toxicity due to combination of essitalopram and isoniazid, which was rarely reported before. Moreover, we observed transient neurogenic denervation potentials in needle electromyography, which disappeared with the treatment of serotonergic toxicity. As to our best knowledge, this is the first case, reporting transient electromyographic changes probably due to serotonergic toxicity.

Activation of glucocorticoid receptors increases 5-HT2A receptor levels

DEFF Research Database (Denmark)

Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

2009-01-01

an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased......Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker...... of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...

Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression.

Directory of Open Access Journals (Sweden)

Thibault Renoir

Full Text Available Depression is the most common psychiatric disorder in Huntington's disease (HD patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT and the forced-swimming test (FST. The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2 mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism

Directory of Open Access Journals (Sweden)

Dietmar Fuchs

2010-08-01

Full Text Available Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC and the non-psychotropic cannabidiol (CBD modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC. The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO, suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.

Evaluation of the Serotonergic Genes htr1A, htr1B, htr2A, and slc6A4 in Aggressive Behavior of Golden Retriever Dogs

NARCIS (Netherlands)

Berg, L. van den; Vos-Loohuis, M.; Schilder, M.B.H.; Oost, B.A. van; Hazewinkel, H.A.W.; Wade, C.M.; Karlsson, E.K.; Lindblad-Toh, K.; Liinamo, A.E.; Leegwater, P.A.J.

2008-01-01

Aggressive behavior displays a high heritability in our study group ofGolden Retriever dogs.Alterations in brain serotonin metabolism have been described in aggressive dogs before. Here, we evaluate whether four genes of the canine serotonergic system, coding for the serotonin receptors 1A, 1B,

3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.

Science.gov (United States)

Wermuth, C G; Schlewer, G; Bourguignon, J J; Maghioros, G; Bouchet, M J; Moire, C; Kan, J P; Worms, P; Biziere, K

1989-03-01

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.

Studies on the characterization and regulation of alpha-1 adrenergic receptors and [3H]WB4101 binding sites in the central nervous system

International Nuclear Information System (INIS)

Morrow, A.L.

1985-01-01

The purpose of these studies has been to resolve the anomalous binding characteristics of two alpha adrenergic receptor ligands, [ 3 H]WB4101 and [ 3 H]prazosin and to study the regulation of the receptors labeled by these compounds after surgical denervation and chronic drug treatments. Preliminary studies indicated that [ 3 H]WB4101 binding sites, which were believed to represent alpha-1 adrenergic receptors, were increased in number following removal of the fimbrial afferents to the hippocampus. This increase was not due to removal of the adrenergic input into this structure since destruction of the locus coeruleus or the dorsal noradrenergic bundle did not produce the up-regulation. Characterization of alpha-1 adrenergic receptors using [ 3 H]prazosin and [ 3 H]WB4101 revealed evidence for subtypes of alpha-1 receptors designated alpha-1A and alpha-1B. The nanomolar affinity component of [ 3 H]WB4101 binding is not adrenergic but serotonergic. The serotonergic agonists, serotonin and 8-hydroxy-dipropylaminotetraline have affinities of 1.5 and 3.0 nM for this site, when studied in the presence of a 30 nM prazosin mask of the alpha-1 component of [ 3 H]WB4101 binding. Fimbria transection or 5,7 dihydroxytryptamine injections produced increases in the Bmax of the nanomolar affinity component of [ 3 H]WB4101 binding in the presence of a prazosin mask. The up-regulated site showed identical serotonergic pharmacology compared to control tissue. Thus, the author concluded that serotonergic denervation of the hippocampus produces the increase in serotonergic binding sites labeled by [ 3 H]WB4101

Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals.

Science.gov (United States)

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; DeBerry, Jennifer J; Gu, Jianguo G

2016-09-13

The evolution of sensory systems has let mammals develop complicated tactile end organs to enable sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. The Merkel disc, a main type of tactile end organ consisting of Merkel cells (MCs) and Aβ-afferent endings, are highly abundant in fingertips, touch domes, and whisker hair follicles of mammals. The Merkel disc has high tactile acuity for an object's physical features, such as texture, shape, and edges. Mechanisms underlying the tactile function of Merkel discs are obscured as to how MCs transmit tactile signals to Aβ-afferent endings leading to tactile sensations. Using mouse whisker hair follicles, we show herein that tactile stimuli are transduced by MCs into excitatory signals that trigger vesicular serotonin release from MCs. We identify that both ionotropic and metabotropic 5-hydroxytryptamine (5-HT) receptors are expressed on whisker Aβ-afferent endings and that their activation by serotonin released from MCs initiates Aβ-afferent impulses. Moreover, we demonstrate that these ionotropic and metabotropic 5-HT receptors have a synergistic effect that is critical to both electrophysiological and behavioral tactile responses. These findings elucidate that the Merkel disc is a unique serotonergic synapse located in the epidermis and plays a key role in tactile transmission. The epidermal serotonergic synapse may have important clinical implications in sensory dysfunctions, such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes, inflammatory diseases, and undergo chemotherapy. It may also have implications in the exaggerated tactile sensations induced by recreational drugs that act on serotoninergic synapses.

Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae)

Science.gov (United States)

Michel, Joanna L; Chen, Yegao; Zhang, Hongjie; Huang, Yue; Krunic, Alecjev; Orjala, Jimmy; Veliz, Mario; Soni, Kapil K.; Soejarto, Djaja Doel; Caceres, Armando; Perez, Alice; Mahady, Gail B

2010-01-01

Ethnopharmacological relevance Our previous work has demonstrated that several plants in the Piperaceae family are commonly used by the Q’eqchi Maya of Livingston, Guatemala to treat amenorrhea, dysmenorrhea, and pain. Extracts of Piper hispidum Swingle (Piperaceae), bound to the estrogen (ER) and serotonin (5-HT7) receptors. Aim of the study To investigate the estrogenic and serotonergic activities of P. hispidum extracts in functionalized assays, identify the active chemical constituents in the leaf extract, and test these compounds as agonists or antagonists of ER and 5-HT7. Materials and methods The effects of the P. hispidum leaf extracts were investigated in estrogen reporter gene and endogenous gene assays in MCF-7 cells to determine if the extracts acted as an estrogen agonist or antagonist. In addition, the active compounds were isolated using ER- and 5-HT7 receptor bioassay-guided fractionation. The structures of the purified compounds were identified using high-resolution LC-MS and NMR spectroscopic methods. The ER- and 5-HT7-agonist effects of the purified chemical constituents were tested in a 2ERE-reporter gene assay in MCF-7 cells and in serotonin binding and functionalized assays. Results Three butenolides including one new compound (1) were isolated from the leaves of P. hispidum, and their structures were determined. Compound 1 bound to the serotonin receptor 5-HT7 with IC50 values of 16.1 and 8.3 μM, respectively, and using GTP shift assays, compound 1 was found to be a partial agonist of the 5-HT7 receptor. The P. hispidum leaf extracts, as well as compounds 2 and 3 enhanced the expression of estrogen responsive reporter and endogenous genes in MCF-7 cells, demonstrating estrogen agonist effects. Conclusions Extracts of P. hispidum act as agonists of the ER and 5-HT7 receptors. Compound 1, a new natural product, identified as 9, 10-methylenedioxy-5,6-Z-fadyenolide, was isolated as the 5-HT7 agonist. Compounds 2 and 3 are reported for the

Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain.

Science.gov (United States)

Carcagno, Abel L; Di Bella, Daniela J; Goulding, Martyn; Guillemot, Francois; Lanuza, Guillermo M

2014-11-12

The development of the nervous system is critically dependent on the production of functionally diverse neuronal cell types at their correct locations. In the embryonic neural tube, dorsoventral signaling has emerged as a fundamental mechanism for generating neuronal diversity. In contrast, far less is known about how different neuronal cell types are organized along the rostrocaudal axis. In the developing mouse and chick neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from ventral p3 progenitors, which possess a common transcriptional identity but are confined to distinct anterior-posterior territories. In this study, we show that the expression of the transcription factor Neurogenin3 (Neurog3) in the spinal cord controls the correct specification of p3-derived neurons. Gain- and loss-of-function manipulations in the chick and mouse embryo show that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program by repressing Ascl1 in spinal p3 progenitors through a mechanism dependent on Hes proteins. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by actively suppressing serotonergic specification in the spinal cord. These results explain how equivalent p3 progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types. Copyright © 2014 the authors 0270-6474/14/3415223-11$15.00/0.

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

Science.gov (United States)

Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

2018-06-01

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

Interaction between harmane, a class of β-carboline alkaloids, and the CA1 serotonergic system in modulation of memory acquisition.

Science.gov (United States)

Nasehi, Mohammad; Ghadimi, Fatemeh; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza

2017-09-01

This study set to assess the involvement of dorsal hippocampus (CA1) serotonergic system on harmane induced memory acquisition deficit. We used one trial step-down inhibitory avoidancetask to evaluate memory retention and then, open field test to evaluate locomotor activity in adult male NMRI mice. The results showed that pre-training intra-peritoneal (i.p.) administration of harmane (12mg/kg) induced impairment of memory acquisition. Pre-training intra-CA1 administration of 5-HT1B/1D receptor agonist (CP94253; 0.5 and 5ng/mouse) and 5-HT2A/2B/2C receptor agonist (α-methyl 5-HT; 50ng/mouse) impaired memory acquisition. Furthermore, intra-CA1 administration of 5-HT1B/1D receptor antagonist (GR127935; 0.5ng/mouse) and 5-HT2 receptor antagonist (cinancerine; 5ng/mouse) improved memory acquisition. In addition, pre-training intra-CA1 injection of sub-threshold dose of CP94253 (0.05ng/mouse) and α-methyl 5-HT (5ng/mouse) potentiated impairment of memory acquisition induced by harmane (12mg/kg, i.p.). On the other hand, pre-training intra-CA1 infusion of sub-threshold dose of GR127935 (0.05ng/mouse) and cinancerine (0.5ng/mouse) with the administration of harmane (12mg/kg, i.p.) weakened impairment of memory acquisition. Moreover, all above doses of drugs did not change locomotor activity. The present findings suggest that there is an interaction between harmane and the CA1 serotonergic system in modulation of memory acquisition. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Brain Aromatase Modulates Serotonergic Neuron by Regulating Serotonin Levels in Zebrafish Embryos and Larvae

Directory of Open Access Journals (Sweden)

Zulvikar Syambani Ulhaq

2018-05-01

Full Text Available Teleost fish are known to express two isoforms of P450 aromatase, a key enzyme for estrogen synthesis. One of the isoforms, brain aromatase (AroB, cyp19a1b, is highly expressed during early development of zebrafish, thereby suggesting its role in brain development. On the other hand, early development of serotonergic neuron, one of the major monoamine neurons, is considered to play an important role in neurogenesis. Therefore, in this study, we investigated the role of AroB in development of serotonergic neuron by testing the effects of (1 estradiol (E2 exposure and (2 morpholino (MO-mediated AroB knockdown. When embryos were exposed to E2, the effects were biphasic. The low dose of E2 (0.005 µM significantly increased serotonin (5-HT positive area at 48 hour post-fertilization (hpf detected by immunohistochemistry and relative mRNA levels of tryptophan hydroxylase isoforms (tph1a, tph1b, and tph2 at 96 hpf measured by semi-quantitative PCR. To test the effects on serotonin transmission, heart rate and thigmotaxis, an indicator of anxiety, were analyzed. The low dose also significantly increased heart rate at 48 hpf and decreased thigmotaxis. The high dose of E2 (1 µM exhibited opposite effects in all parameters. The effects of both low and high doses were reversed by addition of estrogen receptor (ER blocker, ICI 182,780, thereby suggesting that the effects were mediated through ER. When AroB MO was injected to fertilized eggs, 5-HT-positive area was significantly decreased, while the significant decrease in relative tph mRNA levels was found only with tph2 but not with two other isoforms. AroB MO also decreased heart rate and increased thigmotaxis. All the effects were rescued by co-injection with AroB mRNA and by exposure to E2. Taken together, this study demonstrates the role of brain aromatase in development of serotonergic neuron in zebrafish embryos and larvae, implying that brain-formed estrogen is an important factor to

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

Directory of Open Access Journals (Sweden)

Mariana G Fronza

Full Text Available A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT and dopamine transporter (DAT by docking molecular. 5-(4methoxyphenyl-1-(2-(phenylselanylphenyl-1H-1,2,3-triazole-4-carbonitrile (SeTACN exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g. was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist, ketanserin (a 5HT2a/c antagonist and ondansetron (a selective 5ht3 antagonist, PCPA (an inhibitor of serotonin synthesis but not with SCH23390 (dopaminergic D1 antagonist and sulpiride (D2 antagonist. Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT. These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests.

Science.gov (United States)

Inoue, Y; Terao, T; Iwata, N; Okamoto, K; Kojima, H; Okamoto, T; Yoshimura, R; Nakamura, J

2007-02-01

Premenstrual dysphoric disorder (PMDD) has been assumed to be a subtype of premenstrual syndrome (PMS) with depressive symptoms, such as depressive mood, tension, anxiety, and mood liability during luteal phase. At present, no conclusion has been established about serotonergic function in PMDD. The purpose of this study was to investigate the serotonergic function of PMDD subjects in comparison to PMS without PMDD subjects and normal controls via neuroendocrine challenge tests. Twenty-four women (seven with PMDD, eight with PMS without PMDD, and nine normal controls) were tested on three occasions (follicular phase, early luteal phase, and late luteal phase) receiving paroxetine 20 mg orally as a serotonergic probe at 8:00 A: .M: . Plasma ACTH and cortisol were measured prior to the administration and every hour for 6 h thereafter. As a whole, there were significant differences in serotonergic function measured by ACTH and cortisol responses to paroxetine challenge across these three groups. PMDD subjects showed higher serotonergic function in follicular phase but lower serotonergic function in luteal phase, compared with women with PMS without PMDD and normal controls. The present findings suggest that PMDD women have fluctuating serotonergic function across their menstrual cycles and that the pattern may be different from PMS without PMDD.

Serotonergic dysfunctions and abnormal iron metabolism: Relevant to mental fatigue of Parkinson disease.

Science.gov (United States)

Zuo, Li-Jun; Yu, Shu-Yang; Hu, Yang; Wang, Fang; Piao, Ying-Shan; Lian, Teng-Hong; Yu, Qiu-Jin; Wang, Rui-Dan; Li, Li-Xia; Guo, Peng; Du, Yang; Zhu, Rong-Yan; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

2016-12-21

Fatigue is a very common non-motor symptom in Parkinson disease (PD) patients. It included physical fatigue and mental fatigue. The potential mechanisms of mental fatigue involving serotonergic dysfunction and abnormal iron metabolism are still unknown. Therefore, we evaluated the fatigue symptoms, classified PD patients into fatigue group and non-fatigue group, and detected the levels of serotonin, iron and related proteins in CSF and serum. In CSF, 5-HT level is significantly decreased and the levels of iron and transferrin are dramatically increased in fatigue group. In fatigue group, mental fatigue score is negatively correlated with 5-HT level in CSF, and positively correlated with the scores of depression and excessive daytime sleepiness, and disease duration, also, mental fatigue is positively correlated with the levels of iron and transferrin in CSF. Transferrin level is negatively correlated with 5-HT level in CSF. In serum, the levels of 5-HT and transferrin are markedly decreased in fatigue group; mental fatigue score exhibits a negative correlation with 5-HT level. Thus serotonin dysfunction in both central and peripheral systems may be correlated with mental fatigue through abnormal iron metabolism. Depression, excessive daytime sleepiness and disease duration were the risk factors for mental fatigue of PD.

The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test.

Science.gov (United States)

Vega-Rivera, N M; López-Rubalcava, C; Estrada-Camarena, E

2013-10-10

17α-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 μg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 μg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and subjected to the FST. In addition, the participation of α2-adrenergic receptors in the antidepressant-like action of EE2 was explored using the selective α2-receptor antagonist idazoxan (0.25, 0.5 and 1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus

Directory of Open Access Journals (Sweden)

Li Zhou

2017-03-01

Full Text Available Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN.

Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

Directory of Open Access Journals (Sweden)

Kathryn M. Buller

2012-01-01

Full Text Available Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

Science.gov (United States)

Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

2008-08-01

representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D(2) and D(3) signaling. Therefore, A(2A) agonists, through antagonizing D(2) and D(3) signaling within A(2A)/D(2) and A(2A)/D(3) RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB(1)/D(2) interactions requiring A(2A) receptors have also been discovered and possibly operate in CB(1)/D(2)/A(2A) RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A(2A), mGluR5 and/or CB(1) receptors can form integrative units with D(2) receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT(1A) RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT(1A) recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor-receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.

Orexin receptor activation generates gamma band input to cholinergic and serotonergic arousal system neurons and drives an intrinsic Ca2+-dependent resonance in LDT and PPT cholinergic neurons.

Directory of Open Access Journals (Sweden)

Masaru eIshibashi

2015-06-01

Full Text Available A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT and pedunculopontine (PPT tegmental neurons and serotonergic dorsal raphe (DR neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4 - 14 Hz and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep and intracortical

Social isolation reduces serotonergic fiber density in the inferior colliculus of female, but not male, mice.

Science.gov (United States)

Keesom, Sarah M; Morningstar, Mitchell D; Sandlain, Rebecca; Wise, Bradley M; Hurley, Laura M

2018-05-12

Early-life experiences, including maternal deprivation and social isolation during adolescence, have a profound influence on a range of adult social behaviors. Post-weaning social isolation in rodents influences behavior in part through the alteration of neuromodulatory systems, including the serotonergic system. Of significance to social behavior, the serotonergic system richly innervates brain areas involved in vocal communication, including the auditory system. However, the influence of isolation on serotonergic input to the auditory system remains underexplored. Here, we assess whether 4 weeks of post-weaning individual housing alters serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain nucleus in which serotonin alters auditory-evoked activity. Individually housed male and female mice were compared to conspecifics housed socially in groups of three. Serotonergic projections were subsequently visualized with an antibody to the serotonin transporter, which labels serotonergic fibers with relatively high selectivity. Fiber densities were estimated in the three major subregions of the IC using line-scan intensity analysis. Individually housed female mice showed a significantly reduced fiber density relative to socially housed females, which was accompanied by a lower body weight in individually housed females. In contrast, social isolation did not affect serotonergic fiber density in the IC of males. This finding suggests that sensitivity of the serotonergic system to social isolation is sex-dependent, which could be due to a sex difference in the effect of isolation on psychosocial stress. Since serotonin availability depends on social context, this finding further suggests that social isolation can alter the acute social regulation of auditory processing. Copyright © 2018. Published by Elsevier B.V.

Involvement of adrenergic and serotonergic nervous mechanisms in allethrin-induced tremors in mice.

Science.gov (United States)

Nishimura, M; Obana, N; Yagasaki, O; Yanagiya, I

1984-05-01

Oral or intravenous administration of allethrin, a synthetic derivative of the pirethrin-based insecticides, produces neurotoxic symptoms consisting of mild salivation, hyperexcitability, tremors and convulsions which result in death. Intracerebroventricular injection of allethrin to mouse at about one-nineth the dose of intravenous administration, produced qualitatively identical but less prominent symptoms, indicating that at least some of the symptoms may be originated in the central nervous system. To investigate the mechanism of action of the compound, we studied the ability of agents which alter neurotransmission to prevent or potentiate the effect of convulsive doses of technical grade (15.5% cis, 84.5% trans) allethrin. Intraperitoneal pretreatment with drugs which block noradrenergic receptors or norepinephrine synthesis, such as pentobarbital, chlorpromazine, phentolamine, phenoxybenzamine and reserpine, depressed the tremor induced by allethrin. The inhibitory effect of reserpine was reversed by phenylephrine. Both the serotonergic blocker, methysergide, and the serotonin depletor, rho-chlorphenylalanine, potentiated the effect of allethrin. The potentiating effect of methysergide was antagonized by 5-hydroxytryptamine. However, intracerebroventricular administration of methysergide was ineffective in potentiating the effect of allethrin. alpha 2- and beta-adrenoceptor blockers, muscarinic antagonists, GABA mimenergics and morphine had no effect. These results suggest that allethrin produces its neurotoxic responses in mice by acting on the brain and spinal levels. Furthermore, adrenergic excitatory and serotonergic inhibitory mechanisms may be involved in the neural pathway through which the allethrin-induced tremor is evoked.

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

Science.gov (United States)

Pesarico, Ana Paula; Sampaio, Tuane Bazanella; Stangherlin, Eluza Curte; Mantovani, Anderson C; Zeni, Gilson; Nogueira, Cristina Wayne

2014-10-03

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems. Copyright © 2014 Elsevier Inc. All rights reserved.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

Science.gov (United States)

Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

2017-03-21

Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Iodine 125-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial cells

International Nuclear Information System (INIS)

Yagaloff, K.A.; Hartig, P.R.

1985-01-01

125 I-Lysergic acid diethylamide ( 125 I-LSD) binds with high affinity to serotonergic sites on rat choroid plexus. These sites were localized to choroid plexus epithelial cells by use of a novel high resolution stripping film technique for light microscopic autoradiography. In membrane preparations from rat choroid plexus, the serotonergic site density was 3100 fmol/mg of protein, which is 10-fold higher than the density of any other serotonergic site in brain homogenates. The choroid plexus site exhibits a novel pharmacology that does not match the properties of 5-hydroxytryptamine-1a (5-HT1a), 5-HT1b, or 5-HT2 serotonergic sites. 125 I-LSD binding to the choroid plexus site is potently inhibited by mianserin, serotonin, and (+)-LSD. Other serotonergic, dopaminergic, and adrenergic agonists and antagonists exhibit moderate to weak affinities for this site. The rat choroid plexus 125 I-LSD binding site appears to represent a new type of serotonergic site which is located on non-neuronal cells in this tissue

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.

Oppositional effects of serotonin receptors 5-HT1a, 2 and 2c in the regulation of adult hippocampal neurogenesis

Directory of Open Access Journals (Sweden)

Friederike Klempin

2010-07-01

Full Text Available Serotonin (5-HT appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lack acute effects on adult neurogenesis in many studies, which suggests a surprising long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

Directory of Open Access Journals (Sweden)

Peiyan eWong

2015-04-01

Full Text Available Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT mice and mice with deficient tryptophan hydroxylase 2 (TPH2 function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI mice. Whereas, maternal separation (MS stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A. The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex, will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain.

Science.gov (United States)

Jones, Douglas C; Duvauchelle, Christine; Ikegami, Aiko; Olsen, Christopher M; Lau, Serrine S; de la Torre, Rafael; Monks, Terrence J

2005-04-01

The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell gamma-glutamyl transpeptidase (gamma-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of alpha-methyl dopamine (alpha-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of gamma-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-alpha-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA (and alpha-MeDA). The mechanisms by which such metabolites access the brain and produce selective

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape.

Science.gov (United States)

Lloret-Fernández, Carla; Maicas, Miren; Mora-Martínez, Carlos; Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter; Flames, Nuria

2018-03-22

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis -regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans . Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. © 2018, Lloret-Fernández et al.

Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

DEFF Research Database (Denmark)

Nielsen, Kirsten; Brask, Dorthe; Knudsen, Gitte M.

2006-01-01

Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers...... and quantification of serotonin positive fibers has been widely used to detect changes in the serotonergic innervation. However, particularly in conditions with enhanced serotonin metabolism the detection level of serotonin may lead to an underestimation of the true number of serotonergic fibers. The serotonin...... immunostained for serotonin and SERT protein and colocalization was quantified in several brain areas by confocal microscopy. In comparison with untreated rats, MAO inhibitor treated rats had a significantly higher number (almost 200% increase) of serotonin immunopositive fibers whereas no difference...

Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome.

Science.gov (United States)

de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Ferreira, Célio Marcos Dos Reis; Coimbra, Norberto Cysne

2006-09-01

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek's disease

Science.gov (United States)

Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. The serotonergic system m...

Serotonergic modulation of hippocampal pyramidal cells in euthermic, cold-acclimated, and hibernating hamsters

Science.gov (United States)

Horrigan, D. J.; Horwitz, B. A.; Horowitz, J. M.

1997-01-01

Serotonergic fibers project to the hippocampus, a brain area previously shown to have distinctive changes in electroencephalograph (EEG) activity during entrance into and arousal from hibernation. The EEG activity is generated by pyramidal cells in both hibernating and nonhibernating species. Using the brain slice preparation, we characterized serotonergic responses of these CA1 pyramidal cells in euthermic, cold-acclimated, and hibernating Syrian hamsters. Stimulation of Shaffer-collateral/commissural fibers evoked fast synaptic excitation of CA1 pyramidal cells, a response monitored by recording population spikes (the synchronous generation of action potentials). Neuromodulation by serotonin (5-HT) decreased population spike amplitude by 54% in cold-acclimated animals, 80% in hibernating hamsters, and 63% in euthermic animals. The depression was significantly greater in slices from hibernators than from cold-acclimated animals. In slices from euthermic animals, changes in extracellular K+ concentration between 2.5 and 5.0 mM did not significantly alter serotonergic responses. The 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin mimicked serotonergic inhibition in euthermic hamsters. Results show that 5-HT is a robust neuromodulator not only in euthermic animals but also in cold-acclimated and hibernating hamsters.

Neuropeptides as endogenous neuronal growth regulatory factors on serotonergic maturation

International Nuclear Information System (INIS)

Davila-Garcia, M.I.

1989-01-01

Products of the proopiomelanocortin molecule as well as leu- and met-enkephalin were tested for their effects on serotonergic neuronal maturation. High affinity uptake of ( 3 H)5-HT and morphometrics using immunocytochemistry specific for serotonergic neurons were used to monitor neuronal maturation. Cultured brainstem raphe neurons from 14 day fetuses, in the presence or absence of target tissue, were administered neuropeptides at various concentrations for 1,3 or 5 days in culture. ACTH peptides stimulate neurite length and, with the endorphins, the expression of ( 3 H)5-HT uptake by serotonergic fetal neurons cultured alone but had no effect when these neurons were cocultured with hippocampal target cells. A daily dose of leu-enkephalin to these cells inhibited neuronal uptake after 5 days of exposure and decreased neurite cell length in 24 hr cultures. In contrast, a single dose of leu-enkephalin at plating stimulated uptake after 5 days while co-administration of bacitracin inhibited uptake expression. Naloxone reversed the opioid effect and stimulated uptake when administered alone. Desulfated-CCK, which resembles leu-enkephalin, was equally potent as leu-enkephalin in inhibiting uptake

Neuropeptides as endogenous neuronal growth regulatory factors on serotonergic maturation

Energy Technology Data Exchange (ETDEWEB)

Davila-Garcia, M.I.

1989-01-01

Products of the proopiomelanocortin molecule as well as leu- and met-enkephalin were tested for their effects on serotonergic neuronal maturation. High affinity uptake of ({sup 3}H)5-HT and morphometrics using immunocytochemistry specific for serotonergic neurons were used to monitor neuronal maturation. Cultured brainstem raphe neurons from 14 day fetuses, in the presence or absence of target tissue, were administered neuropeptides at various concentrations for 1,3 or 5 days in culture. ACTH peptides stimulate neurite length and, with the endorphins, the expression of ({sup 3}H)5-HT uptake by serotonergic fetal neurons cultured alone but had no effect when these neurons were cocultured with hippocampal target cells. A daily dose of leu-enkephalin to these cells inhibited neuronal uptake after 5 days of exposure and decreased neurite cell length in 24 hr cultures. In contrast, a single dose of leu-enkephalin at plating stimulated uptake after 5 days while co-administration of bacitracin inhibited uptake expression. Naloxone reversed the opioid effect and stimulated uptake when administered alone. Desulfated-CCK, which resembles leu-enkephalin, was equally potent as leu-enkephalin in inhibiting uptake.

Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana

Directory of Open Access Journals (Sweden)

Kühnel Dana

2002-06-01

Full Text Available Abstract Background The cockroach salivary gland consists of secretory acini with peripheral ion-transporting cells and central protein-producing cells, an extensive duct system, and a pair of reservoirs. Salivation is controled by serotonergic and dopaminergic innervation. Serotonin stimulates the secretion of a protein-rich saliva, dopamine causes the production of a saliva without proteins. These findings suggest a model in which serotonin acts on the central cells and possibly other cell types, and dopamine acts selectively on the ion-transporting cells. To examine this model, we have analyzed the spatial relationship of dopaminergic and serotonergic nerve fibers to the various cell types. Results The acinar tissue is entangled in a meshwork of serotonergic and dopaminergic varicose fibers. Dopaminergic fibers reside only at the surface of the acini next to the peripheral cells. Serotonergic fibers invade the acini and form a dense network between central cells. Salivary duct segments close to the acini are locally associated with dopaminergic and serotonergic fibers, whereas duct segments further downstream have only dopaminergic fibers on their surface and within the epithelium. In addition, the reservoirs have both a dopaminergic and a serotonergic innervation. Conclusion Our results suggest that dopamine is released on the acinar surface, close to peripheral cells, and along the entire duct system. Serotonin is probably released close to peripheral and central cells, and at initial segments of the duct system. Moreover, the presence of serotonergic and dopaminergic fiber terminals on the reservoir indicates that the functions of this structure are also regulated by dopamine and serotonin.

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......Background: Sex-hormones influence brain function and are likely to play a role in the gender predisposition to mood and anxiety disorders. Acute fluctuations of sex-hormone levels including hormonal replacement therapy appear to affect serotonergic neurotransmission, but it is unknown if baseline...... levels affect serotonergic neurotransmission. This study was undertaken to examine if baseline levels of endogenous sex hormones are associated with cerebral serotonin 2A (5-HT2A) receptor binding in men. Methods: In a group of 72 healthy men (mean age 37.5 years ±17.4 SD, range 19.6–81.7) we studied...

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...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

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...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

Serotonin receptors expressed in Drosophila mushroom bodies differentially modulate larval locomotion.

Directory of Open Access Journals (Sweden)

Bryon Silva

Full Text Available Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA including serotonin (5HT participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB. The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3(rd-instar exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT1AR, 5HT1BR, 5HT2R and 5HT7R were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT1BR, 5HT2R and 5HT7R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.

A medicinal herb, Melissa officinalis L. ameliorates depressive-like behavior of rats in the forced swimming test via regulating the serotonergic neurotransmitter.

Science.gov (United States)

Lin, Shih-Hang; Chou, Mei-Ling; Chen, Wei-Cheng; Lai, Yi-Syuan; Lu, Kuan-Hung; Hao, Cherng-Wei; Sheen, Lee-Yan

2015-12-04

Depression is a serious psychological disorder that causes extreme economic loss and social problems. However, the conventional medications typically cause side effects that result in patients opting to out of therapy. Lemon balm (Melissa officinalis L., MO) is an old and particularly reliable medicinal herb for relieving feelings of melancholy, depression and anxiety. The present study aims to investigate the antidepressant-like activity of water extract of MO (WMO) by evaluating its influence on the behaviors and the relevant neurotransmitters of rats performed to forced swimming test. Two phases of the experiment were conducted. In the acute model, rats were administered ultrapure water (control), fluoxetine, WMO, or the indicated active compound (rosmarinic acid, RA) three times in one day. In the sub-acute model, rats were respectively administered ultrapure water (control), fluoxetine, or three dosages of WMO once a day for 10 days. Locomotor activity and depression-like behavior were examined using the open field test and the forced swimming test, respectively. The levels of relevant neurotransmitters and their metabolites in the frontal cortex, amygdala, hippocampus, and striatum were analyzed by high performance liquid chromatography. In the acute model, WMO and RA significantly reduced depressive-like behavior but the type of related neurotransmitter could not be determined. The results indicated that the effect of WMO administration on the reduction of immobility time was associated with an increase in swimming time of the rats, indicative of serotonergic neurotransmission modulation. Chromatography data validated that the activity of WMO was associated with a reduction in the serotonin turnover rate. The present study shows the serotonergic antidepressant-like activity of WMO. Hence, WMO may offer a serotonergic antidepressant activity to prevent depression and to assist in conventional therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.

Increased postpartum haemorrhage, the possible relation with serotonergic and other psychopharmacological drugs: a matched cohort study

NARCIS (Netherlands)

Heller, Hanna M.; Ravelli, Anita C. J.; Bruning, Andrea H. L.; de Groot, Christianne J. M.; Scheele, Fedde; van Pampus, Maria G.; Honig, Adriaan

2017-01-01

Postpartum haemorrhage is a major obstetric risk worldwide. Therefore risk factors need to be investigated to control for this serious complication. A recent systematic review and meta-analysis revealed that the use of both serotonergic and non-serotonergic antidepressants in pregnancy are

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

Science.gov (United States)

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.

Science.gov (United States)

Kaushal, Nidhi; Seminerio, Michael J; Robson, Matthew J; McCurdy, Christopher R; Matsumoto, Rae R

2013-08-01

Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Carnosine reverses the aging-induced down regulation of brain regional serotonergic system.

Science.gov (United States)

Banerjee, Soumyabrata; Ghosh, Tushar K; Poddar, Mrinal K

2015-12-01

The purpose of the present investigation was to study the role of carnosine, an endogenous dipeptide biomolecule, on brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) serotonergic system during aging. Results showed an aging-induced brain region specific significant (a) increase in Trp (except cerebral cortex) and their 5-HIAA steady state level with an increase in their 5-HIAA accumulation and declination, (b) decrease in their both 5-HT steady state level and 5-HT accumulation (except cerebral cortex). A significant decrease in brain regional 5-HT/Trp ratio (except cerebral cortex) and increase in 5-HIAA/5-HT ratio were also observed during aging. Carnosine at lower dosages (0.5-1.0μg/Kg/day, i.t. for 21 consecutive days) didn't produce any significant response in any of the brain regions, but higher dosages (2.0-2.5μg/Kg/day, i.t. for 21 consecutive days) showed a significant response on those aging-induced brain regional serotonergic parameters. The treatment with carnosine (2.0μg/Kg/day, i.t. for 21 consecutive days), attenuated these brain regional aging-induced serotonergic parameters and restored towards their basal levels that observed in 4 months young control rats. These results suggest that carnosine attenuates and restores the aging-induced brain regional down regulation of serotonergic system towards that observed in young rats' brain regions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Using novel descriptor accounting for ligand-receptor interactions to define and visually explore biologically relevant chemical space.

Science.gov (United States)

Rabal, Obdulia; Oyarzabal, Julen

2012-05-25

The definition and pragmatic implementation of biologically relevant chemical space is critical in addressing navigation strategies in the overlapping regions where chemistry and therapeutically relevant targets reside and, therefore, also key to performing an efficient drug discovery project. Here, we describe the development and implementation of a simple and robust method for representing biologically relevant chemical space as a general reference according to current knowledge, independently of any reference space, and analyzing chemical structures accordingly. Underlying our method is the generation of a novel descriptor (LiRIf) that converts structural information into a one-dimensional string accounting for the plausible ligand-receptor interactions as well as for topological information. Capitalizing on ligand-receptor interactions as a descriptor enables the clustering, profiling, and comparison of libraries of compounds from a chemical biology and medicinal chemistry perspective. In addition, as a case study, R-groups analysis is performed to identify the most populated ligand-receptor interactions according to different target families (GPCR, kinases, etc.), as well as to evaluate the coverage of biologically relevant chemical space by structures annotated in different databases (ChEMBL, Glida, etc.).

The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function.

Directory of Open Access Journals (Sweden)

Annina Huser

Full Text Available The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.

Development of radioiodinated receptor ligands for cerebral single photon emission tomography

International Nuclear Information System (INIS)

Knapp, F.F. Jr.; McPherson, D.W.

1992-01-01

In the last decade the use of radiolabeled ligands for the imaging of cerebral receptors by emission computed tomography (ECT) has seen rapid growth. The opportunity to routinely perform cerebral single photon emission tomography (SPET) with iodine-123-labeled ligands depends on the availability of receptor ligands into which iodine can be introduced without decreasing the required high target receptor specificity. The use of iodine-123-labeled receptor-specific ligands also depends on the availability of high purity iodine-123 at reasonable costs and the necessary imaging instrumentation. In this paper, the development and current stage of evaluation of various iodine-123-labeled ligands for SPET imaging of dopaminergic, serotonergic and muscarinic acetylcholinergic receptor classes are discussed

Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome

DEFF Research Database (Denmark)

Haugbøl, Steven; Pinborg, Lars H.; Regeur, Lisbeth

2007-01-01

Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imagi...

Differential serotonergic innervation of the amygdala in bonobos and chimpanzees.

Science.gov (United States)

Stimpson, Cheryl D; Barger, Nicole; Taglialatela, Jared P; Gendron-Fitzpatrick, Annette; Hof, Patrick R; Hopkins, William D; Sherwood, Chet C

2016-03-01

Humans' closest living relatives are bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), yet these great ape species differ considerably from each other in terms of social behavior. Bonobos are more tolerant of conspecifics in competitive contexts and often use sexual behavior to mediate social interactions. Chimpanzees more frequently employ aggression during conflicts and actively patrol territories between communities. Regulation of emotional responses is facilitated by the amygdala, which also modulates social decision-making, memory and attention. Amygdala responsiveness is further regulated by the neurotransmitter serotonin. We hypothesized that the amygdala of bonobos and chimpanzees would differ in its neuroanatomical organization and serotonergic innervation. We measured volumes of regions and the length density of serotonin transporter-containing axons in the whole amygdala and its lateral, basal, accessory basal and central nuclei. Results showed that accessory basal nucleus volume was larger in chimpanzees than in bonobos. Of particular note, the amygdala of bonobos had more than twice the density of serotonergic axons than chimpanzees, with the most pronounced differences in the basal and central nuclei. These findings suggest that variation in serotonergic innervation of the amygdala may contribute to mediating the remarkable differences in social behavior exhibited by bonobos and chimpanzees. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

A role for the hippocampal serotonergic system in the pathology of schizophrenia?

International Nuclear Information System (INIS)

Scarr, E.; Pavey, G.M.; Copolov, D.L.; Dean, B.

2002-01-01

Full text: Theories of a role for serotonin in the pathology of schizophrenia predate the dopamine hypothesis of schizophrenia. More recently, interest in the involvement of serotonin in the disorder is primarily due to the fact that the 'atypical' neuroleptic drugs target the serotonergic system, amongst others. We have previously reported decreases in the 5-HT 2A receptors in hippocampi obtained postmortem from subjects with schizophrenia. In the same cohort of subjects we now report decreases (p 3 H]citalopram binding in the CA1 region (17.5 ± 1.4 vs. 21.7 ± 1.3 fmole/mg ETE) and methiothepin-insensitive [3H]sumatriptan binding in the CA1 (2.85 ± 0.25 vs. 3.90 ± 0.33 fmole/mg ETE), the stratum radiatum/lacunosum moleculare (4.11 ± 0.32 vs. 5.35 ± 0.46 fmole/mg ETE) and subiculum (3.87 ± 0.26 vs. 5.08 ± 0.39 fmole/mg ETE) from subjects with schizophrenia. No changes were found in [ 3 H]8-OHDPAT or methiothepin-sensitive [ 3 H]sumatriptan binding. These data indicate that there are regionally specific decreases in the densities of hippocampal serotonin transporter and 5-HT 1F receptors which may be involved in the pathology of schizophrenia. Copyright (2002) Australian Neuroscience Society

Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.

Science.gov (United States)

Baratta, Michael V; Kodandaramaiah, Suhasa B; Monahan, Patrick E; Yao, Junmei; Weber, Michael D; Lin, Pei-Ann; Gisabella, Barbara; Petrossian, Natalie; Amat, Jose; Kim, Kyungman; Yang, Aimei; Forest, Craig R; Boyden, Edward S; Goosens, Ki A

2016-05-15

Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

[Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges].

Science.gov (United States)

Majić, Tomislav; Jungaberle, Henrik; Schmidt, Timo T; Zeuch, Andrea; Hermle, Leo; Gallinat, Jürgen

2017-07-01

Background  Recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (LSD) and entactogens like 3,4-methylendioxymethamphetamine (MDMA) within the framework of psychotherapy has resumed. The present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances. Method  A selective search was carried out in the PubMed and Cochrane Library including studies investigating the clinical use of serotonergic psychoactive substances since 2000. Results  Studies were found investigating the following indications: alcohol (LSD and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (LSD and psilocybin), obsessive-compulsive disorder (OCD) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (PTSD) (MDMA). Discussion  Substance use disorders, PTSD and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. To date, studies indicate efficacy and relatively good tolerability. Further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future. © Georg Thieme Verlag KG Stuttgart · New York.

Novel 2-aminotetralin and 3-aminochroman derivatives as selective serotonin 5-HT7 receptor agonists and antagonists.

Science.gov (United States)

Holmberg, Pär; Sohn, Daniel; Leideborg, Robert; Caldirola, Patrizia; Zlatoidsky, Pavel; Hanson, Sverker; Mohell, Nina; Rosqvist, Susanne; Nordvall, Gunnar; Johansson, Anette M; Johansson, Rolf

2004-07-29

The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans and tetralins, encompassing compounds with nanomolar affinity for the 5-HT(7) receptor and with good selectivity. Within theses classes, we have discovered both agonists and antagonists that can be used for further understanding of the pharmacology of the 5-HT(7) receptor.

Biochemical correlates in an animal model of depression

International Nuclear Information System (INIS)

Johnson, J.O.

1986-01-01

A valid animal model of depression was used to explore specific adrenergic receptor differences between rats exhibiting aberrant behavior and control groups. Preliminary experiments revealed a distinct upregulation of hippocampal beta-receptors (as compared to other brain regions) in those animals acquiring a response deficit as a result of exposure to inescapable footshock. Concurrent studies using standard receptor binding techniques showed no large changes in the density of alpha-adrenergic, serotonergic, or dopaminergic receptor densities. This led to the hypothesis that the hippocampal beta-receptor in responses deficient animals could be correlated with the behavioral changes seen after exposure to the aversive stimulus. Normalization of the behavior through the administration of antidepressants could be expected to reverse the biochemical changes if these are related to the mechanism of action of antidepressant drugs. This study makes three important points: (1) there is a relevant biochemical change in the hippocampus of response deficient rats which occurs in parallel to a well-defined behavior, (2) the biochemical and behavioral changes are normalized by antidepressant treatments exhibiting both serotonergic and adrenergic mechanisms of action, and (3) the mode of action of antidepressants in this model is probably a combination of serotonergic and adrenergic influences modulating the hippocampal beta-receptor. These results are discussed in relation to anatomical and biochemical aspects of antidepressant action

Generation of Pet1210-Cre Transgenic Mouse Line Reveals Non-Serotonergic Expression Domains of Pet1 Both in CNS and Periphery

Science.gov (United States)

Pelosi, Barbara; Migliarini, Sara; Pacini, Giulia; Pratelli, Marta; Pasqualetti, Massimo

2014-01-01

Neurons producing serotonin (5-hydroxytryptamine, 5-HT) constitute one of the most widely distributed neuronal networks in the mammalian central nervous system (CNS) and exhibit a profuse innervation throughout the CNS already at early stages of development. Serotonergic neuron specification is controlled by a combination of secreted molecules and transcription factors such as Shh, Fgf4/8, Nkx2.2, Lmx1b and Pet1. In the mouse, Pet1 mRNA expression appears between 10 and 11 days post coitum (dpc) in serotonergic post-mitotic precursors and persists in serotonergic neurons up to adulthood, where it promotes the expression of genes defining the mature serotonergic phenotype such as tryptophan hydroxylase 2 (Tph2) and serotonin transporter (SERT). Hence, the generation of genetic tools based on Pet1 specific expression represents a valuable approach to study the development and function of the serotonergic system. Here, we report the generation of a Pet1210-Cre transgenic mouse line in which the Cre recombinase is expressed under the control of a 210 kb fragment from the Pet1 genetic locus to ensure a reliable and faithful control of somatic recombination in Pet1 cell lineage. Besides Cre-mediated recombination accurately occurred in the serotonergic system as expected and according to previous studies, Pet1210-Cre transgenic mouse line allowed us to identify novel, so far uncharacterized, Pet1 expression domains. Indeed, we showed that in the raphe Pet1 is expressed also in a non-serotonergic neuronal population intermingled with Tph2-expressing cells and mostly localized in the B8 and B9 nuclei. Moreover, we detected Cre-mediated recombination also in the developing pancreas and in the ureteric bud derivatives of the kidney, where it reflected a specific Pet1 expression. Thus, Pet1210-Cre transgenic mouse line faithfully drives Cre-mediated recombination in all Pet1 expression domains representing a valuable tool to genetically manipulate serotonergic and non-serotonergic

The serotonergic system and cognitive function

Directory of Open Access Journals (Sweden)

Švob Štrac Dubravka

2016-01-01

Full Text Available Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD. The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic system in cognitive function, particularly in AD and schizophrenia.

Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

Directory of Open Access Journals (Sweden)

Luigi F. Agnati

2007-01-01

Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

Concomitant use of opioid medications with triptans or serotonergic antidepressants in US office-based physician visits.

Science.gov (United States)

Molina, Kyle C; Fairman, Kathleen A; Sclar, David A

2018-01-01

Opioids are not recommended for routine treatment of migraine because their benefits are outweighed by risks of medication overuse headache and abuse/dependence. A March 2016 US Food and Drug Administration (FDA) safety communication warned of the risk of serotonin syndrome from using opioids concomitantly with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Epidemiological information about co-prescribing of these medications is limited. The objective of this study was to estimate the nationwide prevalence of co-prescribing of an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by 1) all patients and 2) patients diagnosed with migraine. National Ambulatory Medical Care Survey (NAMCS) data were obtained for 2013 and 2014. Physician office visits that included the new or continued prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI were identified. Co-prescribed opioids were stratified by agent to determine the proportion of co-prescriptions with opioids posing a higher risk of serotonergic agonism (meperidine, tapentadol, and tramadol). Of an annualized mean 903.6 million office-based physician visits in 2013-2014, 17.7 million (2.0% of all US visits) resulted in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI. Opioid-SSRI/SNRI was co-prescribed in 16,044,721 visits, while opioid-triptan was co-prescribed in 1,622,827 visits. One-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol (18.6% of opioid-SSRI/SNRI, 21.8% of opioid-triptan). Of 7,672,193 visits for patients diagnosed with migraine, 16.3% included opioid prescribing and 2.0% included co-prescribed opioid-triptan. During a period approximately 2 years prior to an FDA warning about the risk of serotonin syndrome from opioid-SSRI/SNRI or

Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

Directory of Open Access Journals (Sweden)

Teschemacher Anja G

2009-03-01

Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

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

Science.gov (United States)

Kannen, Vinicius; Fernandes, Cleverson R; Stopper, Helga; Zanette, Dalila L; Ferreira, Frederico R; Frajacomo, Fernando T; Carvalho, Milene C; Brandão, Marcus L; Elias Junior, Jorge; Jordão Junior, Alceu Afonso; Uyemura, Sérgio Akira; Waaga-Gasser, Ana Maria; Garcia, Sérgio B

2013-10-04

Calorie restriction regimens usually promote health and extend life-span in mammals. This is partially related to their preventive effects against malignancies. However, certain types of nutritional restriction failed to induce beneficial effects. The American Institute of Nutrition defines calorie restriction as diets which have only 40% fewer calories, but provide normal amounts of necessary food components such as protein, vitamins and minerals; whereas, food restriction means 40% less of all dietary ingredients plus 40% less calories. Our study aimed to test the hypothesis that the latter type of food deprivation (40% less food than consumed by standard fed rats) might increase cancer risk instead of reducing it, as is generally assumed for all dietary restrictive regimens. Since the endogenous modulation of the colon serotonergic system has been observed to play a role during the early steps of carcinogenesis we also investigated whether the serotoninergic system could be involved in the food intake modulation of cancer risk. For this, rats were exposed to a carcinogen and subjected to food deprivation for 56 days. Triglyceride levels and visceral adipose tissue were reduced while hepatic and colonic lipid peroxidation was increased. This dietary restriction also decreased serotonin levels in colon, and gene expression of its intestinal transporter and receptors. Finally, the numbers of preneoplastic lesions in the colon tissue of carcinogen-exposed rats were increased. Our data suggest that food deprivation enhances formation of early tumorigenic lesions by suppressing serotonergic activity in colon tissue. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Anxiogenic drug administration and elevated plus-maze exposure in rats activate populations of relaxin-3 neurons in the nucleus incertus and serotonergic neurons in the dorsal raphe nucleus.

Science.gov (United States)

Lawther, A J; Clissold, M L; Ma, S; Kent, S; Lowry, C A; Gundlach, A L; Hale, M W

2015-09-10

Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioral symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behavior via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the Gi/o-protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behavior in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30 min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behavior. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression

NARCIS (Netherlands)

van der Vegt, BJ; de Boer, SF; Buwalda, B; de Ruiter, AJH; de Jong, JG; Koolhaas, JM

2001-01-01

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT1A) receptors,

No evidence for a role of the serotonin 4 receptor in five-factor personality traits

DEFF Research Database (Denmark)

Stenbæk, Dea Siggaard; Dam, Vibeke Høyrup; Fisher, Patrick MacDonald

2017-01-01

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...

Serotonergic contribution to boys' behavioral regulation.

Directory of Open Access Journals (Sweden)

Amélie Nantel-Vivier

Full Text Available Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure.Participants were 23 boys (age 10 years with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered.Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter.The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors.

Serotonergic contribution to boys' behavioral regulation.

Science.gov (United States)

Nantel-Vivier, Amélie; Pihl, Robert O; Young, Simon N; Parent, Sophie; Bélanger, Stacey Ageranioti; Sutton, Rachel; Dubois, Marie-Eve; Tremblay, Richard E; Séguin, Jean R

2011-01-01

Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure. Participants were 23 boys (age 10 years) with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered. Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter. The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors.

Serotonin 5HT1A receptor availability and pathological crying after stroke

DEFF Research Database (Denmark)

Møller, Mette; Andersen, G; Gjedde, A

2007-01-01

OBJECTIVES: Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p(B)) of the 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635, which is reversible...... by selective serotonin re-uptake inhibitor (SSRI) treatment. MATERIALS AND METHODS: We PET scanned patients with acute stroke and PC and age-matched control subjects. Maps of receptor availability were generated from the images of eight cortical regions and raphe nuclei. RESULTS: The maps showed highest...

The association between concomitant use of serotonergic antidepressants and lithium-induced polyuria. A multicenter medical chart review study.

Science.gov (United States)

Wilting, I; Egberts, A C G; Movig, K L L; Laarhoven, J H M van; Heerdink, E R; Nolen, W A

2008-07-01

A previous study aimed at revealing the prevalence and determinants of lithium induced polyuria suggested an increased risk of polyuria (urine volume > or =3 L/24 h) in those using serotonergic antidepressants next to lithium. The objective of our study was to re-evaluate this secondary finding in another study population. We performed a multicenter medical chart review study in patients using lithium in whom a 24-hour urine volume had been determined. We included 116 patients, twelve (26%)of the 46 patients with polyuria used serotonergic antidepressants compared to ten (14%) of the 70 patients without polyuria. We found an increased risk of polyuria in lithium users concurrently using serotonergic antidepressants (oddsratio 2.86; 95% confidence interval 1.00-8.21), adjusted for age, gender, use of antiepileptics and thyreomimetics. Our results confirm the previous secondary finding of an increased risk of polyuria in patients using serotonergic antidepressants next to lithium. Physicians should take this into account when evaluating polyuria in patients using lithium and when choosing an antidepressant in patients using lithium.

5HT-1A receptors and anxiety-like behaviours: studies in rats with constitutionally upregulated/downregulated serotonin transporter.

Science.gov (United States)

Bordukalo-Niksic, Tatjana; Mokrovic, Gordana; Stefulj, Jasminka; Zivin, Marko; Jernej, Branimir; Cicin-Sain, Lipa

2010-12-01

Altered activity of brain serotonergic (5HT) system has been implicated in a wide range of behaviours and behavioural disorders, including anxiety. Functioning of 5HT-1A receptor has been suggested as a modulator of emotional balance in both, normal and pathological forms of anxiety. Here, we studied serotonergic modulation of anxiety-like behaviour using a genetic rat model with constitutional differences in 5HT homeostasis, named Wistar-Zagreb 5HT (WZ-5HT) rats. The model, consisting of high-5HT and low-5HT sublines, was developed by selective breeding of animals for extreme activities of peripheral (platelet) 5HT transporter, but selection process had affected also central 5HT homeostasis, as evidenced from neurochemical and behavioural studies. Anxiety-like behaviour in WZ-5HT rats was evaluated by two commonly used paradigms: open field and elevated-plus maze. The involvement of 5HT-1A receptors in behavioural response was assessed by measuring mRNA expression in cell bodies (raphe nuclei) and projection regions (frontal cortex, hippocampus) by use of RT-PCR and in situ hybridization, and by measuring functionality of cortical 5HT-1A receptors by use of [(3)H]8-OH-DPAT radioligand binding. Animals from the high-5HT subline exhibit increased anxiety-like behaviour and decreased exploratory activity when exposed to novel environment. No measurable differences in constitutional (baseline) functionality or expression of 5HT-1A receptors between sublines were found. The results support contribution of increased serotonergic functioning to the anxiety-like behaviour. They also validate the high-5HT subline of WZ-5HT rats as a potential model to study mechanisms of anxiety, especially of its nonpathological form, while the low-5HT subline may be useful to model sensation seeking phenotype. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Association Between Genetic Polymorphisms in the Serotonergic System and Comorbid Personality Disorders Among Patients with First-Episode Depression

DEFF Research Database (Denmark)

Bukh, Jens D; Bock, Camilla; Kessing, Lars V

2014-01-01

Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid...... personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding...... the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C...

The 5-HT₁A receptor CG polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

NARCIS (Netherlands)

Janssen, Paddy K C; van Schaik, R; Zwinderman, Aeilko H; Olivier, Berend|info:eu-repo/dai/nl/073067199; Waldinger, Marcel D|info:eu-repo/dai/nl/163958564

INTRODUCTION: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 min, and has been postulated as a neurobiological dysfunction related to diminished serotonergic neurotransmission with 5-HT₁A receptor hyperfunction and

Low 5-HT1B receptor binding in the migraine brain

DEFF Research Database (Denmark)

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

2018-01-01

Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT1B receptor is considered a key player due to the efficacy of 5-HT1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT1B receptor binding....... Patients who reported migraine brain regions involved in pain modulation as regions of interest and applied a latent variable model (LVM) to assess the group effect on binding across these regions. Results Our data...... support a model wherein group status predicts the latent variable ( p = 0.038), with migraine patients having lower 5-HT1B receptor binding across regions compared to controls. Further, in a whole-brain voxel-based analysis, time since last migraine attack correlated positively with 5-HT1B receptor...

The 5-HT₁A receptor CG polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

NARCIS (Netherlands)

Janssen, Paddy K. C.; van Schaik, R.; Zwinderman, Aeilko H.; Olivier, Berend; Waldinger, Marcel D.

2014-01-01

Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 min, and has been postulated as a neurobiological dysfunction related to diminished serotonergic neurotransmission with 5-HT₁A receptor hyperfunction and 5-HT₂C

Neuroanatomic Relationships between the GABAergic and Serotonergic Systems in the Developing Human Medulla

Science.gov (United States)

Broadbelt, Kevin G.; Paterson, David S.; Rivera, Keith D.; Trachtenberg, Felicia L.; Kinney, Hannah C.

2010-01-01

γ-Amino butyric (GABA) critically influences serotonergic (5-HT) neurons in the raphé and extra-raphé of the medulla oblongata. In this study we hypothesize there are marked changes in the developmental profile of markers of the human medullary GABAergic system relative to the 5-HT system in early life. We used single- and double-label immunocytochemistry and tissue receptor autoradiography in 15 human medullae from fetal and infant cases ranging from 15 gestational weeks to 10 postnatal months, and compared our findings with an extensive 5-HT-related database in our laboratory. In the raphé obscurus, we identified two subsets of GABAergic neurons using glutamic acid decarboxylase (GAD65/67) immunostaining: one comprised of small, round neurons; the other, medium, spindle-shaped neurons. In three term medullae cases, positive immunoflorescent neurons for both tryptophan hydroxylase and GAD65/67 were counted within the raphé obscurus. This revealed approximately 6% of the total neurons counted in this nucleus expressed both GAD65/67 and TPOH suggesting co-production of GABA by a subset of 5-HT neurons. The distribution of GABAA binding was ubiquitous across medullary nuclei, with highest binding in the raphé obscurus. GABAA receptor subtypes α1 and α3 were expressed by 5-HT neurons, indicating the site of interaction of GABA with 5-HT neurons. These receptor subtypes and KCC2, a major chloride transporter, were differentially expressed across early development, from mid-gestation (20wks) and thereafter. The developmental profile of GABAergic markers changed dramatically relative to the 5-HT markers. These data provide baseline information for medullary studies of human pediatric disorders, such as sudden infant death syndrome. PMID:19926534

Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs

DEFF Research Database (Denmark)

Abrams, J K; Johnson, P L; Hay-Schmidt, Anders

2005-01-01

Serotonergic systems play important roles in modulating behavioral arousal, including behavioral arousal and vigilance associated with anxiety states. To further our understanding of the neural systems associated with increases in anxiety states, we investigated the effects of multiple anxiogenic...... and vigilance behaviors consistent with an increase in anxiety state. In addition, these anxiogenic drugs, excluding yohimbine, had convergent actions on an anatomically-defined subset of serotonergic neurons within the middle and caudal, dorsal subdivision of the DR. High resolution topographical analysis...... nucleus, a forebrain structure important for emotional appraisal and modulation of anxiety-related physiological and behavioral responses. Together these findings support the hypothesis that there is a functional topographical organization in the DR and are consistent with the hypothesis that anxiogenic...

Serotonergic neurotransmission in emotional processing

DEFF Research Database (Denmark)

Laursen, Helle Ruff; Henningsson, Susanne; Macoveanu, Julian

2016-01-01

,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational...... ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex...... judgement on each face stimulus. Positron emission tomography with (11)C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets...

Action of naftopidil on spinal serotonergic neurotransmission for inhibition of the micturition reflex in rats.

Science.gov (United States)

Sugaya, Kimio; Nishijima, Saori; Kadekawa, Katsumi; Ashitomi, Katsuhiro; Ueda, Tomoyuki; Yamamoto, Hideyuki; Hattori, Tsuyoshi

2017-03-01

We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil. PCPA decreased and 5-HTP increased urinary 5-HIAA/creatinine. Intraperitoneal injection of PCPA did not influence cystometric parameters. Intraperitoneal injection of 5-HTP significantly shortened the interval between bladder contractions. Intravenous injection of naftopidil transiently abolished bladder contractions. However, the duration of abolishment of bladder contractions after injection of naftopidil in rats given PCPA was significantly shorter than that in rats given vehicle, but significantly longer than that in rats given PCPA and 5-HTP. Intrathecal injection of 5-HT1B, 5-HT3, or 5-HT7 receptor antagonists significantly prolonged the interval between bladder contractions. Intrathecal injection of 5-HT1D or 5-HT2B receptor antagonists significantly shortened the interval between bladder contractions. Combined administration of the maximum non-effective dose of 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, or 5-HT3 receptor antagonists and intravenous injection of naftopidil significantly shortened the duration of abolishment of bladder contraction compared to intravenous injection of naftopidil alone. Naftopidil may inhibit the micturition reflex via 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors in the spinal cord. Neurourol. Urodynam. 36:604-609, 2017. © 2016 Wiley Periodicals, Inc. �

Frontal-subcortical circuits in obsessive-compulsive disorder: role of the dopamine D1 receptor

International Nuclear Information System (INIS)

Olver, J.S.; Reutens, D.C.; Maruff, P.; Burrows, G.D.; Norman, T.R.; Ellen, S.R.; Pantelis, C.; Tochon-Danguy, H.; Ackermann, U.; Stekelenberg, N.

2000-01-01

Full text: Obsessive-Compulsive Disorder (OCD) is an anxiety disorder which is increasingly being recognised as a neurobiological disorder. While serotonergic mechanisms have been proposed, the major competing theory in the pathophysiology of OCD involves the neurotransmitter dopamine. The Dopamine D1 receptor is implicated in OCD following the finding of specific spatial working memory abnormalities in a series of neuropsychological studies. Spatial working memory is known to depend on the integrity of D1 receptor function in the Dorso-lateral Prefrontal Cortex (DLPFC) of primates. This study aims to examine the role of dopamine in patients with OCD and in particular to test the hypothesis that there is an upregulation of dopamine D1 receptors in the DLPFC which correlates with spatial working memory deficits in OCD. Three OCD patients and three normal controls underwent Positron Emission Tomography (PET) following intravenous injection of the D1 antagonist PET ligand SCH23390. Reconstructed PET images were co registered with subject Magnetic Resonance Images (MRI) and regions of interest drawn manually. We will present the analysis of the Binding Potentials of SCH23390 in the regions of interest of the first three OCD patients and compare them with three normal control patients. In conclusion Dopamine-Serotonergic interactions are involved in the pathophysiology of OCD. Copyright (2000) The Australian and New Zealand Society of Nuclear Medicine Inc

Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only.

Science.gov (United States)

Pagani, J H; Williams Avram, S K; Cui, Z; Song, J; Mezey, É; Senerth, J M; Baumann, M H; Young, W S

2015-02-01

Serotonin and oxytocin influence aggressive and anxiety-like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically mediated anxiety-like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open-field, olfactory habituation/dishabituation or, surprisingly, anxiety-like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to 8 of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident-intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety-like behaviors or maternal care. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Possible Modulation of the Anexiogenic Effects of Vitex Agnus-castus by the Serotonergic System.

Science.gov (United States)

Yaghmaei, Parichehr; Oryan, Shahrbanoo; Fatehi Gharehlar, Laleh; Salari, Ali-Akbar; Solati, Jalal

2012-03-01

There is well documented evidence for the increase in widespread use of complementary and alternative medicine in the treatment of physical and psychiatric symptoms and disorders within the populations. In the present study, we investigated the influence of V itex agnus-castus (vitex) on anxiety-like behaviors of rats. Elevated plus maze which is one of the methods used for testing anxiety is used in our present study. Rats were orally administrated with vitex for two week. The anxiety test was carried out after two weeks of oral administration of vitex. For evaluating interaction of vitex and serotonergic systems, rats were anaesthetized with ketamine and special cannulas were inserted stereotaxically into the third ventricle (TV) of brain. After 1 week recovery, the effects of serotonegic agents on anxiety were studied. Oral administration of vitex (100, 200, 300 mg/kg) for two weeks induced an anxiogenic-like effect which was shown through specific decreases in the percentages of open arm time (OAT %) and open arm entries (OAE %). Intra - TV infusion of 5HT1A receptor agonist, 8-OH-DPAT (5, 10 and 25 ng/rat) increased OAT% and OAE%, indicating anxiolytic-like behavior. However, injection of 5HT1A receptor antagonist NAN190 (0.25, 0.5 and 1 µg/rat) produced anxiogenic-like behavior. The most effective dose of 8-OH-DPAT (10 ng/rat), when co-administered with vitex (100, 200, 300 mg/kg), attenuated the anxiogenic-like effects of vitex significantly. Injection of the less effective dose of NAN190 (0.5 µg/rat), in combination with vitex (100, 200, 300 mg/kg), potentiate anxiogenic effects of vitex. These results illustrate that 5HT1A receptor is involved in the anxiogenic effects of vitex.

In vivo binding of 125I-LSD to serotonin 5-HT2 receptors in mouse brain

International Nuclear Information System (INIS)

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

1985-01-01

The binding of 125 I-LSD (2-[ 125 I]-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of 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 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 125 I-LSD. Serotonergic compounds potently inhibited 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 125 I-LSD labels serotonin 5-HT 2 receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, 125 I-LSD labeling occurs predominantly or entirely at serotonic 5-HT 2 sites. In the striatum, 125 I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that 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 2 receptors in the mammalian cortex

Valproic acid silencing of ascl1b/Ascl1 results in the failure of serotonergic differentiation in a zebrafish model of fetal valproate syndrome

Directory of Open Access Journals (Sweden)

John Jacob

2014-01-01

Full Text Available Fetal valproate syndrome (FVS is caused by in utero exposure to the drug sodium valproate. Valproate is used worldwide for the treatment of epilepsy, as a mood stabiliser and for its pain-relieving properties. In addition to birth defects, FVS is associated with an increased risk of autism spectrum disorder (ASD, which is characterised by abnormal behaviours. Valproate perturbs multiple biochemical pathways and alters gene expression through its inhibition of histone deacetylases. Which, if any, of these mechanisms is relevant to the genesis of its behavioural side effects is unclear. Neuroanatomical changes associated with FVS have been reported and, among these, altered serotonergic neuronal differentiation is a consistent finding. Altered serotonin homeostasis is also associated with autism. Here we have used a chemical-genetics approach to investigate the underlying molecular defect in a zebrafish FVS model. Valproate causes the selective failure of zebrafish central serotonin expression. It does so by downregulating the proneural gene ascl1b, an ortholog of mammalian Ascl1, which is a known determinant of serotonergic identity in the mammalian brainstem. ascl1b is sufficient to rescue serotonin expression in valproate-treated embryos. Chemical and genetic blockade of the histone deacetylase Hdac1 downregulates ascl1b, consistent with the Hdac1-mediated silencing of ascl1b expression by valproate. Moreover, tonic Notch signalling is crucial for ascl1b repression by valproate. Concomitant blockade of Notch signalling restores ascl1b expression and serotonin expression in both valproate-exposed and hdac1 mutant embryos. Together, these data provide a molecular explanation for serotonergic defects in FVS and highlight an epigenetic mechanism for genome-environment interaction in disease.

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence.

Science.gov (United States)

Lalanne, L; Ayranci, G; Filliol, D; Gavériaux-Ruff, C; Befort, K; Kieffer, B L; Lutz, P-E

2017-07-01

Addiction is a chronic brain disorder that progressively invades all aspects of personal life. Accordingly, addiction to opiates severely impairs interpersonal relationships, and the resulting social isolation strongly contributes to the severity and chronicity of the disease. Uncovering new therapeutic strategies that address this aspect of addiction is therefore of great clinical relevance. We recently established a mouse model of heroin addiction in which, following chronic heroin exposure, 'abstinent' mice progressively develop a strong and long-lasting social avoidance phenotype. Here, we explored and compared the efficacy of two pharmacological interventions in this mouse model. Because clinical studies indicate some efficacy of antidepressants on emotional dysfunction associated with addiction, we first used a chronic 4-week treatment with the serotonergic antidepressant fluoxetine, as a reference. In addition, considering prodepressant effects recently associated with kappa opioid receptor signaling, we also investigated the kappa opioid receptor antagonist norbinaltorphimine (norBNI). Finally, we assessed whether fluoxetine and norBNI could reverse abstinence-induced social avoidance after it has established. Altogether, our results show that two interspaced norBNI administrations are sufficient both to prevent and to reverse social impairment in heroin abstinent animals. Therefore, kappa opioid receptor antagonism may represent a useful approach to alleviate social dysfunction in addicted individuals. © 2016 Society for the Study of Addiction.

Long-term estrogen therapy and 5-HT(2A) receptor binding in postmenopausal women; a single photon emission tomography (SPET) study

NARCIS (Netherlands)

Compton, J.; Travis, M. J.; Norbury, R.; Erlandsson, K.; van Amelsvoort, T.; Daly, E.; Waddington, W.; Matthiasson, P.; Eersels, J. L. H.; Whitehead, M.; Kerwin, R. W.; Ell, P. J.; Murphy, D. G. M.

2008-01-01

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT(2A) receptor in human

An Elongin-Cullin-SOCS Box Complex Regulates Stress-Induced Serotonergic Neuromodulation

Directory of Open Access Journals (Sweden)

Xicotencatl Gracida

2017-12-01

Full Text Available Neuromodulatory cells transduce environmental information into long-lasting behavioral responses. However, the mechanisms governing how neuronal cells influence behavioral plasticity are difficult to characterize. Here, we adapted the translating ribosome affinity purification (TRAP approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing amphid neuron dual ciliated sensory ending (ADF serotonergic sensory neurons, and we found that it plays a role in mediating a long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel-Lindau protein VHL-1, components of an Elongin-Cullin-SOCS box (ECS E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase and a role for an ECS complex in neuromodulation and control of lasting behavioral states.

Impaired social behavior in 5-HT3A receptor knockout mice

Directory of Open Access Journals (Sweden)

Laura A Smit-Rigter

2010-11-01

Full Text Available The 5-HT3 receptor is a ligand-gated ion channel expressed on interneurons throughout the brain. So far, analysis of the 5-HT3A knockout mouse revealed changes in nociceptive processing and a reduction in anxiety related behavior. Recently, it was shown that the 5-HT3 receptor is also expressed on Cajal-Retzius cells which play a key role in cortical development and that knockout mice lacking this receptor showed aberrant growth of the dendritic tree of cortical layer II/III pyramidal neurons. Other mouse models in which serotonergic signaling was disrupted during development showed similar morphological changes in the cortex, and in addition, also deficits in social behavior. Here, we subjected male and female 5-HT3A knockout mice and their non-transgenic littermates to several tests of social behavior. We found that 5-HT3A knockout mice display impaired social communication in the social transmission of food preference task. Interestingly, we showed that in the social interaction test only female 5-HT3A knockout mice spent less time in reciprocal social interaction starting after 5 minutes of testing. Moreover, we observed differences in preference for social novelty for male and female 5-HT3A knockout mice during the social approach test. However, no changes in olfaction, exploratory activity and anxiety were detected. These results indicate that the 5-HT3A knockout mouse displays impaired social behavior with specific changes in males and females, reminiscent to other mouse models in which serotonergic signaling is disturbed in the developing brain.

Serotonina e controle hipotalâmico da fome: uma revisão Serotonin and hypothalamic control of hunger: a review

Directory of Open Access Journals (Sweden)

Fernanda de Matos Feijó

2011-02-01

Full Text Available Este trabalho revisa a participação do sistema serotonérgico no controle da ingestão de alimentos e saciedade. É de grande interesse compreender a relevância desse sistema para o controle fisiológico do balanço energético e da obesidade. Mais de 35 anos de pesquisas sugerem que a serotonina (5-HT desempenha um importante papel na saciedade. Assim, o sistema serotonérgico tem sido um alvo viável para o controle de peso. A 5-HT apresenta controle sobre a fome e a saciedade através de diversos receptores, com diferentes funções. O receptor 5-HT2C parece ser o mais importante na relação entre ingestão alimentar e balanço energético. Nesta revisão serão discutidos os mecanismos do sistema serotonérgico envolvidos no controle da ingestão de alimentos e saciedade.This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.

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...... tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT2A receptor binding. An inverted U-shaped relationship between the 5-HT2A receptor and the SERT binding was identified. The observed regional intercorrelation...

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.

Serotonergic-postsynaptic receptors modulate gripping-induced immobility episodes in male taiep rats.

Science.gov (United States)

Eguibar, José R; Cortés, M C; Ita, M L

2009-09-01

The Taiep rat is a myelin mutant with a motor syndrome characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The rat shows a hypomyelination followed by a progressive demyelination. During immobilities taiep rats show a REM-like sleep pattern and a disorganized sleep-wake pattern suggesting taiep rats as a model of narcolepsy-cataplexy. Our study analyzed the role of postsynaptic serotonin receptors in the expression of gripping-induced immobility episodes (IEs) in 8-month-old male taiep rats. The specific postsynaptic serotonin agonist +/-1-(2,5-dimethoxy-4-iodoamphetamine hydrochloride (+/-DOI) decreased the frequency of gripping-induced IEs, but that was not the case with alpha-methyl-serotonin maleate (alpha-methyl-5HT), a nonspecific postsynaptic agonist. Although the serotonin antagonists, ketanserine and metergoline, produced a biphasic effect, first a decrease followed by an increase with higher doses, similar effects were obtained with a mean duration of gripping-induced IEs. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which serotonin-reuptake inhibitors improve cataplexy, particularly in long-term treatment that could change the serotonin receptor levels. Polysomnographic recordings showed an increase in the awakening time and a decrease in the slow wave and rapid eye movement sleep concomitant with a decrease in immobilities after use of +/-DOI, this being stronger with the highest dose. Taken together, our results show that postsynaptic serotonin receptors are involved in the modulation in gripping-induced IEs caused by the changes in the organization of the sleep-wake cycle in taiep rats. It is possible that specific agonists, without side effects, could be a useful treatment in human narcoleptic patients. 2009 Wiley-Liss, Inc.

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

Science.gov (United States)

Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

2014-01-01

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635

International Nuclear Information System (INIS)

Stein, Patrycja; Savli, Markus; Fink, Martin; Spindelegger, Christoph; Moser, Ulrike; Kasper, Siegfried; Lanzenberger, Rupert; Wadsak, Wolfgang; Dudczak, Robert; Kletter, Kurt; Mitterhauser, Markus; Mien, Leonhard-Key

2008-01-01

The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT 1A ) receptor. Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl- 11 C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT 1A receptor BP ND was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling. The 5-HT 1A receptor BP ND was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP ND values in every region investigated, with a borderline significant sex difference in the hypothalamus (p=0.012, uncorrected). There was a high intersubject variability of the 5-HT 1A receptor BP ND within both sexes compared to the small mean differences between men and women. To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT 1A receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT 1A receptor expression. (orig.)

Quantitative accuracy of serotonergic neurotransmission imaging with high-resolution 123I SPECT

International Nuclear Information System (INIS)

Kuikka, J.T.

2004-01-01

Aim: Serotonin transporter (SERT) imaging can be used to study the role of regional abnormalities of neurotransmitter release in various mental disorders and to study the mechanism of action of therapeutic drugs or drugs' abuse. We examine the quantitative accuracy and reproducibility that can be achieved with high-resolution SPECT of serotonergic neurotransmission. Method: Binding potential (BP) of 123 I labeled tracer specific for midbrain SERT was assessed in 20 healthy persons. The effects of scatter, attenuation, partial volume, misregistration and statistical noise were estimated using phantom and human studies. Results: Without any correction, BP was underestimated by 73%. The partial volume error was the major component in this underestimation whereas the most critical error for the reproducibility was misplacement of region of interest (ROI). Conclusion: The proper ROI registration, the use of the multiple head gamma camera with transmission based scatter correction introduce more relevant results. However, due to the small dimensions of the midbrain SERT structures and poor spatial resolution of SPECT, the improvement without the partial volume correction is not great enough to restore the estimate of BP to that of the true one. (orig.) [de

Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

NARCIS (Netherlands)

Veenema, AH; Cremers, TIFH; Jongsma, ME; Steenbergen, PJ; de Boer, SF; Koolhaas, JM; Jongsma, Minke E.

Rationale: Male wild house- mice genetically selected for long attack latency ( LAL) and short attack latency ( SAL) differ in structural and functional properties of postsynaptic serotonergic- 1A ( 5- HT1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming

Interaction between estradiol and 5-HT1A receptors in the median raphe nucleus on acquisition of aversive information and association to the context in ovariectomized rats

Directory of Open Access Journals (Sweden)

Telma Gonçalves Carneiro Spera de Andrade

2017-12-01

Full Text Available The median raphe nucleus (MRN is related to stress resistance and defensive responses, a crucial source of serotonergic neurons that project to prosencephalic structures related to stress and anxiety. Estrogen receptors were identified in this mesencephalic structure. It is possible that the estrogen action is related to serotonin effect on somatodendritic 5-HT1A receptors, inhibiting the function of serotonergic neurons and thus preventing of the stress effect and inducing anxiolysis. So, in order to evaluate these aspects, female Wistar rats were ovariectomized and 21 days later were given a direct microinjection of estradiol benzoate (EB (1200 ng into the MRN, preceded by microinjections of saline or WAY100.635 (100 ng, a 5-HT1A receptor antagonist. Immediately after the two microinjections, the ovariectomized rats were conditioned with an aversive event (foot shock session in a Skinner box. Twenty-four hours later, they were exposed to the same context in a test session for 5 min for behavioral assessment: freezing, rearing, locomotion, grooming, and autonomic responses (fecal boluses and micturition. EB microinjection in the MRN prior to the exposure of animals to the foot shocks in the conditioning session did not alter their behavior in this session, but neutralized the association of the aversive experience to the context: there was a decrease in the expression of freezing and an increased rearing activity in the test session. This effect was reversed by prior microinjection of WAY100.635. In conclusion, EB acted on serotonergic neurons in the MRN of the ovariectomized rats, impairing the association of the aversive experience to the context, by co-modulating the functionality of somatodendritic 5-HT1A. Keywords: Contextual conditioning, Median raphe nucleus, Estradiol benzoate, 5-HT1A receptors, WAY100.635, Ovariectomized rats, Anxiety

A Subset of Serotonergic Neurons Evokes Hunger in Adult Drosophila.

Science.gov (United States)

Albin, Stephanie D; Kaun, Karla R; Knapp, Jon-Michael; Chung, Phuong; Heberlein, Ulrike; Simpson, Julie H

2015-09-21

Hunger is a complex motivational state that drives multiple behaviors. The sensation of hunger is caused by an imbalance between energy intake and expenditure. One immediate response to hunger is increased food consumption. Hunger also modulates behaviors related to food seeking such as increased locomotion and enhanced sensory sensitivity in both insects and vertebrates. In addition, hunger can promote the expression of food-associated memory. Although progress is being made, how hunger is represented in the brain and how it coordinates these behavioral responses is not fully understood in any system. Here, we use Drosophila melanogaster to identify neurons encoding hunger. We found a small group of neurons that, when activated, induced a fed fly to eat as though it were starved, suggesting that these neurons are downstream of the metabolic regulation of hunger. Artificially activating these neurons also promotes appetitive memory performance in sated flies, indicating that these neurons are not simply feeding command neurons but likely play a more general role in encoding hunger. We determined that the neurons relevant for the feeding effect are serotonergic and project broadly within the brain, suggesting a possible mechanism for how various responses to hunger are coordinated. These findings extend our understanding of the neural circuitry that drives feeding and enable future exploration of how state influences neural activity within this circuit. Copyright © 2015 Elsevier Ltd. All rights reserved.

Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self-harm patients

International Nuclear Information System (INIS)

Audenaert, K.; Laere, K. van; Dierckx, R.A.; Dumont, F.; Slegers, G.; Mertens, J.; Heeringen, C. van

2001-01-01

Studies of serotonin metabolites in body fluids in attempted suicide patients and of post-mortem brain tissue of suicide victims have demonstrated the involvement of the serotonergic neurotransmission system in the pathogenesis of suicidal behaviour. Recently developed neuroimaging techniques offer the unique possibility of investigating in vivo the functional characteristics of this system. In this study the 5-HT 2a receptor population of patients who had recently attempted suicide was studied by means of the highly specific radio-iodinated 5-HT 2a receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl] -5-iodo-2-methox ybenzamide or 123 I-5-I-R91150. Nine patients who had recently (1-7 days) attempted suicide and 12 age-matched healthy controls received an intravenous injection of 185 MBq 123 I-5-I-R91150 and were scanned with high-resolution brain single-photon emission tomography (SPET). Stereotactic realigned images were analysed semi-quantitatively using predefined volumes of interest. Serotonin binding capacity was expressed as the ratio of specific to non-specific activity. The cerebellum was used as a measure of non-specific activity. An age-dependent 5-HT 2a binding index was found, in agreement with previous literature. Deliberate self-harm patients had a significantly reduced mean frontal binding index after correction for age (P=0.002) when compared with controls. The reduction was more pronounced among deliberate self-injury patients (DSI) (P 2a serotonin receptor system in attempted suicide patients who are free of drugs influencing the serotonergic system shows in vivo evidence of a decreased frontal binding index of the 5-HT 2a receptor, indicating a decrease in the number and/or in the binding affinity of 5-HT 2a receptors. (orig.)

MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users.

Science.gov (United States)

Parrott, Andrew C

2013-09-01

Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component. Copyright © 2013 Elsevier Ltd. All rights reserved.

Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children.

Science.gov (United States)

Brown, Hilary K; Ray, Joel G; Wilton, Andrew S; Lunsky, Yona; Gomes, Tara; Vigod, Simone N

2017-04-18

Previous observations of a higher risk of child autism spectrum disorder with serotonergic antidepressant exposure during pregnancy may have been confounded. To evaluate the association between serotonergic antidepressant exposure during pregnancy and child autism spectrum disorder. Retrospective cohort study. Health administrative data sets were used to study children born to mothers who were receiving public prescription drug coverage during pregnancy in Ontario, Canada, from 2002-2010, reflecting 4.2% of births. Children were followed up until March 31, 2014. Serotonergic antidepressant exposure was defined as 2 or more consecutive maternal prescriptions for a selective serotonin or serotonin-norepinephrine reuptake inhibitor between conception and delivery. Child autism spectrum disorder identified after the age of 2 years. Exposure group differences were addressed by inverse probability of treatment weighting based on derived high-dimensional propensity scores (computerized algorithm used to select a large number of potential confounders) and by comparing exposed children with unexposed siblings. There were 35 906 singleton births at a mean gestational age of 38.7 weeks (50.4% were male, mean maternal age was 26.7 years, and mean duration of follow-up was 4.95 years). In the 2837 pregnancies (7.9%) exposed to antidepressants, 2.0% (95% CI, 1.6%-2.6%) of children were diagnosed with autism spectrum disorder. The incidence of autism spectrum disorder was 4.51 per 1000 person-years among children exposed to antidepressants vs 2.03 per 1000 person-years among unexposed children (between-group difference, 2.48 [95% CI, 2.33-2.62] per 1000 person-years; hazard ratio [HR], 2.16 [95% CI, 1.64-2.86]; adjusted HR, 1.59 [95% CI, 1.17-2.17]). After inverse probability of treatment weighting based on the high-dimensional propensity score, the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]). The association was also not significant when exposed children

Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs).

Science.gov (United States)

Fischer, J A; Muff, R; Born, W

2002-08-01

The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8-32) and not by CGRP-(8-37), and CRLR-RAMP1, antagonized by CGRP-(8-37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

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.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

Science.gov (United States)

Brezo, J; Bureau, A; Mérette, C; Jomphe, V; Barker, E D; Vitaro, F; Hébert, M; Carbonneau, R; Tremblay, R E; Turecki, G

2010-08-01

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts

The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-{sup 11}C]WAY-100635

Energy Technology Data Exchange (ETDEWEB)

Stein, Patrycja; Savli, Markus; Fink, Martin; Spindelegger, Christoph; Moser, Ulrike; Kasper, Siegfried; Lanzenberger, Rupert [Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna (Austria); Wadsak, Wolfgang; Dudczak, Robert; Kletter, Kurt [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Mitterhauser, Markus; Mien, Leonhard-Key [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutical Technology, Vienna (Austria)

2008-12-15

The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT{sub 1A}) receptor. Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-{sup 11}C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT{sub 1A} receptor BP{sub ND} was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling. The 5-HT{sub 1A} receptor BP{sub ND} was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP{sub ND} values in every region investigated, with a borderline significant sex difference in the hypothalamus (p=0.012, uncorrected). There was a high intersubject variability of the 5-HT{sub 1A} receptor BP{sub ND} within both sexes compared to the small mean differences between men and women. To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT{sub 1A} receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT{sub 1A} receptor expression. (orig.)

Serotonergic neurotransmission in emotional processing: New evidence from long-term recreational poly-drug ecstasy use.

Science.gov (United States)

Laursen, Helle Ruff; Henningsson, Susanne; Macoveanu, Julian; Jernigan, Terry L; Siebner, Hartwig R; Holst, Klaus K; Skimminge, Arnold; Knudsen, Gitte M; Ramsoy, Thomas Z; Erritzoe, David

2016-12-01

The brain's serotonergic system plays a crucial role in the processing of emotional stimuli, and several studies have shown that a reduced serotonergic neurotransmission is associated with an increase in amygdala activity during emotional face processing. Prolonged recreational use of ecstasy (3,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex judgement on each face stimulus. Positron emission tomography with 11 C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets was associated with an increase in amygdala activity during angry face processing. Conversely, time since the last ecstasy intake was associated with a trend toward a decrease in amygdala activity during angry and sad face processing. These results indicate that the effects of long-term serotonin depletion resulting from ecstasy use are dose-dependent, affecting the functional neural basis of emotional face processing. © The Author(s) 2016.

Acute restriction impairs memory in the elevated T-maze (ETM) and modifies serotonergic activity in the dorsolateral striatum.

Science.gov (United States)

Cruz-Morales, Sara Eugenia; García-Saldívar, Norma Laura; González-López, María Reyes; Castillo-Roberto, Georgina; Monroy, Juana; Domínguez, Roberto

2008-12-16

Serotonin (5-HT) is involved in behaviors such as sleep, eating, memory, in mental disorders like anxiety and depression and plays an important role in the modulation of stress. On the other hand, exposure to stress influence learning as well as declarative and non-declarative memory. These effects are dependent on the type of stressor, their magnitude, and the type of memory. The striatum has been associated with non-declarative procedural memory, while the information about stress effects on procedural memory and their relation with striatal serotonin is scarce. The objective of this study was to evaluate the effects of stress on the modifications of the striatal serotonergic system. In Experiment 1, the effects of either 60 min of restraint (R) or exposure to the elevated T-maze (ETM) was assessed. Exposure to ETM decreased 5-HT concentration and to R increased 5-HT activity ([metabolite]/[neurotransmitter]). In Experiment 2, we evaluated the effects of restraint on ETM trained immediately, 24 or 48 h after restraint. No effects were detected in acquisition or escape latencies, while retention latencies were lower in all groups compared with the non-restrained group, although significant effects were detected immediately and 24h after restraint. The memory impairment seems to be associated with changes in striatal serotonergic system, given that 5-HT concentration increased, while serotonergic activity decreased. The differences in the activity of 5-HT detected in each experiment could be explained by the effects of different stressors on the serotonergic neurons ability to synthesize the neurotransmitter. Thus, we suggest that exposure to stress impairs procedural memory and that striatal serotonin modulates this effect.

Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus.

Science.gov (United States)

Tuckwell, Henry C

2013-06-01

Serotonergic neurons of the dorsal raphe nuclei, with their extensive innervation of nearly the whole brain have important modulatory effects on many cognitive and physiological processes. They play important roles in clinical depression and other psychiatric disorders. In order to quantify the effects of serotonergic transmission on target cells it is desirable to construct computational models and to this end these it is necessary to have details of the biophysical and spike properties of the serotonergic neurons. Here several basic properties are reviewed with data from several studies since the 1960s to the present. The quantities included are input resistance, resting membrane potential, membrane time constant, firing rate, spike duration, spike and afterhyperpolarization (AHP) amplitude, spike threshold, cell capacitance, soma and somadendritic areas. The action potentials of these cells are normally triggered by a combination of sodium and calcium currents which may result in autonomous pacemaker activity. We here analyse the mechanisms of high-threshold calcium spikes which have been demonstrated in these cells the presence of TTX (tetrodotoxin). The parameters for calcium dynamics required to give calcium spikes are quite different from those for regular spiking which suggests the involvement of restricted parts of the soma-dendritic surface as has been found, for example, in hippocampal neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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.

Interaction between the 5-HT system and the basal ganglia: Functional implication and therapeutic perspective in Parkinson’s disease

Directory of Open Access Journals (Sweden)

Cristina eMiguelez

2014-03-01

Full Text Available The neurotransmitter serotonin (5-HT has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7 and ligand-gated ion channels (5-HT3. The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN share common projecting areas, in the basal ganglia (BG nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen, subthalamic nucleus (STN, internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe and substantia nigra (pars compacta, SNc, and pars reticulata, SNr. The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson’s disease. This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating Parkinson’s disease and the motor complications induced by chronic treatment with L-DOPA.

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease.

Science.gov (United States)

Miguelez, Cristina; Morera-Herreras, Teresa; Torrecilla, Maria; Ruiz-Ortega, Jose A; Ugedo, Luisa

2014-01-01

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

Serotonergic changes following proestrous treatment with p,p'-DDT

International Nuclear Information System (INIS)

Uphouse, L.; Eckols, K.; Croissant, D.; Stewart, G.

1990-01-01

The effects of 25 and 75 mg/kg p,p'-DDT on the CNS serotonergic system were examined in proestrous female rats. Females were treated with p,p'-DDT on the morning of proestrus and were sacrificed that evening. Levels of serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were examined in cortex, hippocampus, hypothalamus and preoptic areas. The binding of 3'-8-OH-DPAT [2-hydroxy-2-N, N-(di-propylamino)-tetralin], an agonist for 5-HT1A receptors, was examined in hippocampus and frontal cortex. P,p'-DDT decreased the level of 5-HT in frontal cortex and hippocampus. Elevations in 5-HIAA were present in the hypothalamus but only at the higher dose of p,p'-DDT. The dose of 25 mg/kg p,p'-DDT produced an increase in the Bmax for 3H-8-OH-DPAT binding to frontal cortical and hippocampal membranes. Membrane preparations from females given 75 mg/kg p,p'-DDT fell into two categories. Some were similar to the control but with a slightly higher Kd; others could not be analyzed by traditional linear or nonlinear regression procedures because they showed a constant proportion of bound label, independent of the concentration of 3H-ligand in the reaction. In vitro, p,p'-DDT did not compete with 3H-8-OH-DPAT for binding to cortical membranes so it is unlikely that residual pesticide in the membrane preparation accounted for the binding results. These binding results are particularly interesting because, in previous studies, the dose of 25 mg/kg p,p'-DDT was shown to be more potent than 75 mg/kg p,p'-DDT in reducing female rodent lordosis behavior

Ethanol induced antidepressant-like effect in the mouse forced swimming test: modulation by serotonergic system.

Science.gov (United States)

Jain, Nishant S; Kannamwar, Uday; Verma, Lokesh

2017-02-01

The present investigation explored the modulatory role of serotonergic transmission in the acute ethanol-induced effects on immobility time in the mouse forced swim test (FST). Acute i.p. administration of ethanol (20% w/v, 2 or 2.5 g/kg, i.p.) decreased the immobility time in FST of mice, indicating its antidepressant-like effect while lower doses of ethanol (1, 1.5 g/kg, i.p.) were devoid of any effect in the FST. The mice pre-treated with a sub-effective dose of 5-HT 2A agonist, DOI (10 μg/mouse, i.c.v.) or 5-HT 1A receptor antagonist, WAY 100635 (0.1 μg/mouse, i.c.v.) but not with the 5-HT 2A/2C antagonist, ketanserin (1.5 μg/mouse, i.c.v.) exhibited a synergistic reduction in the immobility time induced by sub-effective dose of ethanol (1.5 g/kg, i.p.). On the other hand, ethanol (2.5 g/kg, i.p.) failed to decrease the immobility time in mice, pre-treated with 5-HT 1A agonist, 8-OH-DPAT (0.1 μg/mouse, i.c.v.) or ketanserin (1.5 μg/mouse, i.c.v.). In addition, pre-treatment with a 5-HT neuronal synthesis inhibitor, p-CPA (300 mg/kg, i.p. × 3 days) attenuated the anti-immobility effect ethanol (2.5 g/kg, i.p.) in mouse FST. Thus, the results of the present study points towards the essentiality of the central 5-HT transmission at the synapse for the ethanol-induced antidepressant-like effect in the FST wherein the regulatory role of the 5-HT 1A receptor or contributory role of the 5-HT 2A/2C receptor-mediated mechanism is proposed in the anti-immobility effect of acute ethanol in mouse FST.

Serotonergic outcome, stress and sexual steroid hormones, and growth in a South American cichlid fish fed with an L-tryptophan enriched diet.

Science.gov (United States)

Morandini, Leonel; Ramallo, Martín Roberto; Moreira, Renata Guimarães; Höcht, Christian; Somoza, Gustavo Manuel; Silva, Ana; Pandolfi, Matías

2015-11-01

Reared animals for edible or ornamental purposes are frequently exposed to high aggression and stressful situations. These factors generally arise from conspecifics in densely breeding conditions. In vertebrates, serotonin (5-HT) has been postulated as a key neuromodulator and neurotransmitter involved in aggression and stress. The essential amino acid L-tryptophan (trp) is crucial for the synthesis of 5-HT, and so, leaves a gateway for indirectly augmenting brain 5-HT levels by means of a trp-enriched diet. The cichlid fish Cichlasoma dimerus, locally known as chanchita, is an autochthonous, potentially ornamental species and a fruitful laboratory model which behavior and reproduction has been studied over the last 15years. It presents complex social hierarchies, and great asymmetries between subordinate and dominant animals in respect to aggression, stress, and reproductive chance. The first aim of this work was to perform a morphological description of chanchita's brain serotonergic system, in both males and females. Then, we evaluated the effects of a trp-supplemented diet, given during 4weeks, on brain serotonergic activity, stress and sexual steroid hormones, and growth in isolated specimens. Results showed that chanchita's brain serotonergic system is composed of several populations of neurons located in three main areas: pretectum, hypothalamus and raphe, with no clear differences between males and females at a morphological level. Animals fed with trp-enriched diets exhibited higher forebrain serotonergic activity and a significant reduction in their relative cortisol levels, with no effects on sexual steroid plasma levels or growth parameters. Thus, this study points to food trp enrichment as a "neurodietary'' method for elevating brain serotonergic activity and decreasing stress, without affecting growth or sex steroid hormone levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Monocrotophos, an organophosphorus insecticide, disrupts the expression of HpNetrin and its receptor neogenin during early development in the sea urchin (Hemicentrotus pulcherrimus).

Science.gov (United States)

Zhang, Xiaona; Xu, Lei; Tian, Hua; Wang, Cuicui; Wang, Wei; Ru, Shaoguo

2017-09-01

Netrins, chemotropic guidance cues, can guide the extension of serotonergic axons by binding to netrin receptors during neural development. However, little is known about whether disruption of netrin signaling is involved in the mechanisms by which organophosphorus pesticides affect serotonergic nervous system (SNS) development. In this study, we evaluated the effects of the pesticide monocrotophos (MCP) on the expression patterns of HpNetrin and its receptor neogenin as well as on the intracellular calcium ion (Ca 2+ ) levels in Hemicentrotus pulcherrimus (sea urchin) by exposing fertilized embryos to 0, 0.01, 0.10, and 1.00mg/L MCP. The results showed that MCP disrupted HpNetrin and neogenin expression at different developmental stages in H. pulcherrimus and that Ca 2+ appeared to be involved in the MCP-induced developmental neurotoxicity. Specifically, the lower concentrations of MCP elevated HpNetrin and neogenin transcription, resulting in higher intracellular Ca 2+ levels during the early developmental stages in the sea urchin; this may affect netrin-directed cell migration/axon extension and subsequently disrupt serotonergic axon branching and synapse formation. In contrast, 1.00mg/L MCP exhibited an inhibitory effect on HpNetrin and neogenin transcription. This finding implies that the regulatory roles of these factors may be diminished during early development, thereby causing developmental defects in the sea urchin. Collectively, our results provide a basis for exploring the involvement of netrin and neogenin in the organophosphate-induced disruption of the SNS during development. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-Depressant-Like Effect of Kaempferitrin Isolated from Justicia spicigera Schltdl (Acanthaceae in Two Behavior Models in Mice: Evidence for the Involvement of the Serotonergic System

Directory of Open Access Journals (Sweden)

Julia Cassani

2014-12-01

Full Text Available We evaluated the antidepressant-like effect of kaempferitrin (Km isolated from the plant Justicia spicigera (Asteraceae, which is used in traditional medicine for relieving emotional disorders, such as “la tristeza” (sadness or dysthymia and “el humor” (mood changes. The actions of Km were evaluated in a forced swimming test (FST and a suspension tail test (TST in mice. We explored the involvement of the serotonergic system and the hypothalamic-hypophysis-adrenal axis (HPA in the antidepressant-like effect of Km. To evaluate nonspecific effects of Km on general activity, the open field test (OFT was performed. Km at 5, 10, and 20 mg/kg induced an antidepressant-like effect. Sub-effective dose of Km (1 mg/kg produced a synergistic effect with imipramine (6.25 mg/kg and fluoxetine (10 mg/kg but not with desipramine (3.12 mg/kg. Pretreatment with p-chlorophenylalanine methyl ester (PCPA, a serotonin synthesis inhibitor, N-{2-(4-(2-methoxyphenyl-1-piperazinyl}-N-(2-pyridinylcyclohexecarboxamide (WAY-100635, a selective 5-HT1A receptor antagonist, and 8OH-DPAT, a selective 5-HT1A agonist, but not pindolol (10 mg/kg blocked the anti- immobility effect induced by Km. Taken together, these results indicate that the antidepressant-like effect of Km is related to the serotonergic system, principally 5-HT1A. This effect was not related to changes in locomotor activity.

Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice.

Science.gov (United States)

Poleszak, Ewa; Stasiuk, Weronika; Szopa, Aleksandra; Wyska, Elżbieta; Serefko, Anna; Oniszczuk, Anna; Wośko, Sylwia; Świąder, Katarzyna; Wlaź, Piotr

2016-08-01

One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals' behavior using the forced swim test (FST), as well as the effect of traxoprodil (10 mg/kg) on the activity of antidepressants, such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg) and reboxetine (2.5 mg/kg). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT1A and 5-HT2 was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals' locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals' behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT1A and 5-HT2 serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase.

Dopamine D/sub 2/ and D/sub 1/ receptors: biochemical characterization

Energy Technology Data Exchange (ETDEWEB)

Niznik, H B

1986-01-01

In order to label dopamine D/sub 2/ receptors reversibly and selectively the potent substituted benzamide neuroleptic, YM-09151-2, was tritium labeled and its binding characteristics to striatal homogenates investigated. (/sup 3/H) YM-09151-2 bound to D/sub 2/ receptors with high affinity in a specific, saturable, reversible and sodium dependent fashion, displaying an appropriate pharmacological D/sub 2/ receptor profile. (/sup 3/H) YM-09151-2 appears to be the ligand of choice for labeling D/sub 2/ receptors since it displays approximately 20-fold lower affinity for serotonergic S/sub 2/ receptors than does (/sup 3/H) spiperone. As an initial step towards the molecular identification of the ligand binding subunit of the striatal D/sub 2/ receptor, photolabile analogues of the substituted benzamide clebopride were synthesized and their reversible and irreversible binding interactions to D/sub 2/ receptors characterized. D/sub 2/ receptor photoinactivation was prevented in a concentration and stereoselective manner by dopaminergic agonists and antagonists. In vivo biodistribution studies with (/sup 125/I) iodoazidoclebopride confirmed the ligand's ability to bind to D/sub 2/ receptor-rich regions and as such, may become a useful tool for the molecular characterization of D/sub 2/ receptor proteins. Digitonin solubilized striatal dopamine D/sub 2/ and D/sub 1/ receptors can be completely separated with full retention of biological activity by steric exclusion High Pressure Liquid Chromatography (HPLC) with corresponding Stokes radii of 7.1 and 5.6 nm.

The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive-aggressive dog, as measured with 123I-5-I-R91150 SPECT

International Nuclear Information System (INIS)

Peremans, K.; Hoybergs, Y.; Gielen, I.; Audenaert, K.; Vervaet, M.; Heeringen, C. van; Otte, A.; Goethals, I.; Dierckx, R.; Blankaert, P.

2005-01-01

Involvement of the serotonergic system in impulsive aggression has been demonstrated in both human and animal studies. The purpose of the present study was to investigate the effect of citalopram hydrobromide (a selective serotonin re-uptake inhibitor) on the 5-HT 2A receptor and brain perfusion in impulsive-aggressive dogs by means of single-photon emission computed tomography. The binding index of the radioligand 123 I-5-I-R91150 was measured before and after treatment with citalopram hydrobromide in nine impulsive-aggressive dogs. Regional perfusion was measured with 99m Tc-ethyl cysteinate dimer (ECD). Behaviour was assessed before treatment and again after 6 weeks of treatment. A correlation was found between decreased binding and behavioural improvement in eight out of nine dogs. The 5-HT 2A receptor binding index was significantly reduced after citalopram hydrobromide treatment in all cortical regions but not in the subcortical area. None of the dogs displayed alterations in perfusion on the post-treatment scans. This study supports previous findings regarding the involvement of the serotonergic system in impulsive aggression in dogs in general. More specifically, the effect of treatment on the 5-HT 2A receptor binding index could be demonstrated and the decreased binding index correlated with behavioural improvement. (orig.)

Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis.

Science.gov (United States)

Berglund, Eric D; Liu, Chen; Sohn, Jong-Woo; Liu, Tiemin; Kim, Mi Hwa; Lee, Charlotte E; Vianna, Claudia R; Williams, Kevin W; Xu, Yong; Elmquist, Joel K

2013-12-01

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

Science.gov (United States)

Kinney, Hannah C; Broadbelt, Kevin G; Haynes, Robin L; Rognum, Ingvar J; Paterson, David S

2011-07-01

The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain. Copyright © 2011 Elsevier B.V. All rights reserved.

Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT 1a receptor in the brain

International Nuclear Information System (INIS)

Saidi, Mouldi; Trabelsi, Adel; MEKNI, Abdelkader; Kretzschmar, M.; Sefert, S.; Bergmann, R.; Pietzsch, H.-J.

2005-01-01

The present interest in the 5-HT 1a receptor is due to its implicated role in several major neuropsychiatric disorders such as depression, eating disorders and anxiety. For the diagnosis of these pathophysiological processes it is important to have radioligands in hand able to specifically bind on the 5-HT 1a receptor in order to allow brain imaging. due to the optimal radiation properties of 99mTc there is a considerable interest in the development of 99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). Here we introduce two cyclopentadienyl technitium tricarbonyl conjugates of piperidine derivatives which show high accumulation of radioactivity in brain areas rich in 5-HT 1a receptors

Hippocampal deletion of BDNF gene attenuates gamma oscillations in area CA1 by up-regulating 5-HT3 receptor.

Directory of Open Access Journals (Sweden)

Ying Huang

2011-01-01

Full Text Available Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown.Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this receptor partially restored power of gamma oscillations in slices from KO mice, but had no effect in slices from WT mice.These data suggest that BDNF facilitates gamma oscillations in the hippocampus by attenuating signaling through 5-HT3 receptor. Thus, BDNF modulates hippocampal oscillations through serotonergic system.

Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

Science.gov (United States)

Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

2016-11-10

On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

A G Protein-biased Designer G Protein-coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-dependent Signaling Pathways.

Science.gov (United States)

Hu, Jianxin; Stern, Matthew; Gimenez, Luis E; Wanka, Lizzy; Zhu, Lu; Rossi, Mario; Meister, Jaroslawna; Inoue, Asuka; Beck-Sickinger, Annette G; Gurevich, Vsevolod V; Wess, Jürgen

2016-04-08

Designerreceptorsexclusivelyactivated by adesignerdrug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger β-arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediatedversusβ-arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and β-arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3muscarinic receptor that can activate Gq/11with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is activein vivoand that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)-dependentversusβ-arrestin-dependent signaling in hepatocytes. Thus, this novel Gq/11-biased DREADD represents a powerful new tool to study the physiological relevance of Gq/11-dependent signaling in distinct tissues and cell types, in the absence of β-arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek’s disease

Science.gov (United States)

1. Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals and birds. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. 2. Our obje...

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 ....... Thus, we here describe [C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68....... 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...

The effect of citalopram hydrobromide on 5-HT{sub 2A} receptors in the impulsive-aggressive dog, as measured with {sup 123}I-5-I-R91150 SPECT

Energy Technology Data Exchange (ETDEWEB)

Peremans, K.; Hoybergs, Y.; Gielen, I. [Ghent University, Department of Medical Imaging, Faculty of Veterinary Medicine, Merelbeke (Belgium); Audenaert, K.; Vervaet, M.; Heeringen, C. van [Ghent University, Department of Psychiatry and Medical Psychology, Gent (Belgium); Otte, A.; Goethals, I.; Dierckx, R. [Ghent University Hospital, Division of Nuclear Medicine, Gent (Belgium); Blankaert, P. [Ghent University, Laboratory of Radiopharmacy, Gent (Belgium)

2005-06-01

Involvement of the serotonergic system in impulsive aggression has been demonstrated in both human and animal studies. The purpose of the present study was to investigate the effect of citalopram hydrobromide (a selective serotonin re-uptake inhibitor) on the 5-HT{sub 2A} receptor and brain perfusion in impulsive-aggressive dogs by means of single-photon emission computed tomography. The binding index of the radioligand {sup 123}I-5-I-R91150 was measured before and after treatment with citalopram hydrobromide in nine impulsive-aggressive dogs. Regional perfusion was measured with {sup 99m}Tc-ethyl cysteinate dimer (ECD). Behaviour was assessed before treatment and again after 6 weeks of treatment. A correlation was found between decreased binding and behavioural improvement in eight out of nine dogs. The 5-HT{sub 2A} receptor binding index was significantly reduced after citalopram hydrobromide treatment in all cortical regions but not in the subcortical area. None of the dogs displayed alterations in perfusion on the post-treatment scans. This study supports previous findings regarding the involvement of the serotonergic system in impulsive aggression in dogs in general. More specifically, the effect of treatment on the 5-HT{sub 2A} receptor binding index could be demonstrated and the decreased binding index correlated with behavioural improvement. (orig.)

Functional relevance of neurotransmitter receptor heteromers in the central nervous system.

Science.gov (United States)

Ferré, Sergi; Ciruela, Francisco; Woods, Amina S; Lluis, Carme; Franco, Rafael

2007-09-01

The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre- and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutamatergic neurotransmission.

Exploration of N-arylpiperazine Binding Sites of D2 Dopaminergic Receptor.

Science.gov (United States)

Soskic, Vukic; Sukalovic, Vladimir; Kostic-Rajacic, Sladjana

2015-01-01

The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by us and other scientists as a template for the homology modeling and ligand docking analysis of related GPCRs. Our main scientific interest lies in the field of pharmacologically active N-arylpiperazines that exhibit antipsychotic and/or antidepressant properties, and as such are dopaminergic and serotonergic receptor ligands. In this short review article we are presenting synthesis and biological data on the new N-arylpipereazine as well our results on molecular modeling of the interactions of those N-arylpiperazines with the model of D2 dopamine receptors. To obtain that model the crystal structure of the D3 dopamine receptor was used. Our results show that the N-arylpiperazines binding site consists of two pockets: one is the orthosteric binding site where the N-arylpiperazine part of the ligand is docked and the second is a non-canonical accessory binding site for N-arylpipereazine that is formed by a second extracellular loop (ecl2) of the receptor. Until now, the structure of this receptor region was unresolved in crystal structure analyses of the D3 dopamine receptor. To get a more complete picture of the ligand - receptor interaction, DFT quantum mechanical calculations on N-arylpiperazine were performed and the obtained models were used to examine those interactions.

Putaminal serotonergic innervation: monitoring dyskinesia risk in Parkinson disease.

Science.gov (United States)

Lee, Jee-Young; Seo, Seongho; Lee, Jae Sung; Kim, Han-Joon; Kim, Yu Kyeong; Jeon, Beom S

2015-09-08

To explore serotonergic innervation in the basal ganglia in relation to levodopa-induced dyskinesia in patients with Parkinson disease (PD). A total of 30 patients with PD without dementia or depression were divided into 3 matched groups (dyskinetic, nondyskinetic, and drug-naive) for this study. We acquired 2 PET scans and 3T MRI for each patient using [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ((11)C-DASB) and N-(3-[(18)F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane ((18)F-FP-CIT). Then we analyzed binding potentials of the 2 radiotracers at basal ganglia structures and correlations with clinical variables. We observed no difference in (18)F-FP-CIT binding between dyskinetic and nondyskinetic patients, whereas there were differences in (11)C-DASB binding for the caudate and putamen. Binding potential ratios ((11)C-DASB/(18)F-FP-CIT) at the putamen, which indicate serotoninergic fiber innervation relative to dopaminergic fiber availability, were highest in the dyskinetic group, followed by the nondyskinetic and drug-naive PD groups. (11)C-DASB/(18)F-FP-CIT ratios at the putamen and pallidum correlated positively with Unified Parkinson's Disease Rating Scale (UPDRS) total scores and duration of PD, and pallidal binding ratio also correlated with the UPDRS motor scores. Ratios were not dependent on dopaminergic medication dosages for any of the regions studied. Relative serotonergic innervation of the putamen and pallidum increased with clinical PD progression and was highest in patients with established dyskinesia. The serotonin/dopamine transporter ratio might be a potential marker of disease progression and an indicator of risk for levodopa-induced dyskinesia in PD. A prospective evaluation is warranted in the future. © 2015 American Academy of Neurology.

A happy valve in a happy patient? Serotonergic antidepressants and the risk of valvular heart disease (SERVAL). A case-control study.

Science.gov (United States)

De Backer, Tine; Petrovic, Mirko; Audenaert, Kurt; Coeman, Mathieu; De Bacquer, Dirk

2016-02-01

The objective was to investigate the risk of valvular heart disease in humans in relation to the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors. A case-control study. We conducted a case-control study within this cohort in which patients with newly diagnosed cardiac valve regurgitation were age-matched to controls. Patient demographics, their cardiovascular risk factors and medication use were extracted in both series. Use of SSRIs, serotonin and noradreline reuptake inhibitors (SNRIs) and other pro-serotonergic agents, their dose and treatment duration were recorded. Logistic regression analysis was used to establish the strength of the association between SSRI/SNRI use and valvular heart disease. Outpatient clinic of the cardiology department at the Ghent University Hospital, East-Flanders in Belgium. Total of 2911 persons 21-58 years of age who had undergone an echocardiogram in the period 2006-2010 and had no known cardiovascular disease or previous cardiac intervention. Two hundred and six echocardiographically proven cases of valvular regurgitation and 195 matched controls. Odd ratio of valvular disease associated with intake of serotonergic drugs. Of the 206 patients with newly diagnosed cardiac valve regurgitation, 11.6% were exposed to serotonergic agents compared to 4.1% in the 195 control patients, leading to an odds ratio of 3.08 (95% confidence interval [CI] 1.35-7.04). The analysis of doses and treatment durations revealed a dose-relationship pattern between SSRI/SNRI use and prevalent valvular heart disease. In this study, use of serotonergic antidepressants was associated with an increased rate of valvular regurgitation in humans.

Effect of diet on serotonergic neurotransmission in depression.

Science.gov (United States)

Shabbir, Faisal; Patel, Akash; Mattison, Charles; Bose, Sumit; Krishnamohan, Raathathulaksi; Sweeney, Emily; Sandhu, Sarina; Nel, Wynand; Rais, Afsha; Sandhu, Ranbir; Ngu, Nguasaah; Sharma, Sushil

2013-02-01

Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy. Clinical and experimental evidence indicates that an appropriate diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B(6). Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavailability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these agents are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors. However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. This report highlights the clinical significance of tryptophan-rich diet and vitamin B(6) to boost serotonergic neurotransmission in

Decreased frontal serotonin 5-HT{sub 2a} receptor binding index in deliberate self-harm patients

Energy Technology Data Exchange (ETDEWEB)

Audenaert, K. [Dept. of Psychiatry and Medical Psychology, Ghent University Hospital (Belgium); Dept. of Nuclear Medicine, Ghent University Hospital (Belgium); Laere, K. van; Dierckx, R.A. [Dept. of Nuclear Medicine, Ghent University Hospital (Belgium); Dumont, F.; Slegers, G. [Dept. of Radiopharmacy, Ghent Univ. (Belgium); Mertens, J. [VUB-Cyclotron, Brussels (Belgium); Heeringen, C. van [Dept. of Psychiatry and Medical Psychology, Ghent University Hospital (Belgium)

2001-02-01

Studies of serotonin metabolites in body fluids in attempted suicide patients and of post-mortem brain tissue of suicide victims have demonstrated the involvement of the serotonergic neurotransmission system in the pathogenesis of suicidal behaviour. Recently developed neuroimaging techniques offer the unique possibility of investigating in vivo the functional characteristics of this system. In this study the 5-HT{sub 2a} receptor population of patients who had recently attempted suicide was studied by means of the highly specific radio-iodinated 5-HT{sub 2a} receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide or {sup 123}I-5-I-R91150. Nine patients who had recently (1-7 days) attempted suicide and 12 age-matched healthy controls received an intravenous injection of 185 MBq {sup 123}I-5-I-R91150 and were scanned with high-resolution brain single-photon emission tomography (SPET). Stereotactic realigned images were analysed semi-quantitatively using predefined volumes of interest. Serotonin binding capacity was expressed as the ratio of specific to non-specific activity. The cerebellum was used as a measure of non-specific activity. An age-dependent 5-HT{sub 2a} binding index was found, in agreement with previous literature. Deliberate self-harm patients had a significantly reduced mean frontal binding index after correction for age (P=0.002) when compared with controls. The reduction was more pronounced among deliberate self-injury patients (DSI) (P<0.001) than among deliberate self-poisoning patients (DSP). Frontal binding index was significantly lower in DSI patients than in DSP suicide attempters (P<0.001). It is concluded that brain SPET of the 5-HT{sub 2a} serotonin receptor system in attempted suicide patients who are free of drugs influencing the serotonergic system shows in vivo evidence of a decreased frontal binding index of the 5-HT{sub 2a} receptor, indicating a decrease in the number and/or in

Antidepressant-Like Effects of Sanggenon G, Isolated from the Root Bark of Morus alba, in Rats: Involvement of the Serotonergic System.

Science.gov (United States)

Lim, Dong Wook; Jung, Jae-Woo; Park, Ji-Hae; Baek, Nam-In; Kim, Yun Tai; Kim, In-Ho; Han, Daeseok

2015-01-01

The root bark of Morus alba is commonly used as an alternative medicine due to its numerous health benefits in humans. However, the antidepressant effects of various active components from M. alba have not been fully elucidated. In this study, we aimed to determine whether sanggenon G, an active compound isolated from the root bark of M. alba, exhibited antidepressant-like activity in rats subjected to forced swim test (FST)-induced depression. Acute treatment of rats with sanggenon G (30 mg/kg, intraperitoneally (i.p.)) significantly reduced immobility time and increased swimming time without any significant change in climbing. Rats treated with sanggenon G also exhibited a decrease in the limbic hypothalamic-pituitary-adrenal (HPA) axis response to the FST, as indicated by attenuation of the corticosterone response and decreased c-Fos immunoreactivity in the hypothalamic paraventricular nucleus (PVN). In addition, the antidepressant-like effects of sanggenon G were significantly inhibited by WAY100635 (1 mg/kg, i.p.; a selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonist), but not SCH23390 (0.05 mg/kg, i.p.; a dopamine D1 receptor antagonist). Our findings suggested that the antidepressant-like effects of sanggenon G were mediated by an interaction with the serotonergic system. Further studies are needed to evaluate the potential of sanggenon G as an alternative therapeutic approach for the treatment of depression.

The anatomy of the serotonergic nervous system of an entoproct creeping-type larva and its phylogenetic implications

DEFF Research Database (Denmark)

Wanninger, Andreas Wilhelm Georg; Fuchs, Judith; Haszprunar, Gerhard

2007-01-01

the anatomy of the serotonergic nervous system of the creeping-type larva of Loxosomella murmanica. The apical organ is very complex and comprises six to eight centrally positioned flask cells and eight bipolar peripheral cells. In addition, a prototroch nerve ring, an anterior nerve loop, a paired buccal...... molluscs and may be diagnostic for a mollusc-entoproct clade. In addition, the larva of Loxosomella expresses a mosaic of certain neural features that are also found in other larval or adult Spiralia, e.g., a prototroch nerve ring, an anterior nerve loop, and a buccal nervous system....... ones, are found along the anterior-posterior axis. The combination of a complex larval serotonergic apical organ and (adult) tetraneury, comprising one pair of ventral and one pair of more dorsally situated lateral longitudinal nerve cords without ganglia, has so far only been reported for basal...

Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain.

Science.gov (United States)

Komorowski, A; James, G M; Philippe, C; Gryglewski, G; Bauer, A; Hienert, M; Spies, M; Kautzky, A; Vanicek, T; Hahn, A; Traub-Weidinger, T; Winkler, D; Wadsak, W; Mitterhauser, M; Hacker, M; Kasper, S; Lanzenberger, R

2017-01-01

Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post-mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5-HT1A) and excitatory (5-HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase-A (MAO-A), using Spearman's correlation coefficients (rs) in a voxel-wise and region-wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5-HT1A (voxel-wise rs = 0.71; region-wise rs = 0.93) and the 5-HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO-A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region-wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5-HT1Ars = 0.82; 5-HT2Ars = 0.88; MAO-A rs = 0.50; SERT rs = -0.01). The SERT and MAO-A appear to be regulated in a region-specific manner across the whole brain. In contrast, the serotonin-1A and -2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins. © The Author 2016. Published by Oxford University Press.

Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia.

Science.gov (United States)

Miyauchi, Masanori; Neugebauer, Nichole M; Meltzer, Herbert Y

2017-04-01

Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D 4 receptor, but the relevance to the efficacy for the treatment of cognitive impairment associated with schizophrenia (CIAS) is poorly understood. The aim of this study was to investigate the effects of D 4 receptor stimulation or blockade on novel object recognition (NOR) in normal rats and on the sub-chronic phencyclidine (PCP)-induced novel object recognition deficit. The effect of the D 4 agonist, PD168077, and the D 4 antagonist, L-745,870, were studied alone, and in combination with clozapine and lurasidone. In normal rats, L-745,870 impaired novel object recognition, whereas PD168077 had no effect. PD168077 acutely reversed the sub-chronic phencyclidine-induced novel object recognition deficit. Co-administration of a sub-effective dose (SED) of PD168077 with a sub-effective dose of lurasidone also reversed this deficit, but a sub-effective dose of PD168077 with a sub-effective dose of clozapine, a more potent D 4 antagonist than lurasidone, did not reverse the sub-chronic phencyclidine-induced novel object recognition deficit. At a dose that did not induce a novel object recognition deficit, L-745,870 blocked the ability of clozapine, but not lurasidone, to reverse the novel object recognition deficit. D 4 receptor agonism has a beneficial effect on novel object recognition in sub-chronic PCP-treated rats and augments the cognitive enhancing efficacy of an atypical antipsychotic drug that lacks affinity for the D 4 receptor, lurasidone.

The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

DEFF Research Database (Denmark)

Frederiksen, Kristian Steen; Oranje, Bob; Wienberg, Malene

2007-01-01

Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic...

Characterization of the serotonin transporter knockout rat : A selective change in the functioning of the serotonergic system

NARCIS (Netherlands)

Homberg, J. R.; Olivier, J.D.A.; Smits, B. M. G.; Mul, J. D.; Mudde, J.; Verheul, M.; Nieuwenhuizen, O. F. M.; Cools, A. R.; Ronken, E; Cremers, Thomas; Schoffelmeere, A. N. M.; Ellenbroeik, B. A.; Cuppen, E.

2007-01-01

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by

Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system.

NARCIS (Netherlands)

Homberg, J.R.; Olivier, J.D.A.; Smits, B.M.; Mul, J.D.; Mudde, J.; Verheul, M.; Nieuwenhuizen, O.F.; Cools, A.R.; Ronken, E.; Cremers, T.; Schoffelmeer, A.N.; Ellenbroek, B.A.; Cuppen, E.

2007-01-01

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

Science.gov (United States)

Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex

Directory of Open Access Journals (Sweden)

Daniel W. Sparks

2018-01-01

Full Text Available Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh and serotonin (5-HT have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex.

Science.gov (United States)

Sparks, Daniel W; Tian, Michael K; Sargin, Derya; Venkatesan, Sridevi; Intson, Katheron; Lambe, Evelyn K

2017-01-01

Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.

Functional expression of the 5-HT1c receptor in neuronal and nonneuronal cells

International Nuclear Information System (INIS)

Julius, D.; MacDermott, A.B.; Jessel, T.M.; Huang, K.; Molineaux, S.; Schieren, I.; Axel, R.

1988-01-01

The isolation of the genes encoding the multiple serotonin receptor subtypes and the ability to express these receptors in new cellular environments will help to elucidate the molecular mechanisms of action of serotonin in the mammalian brain. The cloning of most neurotransmitter receptors has required the purification of receptor, the determination of partial protein sequence, and the synthesis of oligonucleotide probes with which to obtain cDNA or genomic clones. However, the serotonin receptors have not been purified and antibodies have not been generated. The authors therefore designed a cDNA expression system that permits the identification of functional cDNA clones encoding serotonin receptors in the absence of protein sequence information. They have combined cloning in RNA expression vectors with an electrophysiological assay in oocytes to isolate a functional cDNA clone encoding the entire 5-HT 1c receptor. The sequence of this clone reveals that the 5-HT 1c receptor belongs to a family of G-protein-coupled receptors that are thought to traverse the membrane seven times. Mouse fibroblasts transformed with this clone bind serotonergic ligands and respond to serotonin with an elevation in intracellular calcium. Moreover, in situ hybridization and Northern blot analysis indicate that the 5-HT 1c receptor mRNA is expressed in a wide variety of neurons in the rat central nervous system, suggesting that this receptor plays a prominent role in neuronal function

(/sup 3/H)Spiperone binding sites in brain: autoradiographic localization of multiple receptors

Energy Technology Data Exchange (ETDEWEB)

Palacios, J M; Niehoff, D L; Kuhar, M J [Johns Hopkins Univ., Baltimore, MD (USA). School of Medicine

1981-01-01

(/sup 3/H)Spiperone ((/sup 3/H)SP) binding sites were localized by light microscopic autoradiography, after in vitro labelling. The kinetic and pharmacological characteristics of these binding sites were studied in slide-mounted sections of rat forebrain, and optimal labeling conditions were defined. Autoradiograms were obtained by apposing emulsion-coated coverslips to labeled sections. Differential drug sensitivity allowed the selective displacement of (/sup 3/H)SP from dopamine receptors by ADTN, from serotonin receptors by cinanserin, from both by haloperidol and from unique spiperone sites by unlabeled spiperone. The various sites presented a differential anatomical localization. For example, only dopaminergic sites were found in the glomerular layer of the olfactory bulb; only serotonergic sites were found in lamina IV of the neocortex, and a high concentration of unique spiperone sites were found in parts of the hippocampus.

Spatial memory deficit across aging: current insights of the role of 5-HT7 receptors

Directory of Open Access Journals (Sweden)

Gregory eBeaudet

2015-01-01

Full Text Available Elderly persons often face biological, psychological or social changes over time that may cause discomfort or morbidity. While some cognitive domains remain stable over time, others undergo a decline. Spatial navigation is a complex cognitive function essential for independence, safety and quality of life. While egocentric (body-centered navigation is quite preserved during aging, allocentric (externally-centered navigation — based on a cognitive map using distant landmarks — declines with age. Recent preclinical studies showed that serotonergic 5-HT7 receptors are localized in brain regions associated with allocentric spatial navigation processing. Behavioral assessments with pharmacological or genetic tools have confirmed the role of 5-HT7 receptors in allocentric navigation. Moreover, few data suggested a selective age-related decrease in the expression of 5-HT7 receptors in pivotal brain structures implicated in allocentric navigation such as the hippocampal CA3 region. We aim to provide a short overview of the potential role of 5-HT7 receptors in spatial navigation, and to argue for their interests as therapeutic targets against age-related cognitive decline.

Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion

DEFF Research Database (Denmark)

Macoveanu, Julian; Hornboll, Bettina; Elliott, Rebecca

2013-01-01

in subjects with low 5-HT(2A) BP(P) but reduced the NoGo response in those with high 5-HT(2A) BP(P). These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders...

Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons:a sensitive target for ethanol

OpenAIRE

Maguire, Edward P.; Mitchell, Elizabeth A.; Greig, Scott J.; Corteen, Nicole; Balfour, David J. K.; Swinny, Jerome; Lambert, Jeremy J.; Belelli, Delia

2014-01-01

Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inh...

Intraspinal serotonergic neurons consist of two, temporally distinct populations in developing zebrafish.

Science.gov (United States)

Montgomery, Jacob E; Wiggin, Timothy D; Rivera-Perez, Luis M; Lillesaar, Christina; Masino, Mark A

2016-06-01

Zebrafish intraspinal serotonergic neuron (ISN) morphology and distribution have been examined in detail at different ages; however, some aspects of the development of these cells remain unclear. Although antibodies to serotonin (5-HT) have detected ISNs in the ventral spinal cord of embryos, larvae, and adults, the only tryptophan hydroxylase (tph) transcript that has been described in the spinal cord is tph1a. Paradoxically, spinal tph1a is only expressed transiently in embryos, which brings the source of 5-HT in the ISNs of larvae and adults into question. Because the pet1 and tph2 promoters drive transgene expression in the spinal cord, we hypothesized that tph2 is expressed in spinal cords of zebrafish larvae. We confirmed this hypothesis through in situ hybridization. Next, we used 5-HT antibody labeling and transgenic markers of tph2-expressing neurons to identify a transient population of ISNs in embryos that was distinct from ISNs that appeared later in development. The existence of separate ISN populations may not have been recognized previously due to their shared location in the ventral spinal cord. Finally, we used transgenic markers and immunohistochemical labeling to identify the transient ISN population as GABAergic Kolmer-Agduhr double-prime (KA″) neurons. Altogether, this study revealed a novel developmental paradigm in which KA″ neurons are transiently serotonergic before the appearance of a stable population of tph2-expressing ISNs. © 2015 Wiley Periodicals, Inc.

An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

International Nuclear Information System (INIS)

Roper, I.

1987-01-01

Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

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 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...... and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A...

Serotonin-1A receptor polymorphism (rs6295 associated with thermal pain perception.

Directory of Open Access Journals (Sweden)

Fredrik Lindstedt

Full Text Available BACKGROUND: Serotonin (5-HT is highly involved in pain regulation and serotonin-1A (5-HT1A receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities. METHODS: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C. Nociceptive-flexion reflex (NFR thresholds were also assessed. RESULTS: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged. CONCLUSION/SIGNIFICANCE: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain

Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: Possible association but no influence of personality disorders

OpenAIRE

Preuss, Ulrich W.; Koller, G.; Bondy, Brigitta; Bahlmann, Miriam; Soyka, Michael

2001-01-01

Objective: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impu...

A reassessment of the role of serotonergic system in the control of feeding behavior

Directory of Open Access Journals (Sweden)

Medeiros Magda A.

2005-01-01

Full Text Available The role of serotonergic system in the feeding behaviorwas appraised by electrolytic lesions in the dorsal raphe nucleus (DRN and administration of para-chlorophenylalanine (PCPA, 3 mg/5 mul, icv. Chronic evaluations were accomplished through 120 and 360 days in PCPA-injected and DRN-lesioned rats, respectively. Acute food intake was evaluated in fasted rats and submitted to injection of PCPA and hydroxytryptophan (LHTP, 30 mg/kg, ip. DRN-lesioned rats exhibited 22-80% increase in food intake up to sixth month, whereas the obesity was evident and sustained by whole period. In PCPA-injected rats was observed an initial increase in the food intake followed by hypophagy from 25th to 30th day and a transitory increase of body weight from 5th to 60th day. In the acute study, the LHTP reverted partially the PCPA-induced increase in food intake of fasted rats suggesting a sustained capacity of decarboxylation of precursor by serotonergic neurons. Slow restoration of the levels of food intake in DRN-lesioned rats reveals a neuroplasticity in the systems that regulate feeding behavior. A plateau on the body weight curve in lesioned rats possibly represents the establishment of a new and higher set point of energetic balance.

Localization of serotonin and ultrastructure of serotonergic neutrons in the nervous system of fasciola hepatica

International Nuclear Information System (INIS)

Huang Shile; Cheng Bing; Rong Yaofang

1993-01-01

Rabbits antisera were raised against an antigen prepared by coupling 5-HT to bovine serum albumin (BSA) using formaldehyde as a coupling reagent. The fresh adult Fasciola hepatica were fixed with 4% formaldehyde and sectioned on a cryostat. The sections were stained by indirect immunofluorescence technique. Abundant immunofluorescence specific for 5-HT was observed in ganglion cell bodies and their processes, the transverse commissure that connects two ganglia and longitudinal axes extending from the ganglia. Immuno-reactivity to 5-HT was also found in the nerve fibre innervating tegument, gut wall, the epithelium of testes or ovary, the musculature of uterus and ootype, etc. The ultrastructure of serotonergic neurons was visualized. As in other invertebrates, the serotonergic neutrons of Fasciola hepatica consisted of cell bodies, axons, synapses, herring bodies and neuromuscular junctions. The nerve cell bodies were aggregatively located in ganglia and many dispersed spherical granular vesicles were present in cytoplasm. The nerve axons branched out to the muscles forming synapses, where synaptic vesicles contained 5-HT dense-core granules were found. The distribution of 5-HT within the neurons strongly suggested that 5-HT was functioning as a neurotrasmitter in Fasciola hepatica

Olanzapine and sibutramine have opposing effects on the motivation for palatable food

NARCIS (Netherlands)

van der Zwaal, Esther M.; Janhunen, Sanna K.; Luijendijk, Mieneke C. M.; Baclesanu, Roxana; Vanderschuren, Louk J. M. J.; Adan, Roger A. H.; la Fleur, Susanne E.

2012-01-01

Both olanzapine and sibutramine target serotonergic and noradrenergic neurotransmission and influence body weight, but in opposite ways. The second-generation antipsychotic olanzapine, an antagonist at serotonergic and noradrenergic receptors, frequently induces weight gain as a side-effect, whereas

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

Science.gov (United States)

Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

Directory of Open Access Journals (Sweden)

Cristina Miguelez

2017-09-01

Full Text Available The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA and the serotonergic (5-HT system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.

The Effect of Tongue Exercise on Serotonergic Input to the Hypoglossal Nucleus in Young and Old Rats

Science.gov (United States)

Behan, Mary; Moeser, Adam E.; Thomas, Cathy F.; Russell, John A.; Wang, Hao; Leverson, Glen E.; Connor, Nadine P.

2012-01-01

Purpose: Breathing and swallowing problems affect elderly people and may be related to age-associated tongue dysfunction. Hypoglossal motoneurons that innervate the tongue receive a robust, excitatory serotonergic (5HT) input and may be affected by aging. We used a rat model of aging and progressive resistance tongue exercise to determine whether…

The association between concomitant use of serotonergic antidepressants and lithium-induced polyuria. A multicenter medical chart review study

NARCIS (Netherlands)

Wilting, I.; Egberts, A. C. G.; Movig, K. L. L.; van Laarhoven, J. H. M.; Heerdink, E. R.; Nolen, W. A.

Background: A previous Study aimed at revealing the prevalence and determinants Of lithium induced polyuria Suggested an increased risk of polyuria (urine volume >= 3L/24h) in those using serotonergic antidepressants next to lithium. Objective: The objective of our study was to re-evaluate this

GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon

DEFF Research Database (Denmark)

Ducray, Angélique; Krebs, Sandra H:; Schaller, Benoft

2006-01-01

Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), known as the GDNF family ligands (GFLs), influence the development, survival and differentiation of cultured dopaminergic neurons from ventral mesencephalon (VM). Detailed knowledge about...... factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development....

Requirement for tyrosine phosphatase during serotonergic neuromodulation by protein kinase C.

Science.gov (United States)

Catarsi, S; Drapeau, P

1997-08-01

Tyrosine kinases and phosphatases are abundant in the nervous system, where they signal cellular differentiation, mediate the responses to growth factors, and direct neurite outgrowth during development. Tyrosine phosphorylation can also alter ion channel activity, but its physiological significance remains unclear. In an identified leech mechanosensory neuron, the ubiquitous neuromodulator serotonin increases the activity of a cation channel by activating protein kinase C (PKC), resulting in membrane depolarization and modulation of the receptive field properties. We observed that the effects on isolated neurons and channels were blocked by inhibiting tyrosine phosphatases. Serotonergic stimulation of PKC thus activates a tyrosine phosphatase activity associated with the channels, which reverses their constitutive inhibition by tyrosine phosphorylation, representing a novel form of neuromodulation.

Hydroethanolic extract of Carthamus tinctorius induces antidepressant-like effects: modulation by dopaminergic and serotonergic systems in tail suspension test in mice.

Science.gov (United States)

Abbasi-Maleki, Saeid; Mousavi, Zahra

2017-09-01

Studies indicate that major deficiency in the levels of monoaminergic transmitters is a reason for severe depression. On the other hand, it is shown that Carthamus tinctorius L. (CT) may improve neuropsychological injuries by regulation of the monoamine transporter action. Hence, the present study was undertaken to evaluate the involvement of monoaminergic systems in antidepressant-like effect of CT extract in the tail suspension test (TST) in mice. The mice were intraperitoneally (IP) treated with CT extract (100-400 mg/kg) 1 hr before the TST. To investigate the involvement of monoaminergic systems in antidepressant-like effect, the mice were treated with receptor antagonists 15 min before CT extract treatment (400 mg/kg, IP) and 1 hr before the TST. Findings showed that CT extract (100-400 mg/kg, IP), dose-dependently induced antidepressant-like effect ( P open-field test. Pretreatment of mice with SCH23390, sulpiride, haloperidol, WAY100135, cyproheptadine, ketanserin and p-chlorophenylalanine (PCPA) inhibited the antidepressant-like effect of CT extract (400 mg/kg, IP), but not with prazosin and yohimbine. Co-administration of CT extract (100 mg/kg, IP) with sub-effective doses of fluoxetine (5 mg/kg, IP) or imipramine (5 mg/kg, IP) increased their antidepressant-like response. Our findings firstly showed that components (especially N-Hexadecanoic acid) of CT extract induce antidepressant-like effects by interaction with dopaminergic (D1 and D2) and serotonergic (5HT1A, 5-HT2A receptors) systems. These findings validate the folk use of CT extract for the management of depression.

Serotonergic Projections and Serotonin Receptor Expression in the Reticular Nucleus of the Thalamus in the Rat

Czech Academy of Sciences Publication Activity Database

Rodríguez Arellano, Jose Julio; Noristani, H. N.; Hoover, W. B.; Linley, S. B.; Vertes, R. P.

2011-01-01

Roč. 65, č. 9 (2011), s. 919-928 ISSN 0887-4476 R&D Projects: GA ČR GA309/09/1696 Institutional research plan: CEZ:AV0Z50390703 Keywords : reticular nucleus * thalamus * serotonin receptors Subject RIV: FH - Neurology Impact factor: 2.945, year: 2011

Clinical relevance of the bile acid receptor TGR5 in metabolism

DEFF Research Database (Denmark)

van Nierop, F Samuel; Scheltema, Matthijs J; Eggink, Hannah M

2017-01-01

The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohep......The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

NARCIS (Netherlands)

Rinne, T; Westenberg, HGM; den Boer, JA

2000-01-01

Background: Disturbances of affect, impulse regulation and autoaggressive behavior which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual

Serotonergic Modulation of Conditioned Fear

Directory of Open Access Journals (Sweden)

Judith R. Homberg

2012-01-01

Full Text Available Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall, is essential in the understanding of (individual differences in vulnerability to these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear.

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....

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...... stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission....... 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...

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

NARCIS (Netherlands)

Rinne, T.; Westenberg, H. G.; den Boer, J. A.; van den Brink, W.

2000-01-01

Disturbances of affect, impulse regulation, and autoaggressive behavior, which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual abuse is

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

Directory of Open Access Journals (Sweden)

Albert Paul R

2011-05-01

Full Text Available Abstract The serotonin-1A (5-HT1A receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019G (rs6295 polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making.

Science.gov (United States)

Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha; Zhou, Xiaolin

2017-09-01

The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. © The Author (2017). Published by Oxford University Press.

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making

Science.gov (United States)

Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha

2017-01-01

Abstract The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. PMID:28431168

Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT neurons in mice with altered 5-HT homeostasis

Directory of Open Access Journals (Sweden)

Naozumi eAraragi

2013-08-01

Full Text Available Firing activity of serotonin (5-HT neurons in the dorsal raphe nucleus (DRN is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert -/- and tryptophan hydroxylase-2 knockout (Tph2 -/- mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+-8-hydroxy-2-(di-n-propylaminotetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2 -/- mice and Sert -/- mice, respectively. While 5-HT neurons from Tph2 -/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert -/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP, neurons from both Tph2 -/- and Sert -/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.

Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.

Science.gov (United States)

Stößel, Anne; Brox, Regine; Purkayastha, Nirupam; Hübner, Harald; Hocke, Carsten; Prante, Olaf; Gmeiner, Peter

2017-07-01

Dopamine D 3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D 3 a highly promising biological target. The previously described dopamine D 3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [ 18 F]2, a [ 18 F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D 3 -rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serotonergic and dopaminergic modulation of attentional processes.

Science.gov (United States)

Boulougouris, Vasileios; Tsaltas, Eleftheria

2008-01-01

Disturbances in attentional processes are a common feature of several psychiatric disorders such as schizophrenia, attention deficit/hyperactivity disorder and Huntington's disease. The use of animal models has been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic and vice-versa. In this chapter, a comparative and integrated account is provided on the neuroanatomical and neurochemical modulation of basic behavioural operations such as selective attention, vigilance, set-shifting and executive control focusing on the comparative functions of the serotonin and dopamine systems in the cognitive control exerted by the prefrontal cortex. Specifically, we have reviewed evidence emerging from several behavioural paradigms in experimental animals and humans each of which centres on a different aspect of the attentional function. These paradigms offering both human and animal variants include the five-choice serial reaction time task (5CSRTT), attentional set-shifting and stop-signal reaction time task. In each case, the types of operation that are measured by the given paradigm and their neural correlates are defined. Then, the role of the ascending dopaminergic and serotonergic systems in the neurochemical modulation of its behavioural output are examined, and reference is made to clinical implications for neurological and neuropsychiatric disorders which exhibit deficits in these cognitive tests.

A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity.

Directory of Open Access Journals (Sweden)

Maria Martí-Solano

Full Text Available Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5-HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and β-arrestin signaling at the 5-HT1B receptor but clearly favoring β-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro-switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity.

The loudness dependence of auditory evoked potentials (LDAEP as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms.

Directory of Open Access Journals (Sweden)

Christine Wyss

Full Text Available Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP. The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.

Structural Probing of Off-Target G Protein-Coupled Receptor Activities within a Series of Adenosine/Adenine Congeners

Science.gov (United States)

Paoletta, Silvia; Tosh, Dilip K.; Salvemini, Daniela; Jacobson, Kenneth A.

2014-01-01

We studied patterns of off-target receptor interactions, mostly at G protein-coupled receptors (GPCRs) in the µM range, of nucleoside derivatives that are highly engineered for nM interaction with adenosine receptors (ARs). Because of the considerable interest of using AR ligands for treating diseases of the CNS, we used the Psychoactive Drug Screening Program (PDSP) for probing promiscuity of these adenosine/adenine congeners at 41 diverse receptors, channels and a transporter. The step-wise truncation of rigidified, trisubstituted (at N6, C2, and 5′ positions) nucleosides revealed unanticipated interactions mainly with biogenic amine receptors, such as adrenergic receptors and serotonergic receptors, with affinities as high as 61 nM. The unmasking of consistent sets of structure activity relationship (SAR) at novel sites suggested similarities between receptor families in molecular recognition. Extensive molecular modeling of the GPCRs affected suggested binding modes of the ligands that supported the patterns of SAR at individual receptors. In some cases, the ligand docking mode closely resembled AR binding and in other cases the ligand assumed different orientations. The recognition patterns for different GPCRs were clustered according to which substituent groups were tolerated and explained in light of the complementarity with the receptor binding site. Thus, some likely off-target interactions, a concern for secondary drug effects, can be predicted for analogues of this set of substructures, aiding the design of additional structural analogues that either eliminate or accentuate certain off-target activities. Moreover, similar analyses could be performed for unrelated structural families for other GPCRs. PMID:24859150

Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with 99mTc-ECD and 123I-5-I-R91150

International Nuclear Information System (INIS)

Peremans, Kathelijne; Coopman, Frank; Verschooten, Francis; Bree, Henri van; Audenaert, Kurt; Heeringen, Kees van; Blanckaert, Peter; Slegers, Guido; Jacobs, Filip; Otte, Andreas; Dierckx, Rudi; Mertens, John

2003-01-01

Impulsive aggression in dogs has an important impact on human public health. Better insight into the pathophysiology of this phenomenon could lead to more adequate diagnosis and treatment. Indirect in vivo research on peripheral body fluids and post-mortem studies in impulsive animals and humans indicate a deficient serotonergic system in general and disturbances in the serotonin-2A (5-HT2A) receptor in particular. In this study, brain perfusion and the 5-HT2A receptors were examined in impulsive, aggressive dogs, in comparison with a group of normally behaving animals. In order to decide which dogs to include in this study, owners were asked to describe the general behaviour of the dogs, the circumstances in which aggression occurred and their conduct during aggressive acts. Finally, 19 dogs were retained for this study, showing, according to different behavioural specialists, disinhibited dominance aggression. Functional imaging studies were performed on all these dogs. Single-photon emission tomography (SPET) was used to measure regional brain perfusion using technetium-99m labelled ethyl cysteinate dimer (ECD). The 5-HT2A receptor binding properties were investigated using the selective radioligand iodine-123 labelled 5-I-R91150. A significant increase in uptake of the 5-HT2A radioligand was noted in all cortical areas. No significant alterations were found in regional cortical perfusion, indicating that the increased binding index was not a consequence of increased tracer delivery. This study supports a role for the serotonergic system in canine impulsive aggression. (orig.)

Serotonin blockade delays learning performance in a cooperative fish.

Science.gov (United States)

Soares, Marta C; Paula, José R; Bshary, Redouan

2016-09-01

Animals use learning and memorizing to gather information that will help them to make ecologically relevant decisions. Neuro-modulatory adjustments enable them to make associations between stimuli and appropriate behavior. A key candidate for the modulation of cooperative behavior is serotonin. Previous research has shown that modulation of the serotonergic system spontaneously affects the behavior of the cleaner wrasse Labroides dimidiatus during interactions with so-called 'client' reef fish. Here, we asked whether shifts in serotonin function affect the cleaners' associative learning abilities when faced with the task to distinguish two artificial clients that differ in their value as a food source. We found that the administration of serotonin 1A receptor antagonist significantly slowed learning speed in comparison with saline treated fish. As reduced serotonergic signaling typically enhances fear, we discuss the possibility that serotonin may affect how cleaners appraise, acquire information and respond to client-derived stimuli via manipulation of the perception of danger.

The Role of Hippocampal 5HT3 Receptors in Harmaline-Induced Memory Deficit

Directory of Open Access Journals (Sweden)

Mohammad Nasehi

2015-07-01

Full Text Available Introduction: The plethora of studies indicated that there is a cross talk relationship between harmaline and serotonergic (5-HT system on cognitive and non-cognitive behaviors. Thus, the purpose of this study is to assess the effects of hippocampal 5-HT4 receptor on memory acquisition deficit induced by harmaline.  Methods: Harmaline was injected peritoneally, while 5-HT4 receptor agonist (RS67333 and antagonist (RS23597-190 were injected intra-hippocampal. A single-trial step-down passive avoidance, open field and tail flick tasks were used for measurement of memory, locomotor activity and pain responses, respectively.  Results: The data revealed that pre-training injection of higher dose of harmaline (1 mg/kg, RS67333 (0.5 ng/mouse and RS23597-190 (0.5 ng/mouse decreased memory acquisition process in the adult mice. Moreover, concurrent pre-training administration of subthreshold dose of RS67333 (0.005 ng/mouse or RS23597-190 (0.005 ng/mouse with subthreshold dose of harmaline (0.5 mg/kg, i.p. intensify impairment of memory acquisition. All above interventions did not change locomotion and tail flick behaviors.  Discussion: The results demonstrated that the synergistic effect between both hippocampal 5-HT4 receptor agonist and antagonist with impairment of memory acquisition induced by harmaline, indicating a modulatory effect for hippocampal 5HT4 receptor on Harmaline induced amnesia.

A relevância das células natural killer (NK e killer immunoglobulin-like receptors (KIR no transplante de células-tronco hematopoéticas (TCTH The relevance of natural killer (NK cells and killer immunoglobulin-like receptors (KIR in hematopoietic stem cell transplantation (HSCT

Directory of Open Access Journals (Sweden)

Aline Almeida-Oliveira

2008-08-01

Full Text Available As células natural killer (NK foram identificadas há mais de 30 anos por sua capacidade de matar células tumorais e infectadas por vírus sem precisar de sensibilização prévia. No entanto, a forma como as células NK matam seus alvos ficou desconhecida por muito tempo. Na década de 90, a partir de várias observações, foi proposto que as células NK matariam células com a expressão diminuída de antígeno leucocitário humano (HLA, protegendo as células autólogas normais, o que ficou conhecido como hipótese do missing-self. Esta teoria foi confirmada através da descoberta de vários receptores, principalmente os da família killer immunoglobulin-like receptors (KIR, que reconhecem moléculas de HLA de classe I. Estes novos conceitos levaram à busca da importância dos receptores KIR no transplante de células-tronco hematopoéticas (TCTH. Foi sugerido que as disparidades de HLA entre o doador e o paciente poderiam ser reconhecidas por células NK levando à aloreatividade, o que ajudaria no efeito enxerto contra leucemia. No entanto, apesar de alguns resultados promissores, até hoje, os diferentes estudos sobre o assunto não chegaram a um consenso. Nesta revisão, será abordada a relevância das células NK e dos receptores KIR nos diferentes tipos de TCTH.Natural killer (NK cells were identified over 30 years ago by their ability to kill cancer and virally infected cells without prior sensitization. For years the recognition mechanisms of target cells were unknown, until the 1990s when the "missing-self" hypothesis was proposed. According to this theory, although tolerant to normal autologous cells, NK cells can recognize and attack cells that have down-regulated human leukocyte antigen (HLA class I molecules. The discovery of killer immunoglobulin-like receptors (KIR that specifically recognize HLA class I molecules corroborated this hypothesis. These new concepts point to the importance of studying KIR in hematopoietic stem

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Science.gov (United States)

Croonenberghs, J; Delmeire, L; Verkerk, R; Lin, A H; Meskal, A; Neels, H; Van der Planken, M; Scharpe, S; Deboutte, D; Pison, G; Maes, M

2000-03-01

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

Influence of the 5-HT3A Receptor Gene Polymorphism and Childhood Sexual Trauma on Central Serotonin Activity.

Directory of Open Access Journals (Sweden)

Kuk-In Jang

Full Text Available Gene-environment interactions are important for understanding alterations in human brain function. The loudness dependence of auditory evoked potential (LDAEP is known to reflect central serotonergic activity. Single nucleotide polymorphisms (SNPs in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders. This study aimed to investigate the effect between 5-HT3A receptor gene polymorphisms and childhood sexual trauma on the LDAEP as an electrophysiological marker in healthy subjects.A total of 206 healthy subjects were recruited and evaluated using the childhood trauma questionnaire (CTQ and hospital anxiety and depression scale (HADS. Peak-to-peak N1/P2 was measured at five stimulus intensities, and the LDAEP was calculated as the linear-regression slope. In addition, the rs1062613 SNPs of 5-HT3A (CC, CT, and TT were analyzed in healthy subjects.There was a significant interaction between scores on the CTQ-sexual abuse subscale and 5-HT3A genotype on the LDAEP. Subjects with the CC polymorphism had a significantly higher LDEAP than T carriers in the sexually abused group. In addition, CC genotype subjects in the sexually abused group showed a significantly higher LDAEP compared with CC genotype subjects in the non-sexually abused group.Our findings suggest that people with the CC polymorphism of the 5-HT3A gene have a greater risk of developing mental health problems if they have experienced childhood sexual abuse, possibly due to low central serotonin activity. Conversely, the T polymorphism may be protective against any central serotonergic changes following childhood sexual trauma.

Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with {sup 99m}Tc-ECD and {sup 123}I-5-I-R91150

Energy Technology Data Exchange (ETDEWEB)

Peremans, Kathelijne; Coopman, Frank; Verschooten, Francis; Bree, Henri van [Department of Medical Imaging, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke (Belgium); Audenaert, Kurt; Heeringen, Kees van [Department of Psychiatry and Medical Psychology, Faculty of Medicine, Ghent University Hospital (Belgium); Blanckaert, Peter; Slegers, Guido [Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University (Belgium); Jacobs, Filip; Otte, Andreas; Dierckx, Rudi [Division of Nuclear Medicine, Ghent University Hospital (Belgium); Mertens, John [VUB-Cyclotron, Brussels (Belgium)

2003-11-01

Impulsive aggression in dogs has an important impact on human public health. Better insight into the pathophysiology of this phenomenon could lead to more adequate diagnosis and treatment. Indirect in vivo research on peripheral body fluids and post-mortem studies in impulsive animals and humans indicate a deficient serotonergic system in general and disturbances in the serotonin-2A (5-HT2A) receptor in particular. In this study, brain perfusion and the 5-HT2A receptors were examined in impulsive, aggressive dogs, in comparison with a group of normally behaving animals. In order to decide which dogs to include in this study, owners were asked to describe the general behaviour of the dogs, the circumstances in which aggression occurred and their conduct during aggressive acts. Finally, 19 dogs were retained for this study, showing, according to different behavioural specialists, disinhibited dominance aggression. Functional imaging studies were performed on all these dogs. Single-photon emission tomography (SPET) was used to measure regional brain perfusion using technetium-99m labelled ethyl cysteinate dimer (ECD). The 5-HT2A receptor binding properties were investigated using the selective radioligand iodine-123 labelled 5-I-R91150. A significant increase in uptake of the 5-HT2A radioligand was noted in all cortical areas. No significant alterations were found in regional cortical perfusion, indicating that the increased binding index was not a consequence of increased tracer delivery. This study supports a role for the serotonergic system in canine impulsive aggression. (orig.)

Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection.

Science.gov (United States)

Mann, T; Zilles, K; Dikow, H; Hellfritsch, A; Cremer, M; Piel, M; Rösch, F; Hawlitschka, A; Schmitt, O; Wree, A

2018-03-15

Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that causes a dopamine (DA) deficit in the caudate-putamen (CPu) accompanied by compensatory changes in other neurotransmitter systems. These changes result in severe motor and non-motor symptoms. To disclose the role of various receptor binding sites for DA, noradrenaline, and serotonin in the hemiparkinsonian (hemi-PD) rat model induced by unilateral 6-hydroxydopamine (6-OHDA) injection, the densities of D 1 , D 2 /D 3 , α 1 , α 2 , and 5HT 2A receptors were longitudinally visualized and measured in the CPu of hemi-PD rats by quantitative in vitro receptor autoradiography. We found a moderate increase in D 1 receptor density 3 weeks post lesion that decreased during longer survival times, a significant increase of D 2 /D 3 receptor density, and 50% reduction in 5HT 2A receptor density. α 1 receptor density remained unaltered in hemi-PD and α 2 receptors demonstrated a slight right-left difference increasing with post lesion survival. In a second step, the possible role of receptors on the known reduction of apomorphine-induced rotations in hemi-PD rats by intrastriatally injected Botulinum neurotoxin-A (BoNT-A) was analyzed by measuring the receptor densities after BoNT-A injection. The application of this neurotoxin reduced D 2 /D 3 receptor density, whereas the other receptors mainly remained unaltered. Our results provide novel data for an understanding of the postlesional plasticity of dopaminergic, noradrenergic and serotonergic receptors in the hemi-PD rat model. The results further suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing the interhemispheric imbalance in D 2 /D 3 receptor density. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

The upright posture improves plantar stepping and alters responses to serotonergic drugs in spinal rats.

Science.gov (United States)

Sławińska, Urszula; Majczyński, Henryk; Dai, Yue; Jordan, Larry M

2012-04-01

Recent studies on the restoration of locomotion after spinal cord injury have employed robotic means of positioning rats above a treadmill such that the animals are held in an upright posture and engage in bipedal locomotor activity. However, the impact of the upright posture alone, which alters hindlimb loading, an important variable in locomotor control, has not been examined. Here we compared the locomotor capabilities of chronic spinal rats when placed in the horizontal and upright postures. Hindlimb locomotor movements induced by exteroceptive stimulation (tail pinching) were monitored with video and EMG recordings. We found that the upright posture alone significantly improved plantar stepping. Locomotor trials using anaesthesia of the paws and air stepping demonstrated that the cutaneous receptors of the paws are responsible for the improved plantar stepping observed when the animals are placed in the upright posture.We also tested the effectiveness of serotonergic drugs that facilitate locomotor activity in spinal rats in both the horizontal and upright postures. Quipazine and (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) improved locomotion in the horizontal posture but in the upright posture either interfered with or had no effect on plantar walking. Combined treatment with quipazine and 8-OH-DPAT at lower doses dramatically improved locomotor activity in both postures and mitigated the need to activate the locomotor CPG with exteroceptive stimulation. Our results suggest that afferent input from the paw facilitates the spinal CPG for locomotion. These potent effects of afferent input from the paw should be taken into account when interpreting the results obtained with rats in an upright posture and when designing interventions for restoration of locomotion after spinal cord injury.

Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals.

Science.gov (United States)

Challet, E; Turek, F W; Laute, M; Van Reeth, O

2001-08-03

The circadian pacemaker in the suprachiasmatic nuclei is primarily synchronized to the daily light-dark cycle. The phase-shifting and synchronizing effects of light can be modulated by non-photic factors, such as behavioral, metabolic or serotonergic cues. The present experiments examine the effects of sleep deprivation on the response of the circadian pacemaker to light and test the possible involvement of serotonergic and/or metabolic cues in mediating the effects of sleep deprivation. Photic phase-shifting of the locomotor activity rhythm was analyzed in mice transferred from a light-dark cycle to constant darkness, and sleep-deprived for 8 h from Zeitgeber Time 6 to Zeitgeber Time 14. Phase-delays in response to a 10-min light pulse at Zeitgeber Time 14 were reduced by 30% in sleep-deprived mice compared to control mice, while sleep deprivation without light exposure induced no significant phase-shifts. Stimulation of serotonin neurotransmission by fluoxetine (10 mg/kg), a serotonin reuptake inhibitor that decreases light-induced phase-delays in non-deprived mice, did not further reduce light-induced phase-delays in sleep-deprived mice. Impairment of serotonin neurotransmission with p-chloroamphetamine (three injections of 10 mg/kg), which did not increase light-induced phase-delays in non-deprived mice significantly, partially normalized light-induced phase-delays in sleep-deprived mice. Injections of glucose increased light-induced phase-delays in control and sleep-deprived mice. Chemical damage of the ventromedial hypothalamus by gold-thioglucose (600 mg/kg) prevented the reduction of light-induced phase-delays in sleep-deprived mice, without altering phase-delays in control mice. Taken together, the present results indicate that sleep deprivation can reduce the light-induced phase-shifts of the mouse suprachiasmatic pacemaker, due to serotonergic and metabolic changes associated with the loss of sleep.

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

Science.gov (United States)

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

Science.gov (United States)

Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Toll-like Receptor 4: Innate Immune Regulator of Neuroimmune and Neuroendocrine interactions in Stress and Major Depressive Disorder

Directory of Open Access Journals (Sweden)

Jiajun eLiu

2014-09-01

Full Text Available Major depressive disorder (MDD poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behaviour similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signalling, the main question becomes: What is the role of the innate immune system in MDD?The current review presents evidence that toll-like receptor 4 (TLR4, via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4 – related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD. Therefore, apart from exogenous pathogenic mechanisms, TLR4 is involved in immune changes as a result of endogenous stress signals, playing an integral part in the pathophysiology, and could be a potential target for pharmacological treatments to improve current interventions for MDD.

Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia

NARCIS (Netherlands)

Bousema, J. T.; Bussemakers, M. J.; van Houwelingen, K. P.; Debruyne, F. M.; Verbeek, A. L.; de la Rosette, J. J.; Kiemeney, L. A.

2000-01-01

Little is known about risk factors for the development of benign prostatic hyperplasia (BPH). Recently, associations were observed between prostate cancer (CaP) risk and polymorphisms in the vitamin D receptor (VDR) gene and the androgen receptor (AR) gene. Since both receptors are relevant for

The MC4 receptor and control of appetite

NARCIS (Netherlands)

Adan, R. A. H.; Tiesjema, B.; Hillebrand, J. J. G.; La Fleur, S. E.; Kas, M. J. H.; de Krom, M.

2006-01-01

Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor

Genistein alleviates anxiety-like behaviors in post-traumatic stress disorder model through enhancing serotonergic transmission in the amygdala.

Science.gov (United States)

Wu, Zhong-Min; Ni, Gui-Lian; Shao, Ai-Min; Cui, Rong

2017-09-01

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder, characterized by intense fear, and increased arousal and avoidance of traumatic events. The current available treatments for PTSD have limited therapeutic value. Genistein, a natural isoflavone, modulates a variety of cell functions. In this study, we tested anti-anxiety activity and underlying mechanisms of genistein in a PTSD rat model. The rats were trained to associate a tone with foot shock delivery on day 0, then fear conditioning was performed on day 7, 14 and 21. Genistein (2-8mg/kg) was injected intraperitoneally daily for 7 days. The anti-anxiety effects of genistein were measured by contextual freezing behavior and elevated plus maze. By the end of the experiments, the amygdala was extracted and subject to neurochemistry analysis. Genistein alleviated contextual freezing behavior and improved performance in elevated plus maze dose-dependently in PTSD rats. Furthermore, in these rats, genistein enhanced serotonergic transmission in the amygdala, including upregulation of tryptophan hydroxylase, serotonin, and phosphorylated (p)-CaMKII and p-CREB, as well. Genistein exerts anti-anxiety effects on a PTSD model probably through enhancing serotonergic system and CaMKII/CREB signaling pathway in the amygdala. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Ventilatory response to hypercapnia and hypoxia after extensive lesion of medullary serotonergic neurons in newborn conscious piglets.

Science.gov (United States)

Penatti, E M; Berniker, A V; Kereshi, B; Cafaro, C; Kelly, M L; Niblock, M M; Gao, H G; Kinney, H C; Li, A; Nattie, E E

2006-10-01

Acute inhibition of serotonergic (5-HT) neurons in the medullary raphé (MR) using a 5-HT(1A) receptor agonist had an age-dependent impact on the "CO(2) response" of piglets (33). Our present study explored the effect of chronic 5-HT neuron lesions in the MR and extra-raphé on the ventilatory response to hypercapnia and hypoxia in piglets, with possible implications on the role of 5-HT in the sudden infant death syndrome. We established four experimental groups. Group 1 (n = 11) did not undergo any treatment. Groups 2, 3, and 4 were injected with either vehicle or the neurotoxin 5,7-dihydroxytryptamine in the cisterna magna during the first week of life (group 2, n = 9; group 4, n = 11) or second week of life (group 3, n = 10). Ventilation was recorded in response to 5% CO(2) (all groups) and 12% O(2) (group 2) during wakefulness and sleep up to postnatal day 25. Surprisingly, the piglets did not reveal changes in their CO(2) sensitivity during early postnatal development. Overall, considerable lesions of 5-HT neurons (up to 65% decrease) in the MR and extra-raphé had no impact on the CO(2) response, regardless of injection time. Postlesion raphé plasticity could explain why we observed no effect. 5,7-Dihydroxytryptamine-treated males, however, did present a lower CO(2) response during sleep. Hypoxia significantly altered the frequency during sleep in lesioned piglets. Further studies are necessary to elucidate the role of plasticity, sex, and 5-HT abnormalities in sudden infant death syndrome.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Directory of Open Access Journals (Sweden)

Dolphin Annette C

2009-08-01

descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in α2δ-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement

Science.gov (United States)

Rashid, Mohammed; Ribeiro, Paula

2014-01-01

Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni. PMID:24453972

Altered brain serotonergic neurotransmission following caffeine withdrawal produces behavioral deficits in rats.

Science.gov (United States)

Khaliq, Saima; Haider, Saida; Naqvi, Faizan; Perveen, Tahira; Saleem, Sadia; Haleem, Darakhshan Jabeen

2012-01-01

Caffeine administration has been shown to enhance performance and memory in rodents and humans while its withdrawal on the other hand produces neurobehavioral deficits which are thought to be mediated by alterations in monoamines neurotransmission. A role of decreased brain 5-HT (5-hydroxytryptamine, serotonin) levels has been implicated in impaired cognitive performance and depression. Memory functions of rats were assessed by Water Maze (WM) and immobility time by Forced Swim Test (FST). The results of this study showed that repeated caffeine administration for 6 days at 30 mg/kg dose significantly increases brain 5-HT (pcaffeine. Withdrawal of caffeine however produced memory deficits and significantly increases the immobility time of rats in FST. The results of this study are linked with caffeine induced alterations in serotonergic neurotransmission and its role in memory and depression.

Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer.

Science.gov (United States)

Maughan, Benjamin L; Antonarakis, Emmanuel S

2015-12-01

Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics.

Science.gov (United States)

Tonini, M; Cipollina, L; Poluzzi, E; Crema, F; Corazza, G R; De Ponti, F

2004-02-15

Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the

MS-377, a selective sigma receptor ligand, indirectly blocks the action of PCP in the N-methyl-D-aspartate receptor ion-channel complex in primary cultured rat neuronal cells.

Science.gov (United States)

Karasawa, Jun-ichi; Yamamoto, Hideko; Yamamoto, Toshifumi; Sagi, Naoki; Horikomi, Kazutoshi; Sora, Ichiro

2002-02-22

MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.

Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

International Nuclear Information System (INIS)

Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

1996-01-01

In vivo pharmacokinetic and brain binding characteristics of [ 18 F]RP 62203, a selective high-affinity serotonergic 5-HT 2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 ± 0.07% injected dose/g, % ID/g and 0.08 ± 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT 2A receptor. Furthermore, specific [ 18 F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT 2A receptors, but not with known concentration profiles of dopaminergic D 2 or adrenergic α 1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT 2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [ 18 F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT 2A brain receptors in vivo with positron emission tomography

In vivo and in vitro studies on the potentiation of muscarinic receptor stimulation by alaproclate, a selective 5-HT uptake blocker

International Nuclear Information System (INIS)

Oegren, S.O.; Nordstroem, Oe.; Danielsson, E.; Peterson, L.-L.; Bartfai, T.

1985-01-01

Alaproclate (10-60 mg/kg) injected i.p. into male mice potentiated and prolonged the oxotremorine and physostigmine-induced tremor in a dosedependent manner. Atropine completely blocked the tremor caused by oxotremorine or physostigmine both in the presence and absence of alaproclate. Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate. Biochemical studies indicated that the above effects cannot be explained by assuming that alaproclate a) acts as a cholinergic agonist, b) inhibits the acetylcholine esterase, c) interferes with choline uptake or acetylcholine synthesis, or d) directly potentiates the release of acetylcholine. In ligand binding studies alaproclate was found to be a weak competitive inhibitor of muscarinic antagonist binding to membranes from the rat cerebral cortex, rat striatum, human cerebral cortex and human striatum. (Ksub(i) approximately 28-40 μM in all four tissues). The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the muscarinic cholinergic receptors. (Author)

In vivo and in vitro studies on the potentiation of muscarinic receptor stimulation by alaproclate, a selective 5-HT uptake blocker

Energy Technology Data Exchange (ETDEWEB)

Oegren, S.O. (Astra Pharmaceuticals AB, Soedertaelje (Sweden)); Nordstroem, Oe.; Danielsson, E.; Peterson, L.L.; Bartfai, T.

1985-01-01

Alaproclate (10-60 mg/kg) injected i.p. into male mice potentiated and prolonged the oxotremorine and physostigmine-induced tremor in a dose dependent manner. Atropine completely blocked the tremor caused by oxotremorine or physostigmine both in the presence and absence of alaproclate. Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate. Biochemical studies indicated that the above effects cannot be explained by assuming that alaproclate a) acts as a cholinergic agonist, b) inhibits the acetylcholine esterase, c) interferes with choline uptake or acetylcholine synthesis, or d) directly potentiates the release of acetylcholine. In ligand binding studies alaproclate was found to be a weak competitive inhibitor of muscarinic antagonist binding to membranes from the rat cerebral cortex, rat striatum, human cerebral cortex and human striatum. (Ksub(i) approximately 28-40 ..mu..M in all four tissues). The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the muscarinic cholinergic receptors.

Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain

Science.gov (United States)

Maheux, Jérôme; Vuillier, Laura; Mahfouz, Mylène; Rouillard, Claude; Lévesque, Daniel

2015-01-01

Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT1A and 5-HT2A/2C, and α1- and α2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT2A/2C agonist, MDL11939, a 5-HT2A antagonist, 8-OH-DPAT, a 5-HT1A agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT2A/2C agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs. PMID:21524335

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Directory of Open Access Journals (Sweden)

Min Seong Kwon

2015-03-01

Full Text Available Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH, and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4-mediated nuclear factor κB (NFκB in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb, heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα, from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.

Adenosine Receptors in Developing and Adult Mouse Neuromuscular Junctions and Functional Links With Other Metabotropic Receptor Pathways.

Science.gov (United States)

Tomàs, Josep; Garcia, Neus; Lanuza, Maria A; Santafé, Manel M; Tomàs, Marta; Nadal, Laura; Hurtado, Erica; Simó-Ollé, Anna; Cilleros-Mañé, Víctor; Just-Borràs, Laia

2018-01-01

In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR) in the mammalian neuromuscular junction (NMJ). Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse (nerve, muscle, and glial cells) cross the extracellular cleft to generate signals in target metabotropic receptors. Thus, the integrated interpretation of the complementary function of all these receptors is needed. We previously studied, in the NMJ, the links of AR with mAChR and the neurotrophin receptor TrkB in the control of synapse elimination and transmitter release. We conclude that AR cooperate with these receptors through synergistic and antagonistic effects in the developmental synapse elimination process. In the adult NMJ, this cooperation is manifested so as that the functional integrity of a given receptor group depends on the other receptors operating normally (i.e., the functional integrity of mAChR depends on AR operating normally). These observations underlie the relevance of AR in the NMJ function.

Adenosine Receptors in Developing and Adult Mouse Neuromuscular Junctions and Functional Links With Other Metabotropic Receptor Pathways

Directory of Open Access Journals (Sweden)

Josep Tomàs

2018-04-01

Full Text Available In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR in the mammalian neuromuscular junction (NMJ. Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse (nerve, muscle, and glial cells cross the extracellular cleft to generate signals in target metabotropic receptors. Thus, the integrated interpretation of the complementary function of all these receptors is needed. We previously studied, in the NMJ, the links of AR with mAChR and the neurotrophin receptor TrkB in the control of synapse elimination and transmitter release. We conclude that AR cooperate with these receptors through synergistic and antagonistic effects in the developmental synapse elimination process. In the adult NMJ, this cooperation is manifested so as that the functional integrity of a given receptor group depends on the other receptors operating normally (i.e., the functional integrity of mAChR depends on AR operating normally. These observations underlie the relevance of AR in the NMJ function.

The claustrum’s proposed role in consciousness is supported by the effect and target localization of Salvia Divinorum

Directory of Open Access Journals (Sweden)

Klaus M Stiefel

2014-02-01

Full Text Available This article brings together three findings and ideas relevant for the understanding of human consciousness: (I Crick's and Koch's theory that the claustrum is a conductor of consciousness center crucial for subjective conscious experience. (II Subjective reports of the consciousness-altering effects the plant Salvia divinorum, whose primary active ingredient is salvinorin A, a -opioid receptor agonist. (III The high density of -opioid receptors in the claustrum. Fact III suggests that the consciousness-altering effects of salvinorin A are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the cortex, mainly in prefrontal areas. Consistent with Crick & Koch’s theory that the claustrum plays a key role in consciousness, our analysis of the subjective effects of Salvia divinorum finds that salvia disrupts certain facets of consciousness much more than the largely-serotonergic hallucinogen LSD. Based on this data and on the relevant literature, we suggest that the claustrum does indeed serve as a conductor for certain aspects of higher-order integration of brain activity, while integration of auditory and visual signals mostly relies on coordination by other areas including parietal cortex and the pulvinar.

Receptor imaging of schizophrenic patients under treatment with typical and atypical neuroleptics

International Nuclear Information System (INIS)

Dresel, S.; Tatsch, K.; Meisenzahl, E.; Scherer, J.

2002-01-01

Schizophrenic psychosis is typically treated by typical and atypical neuroleptics. Both groups of drugs differ with regard to induction of extrapyramidal side effects. The occupancy of postsynaptic dopaminergic D2 receptors is considered to be an essential aspect of their antipsychotic properties. The dopamine D2 receptor status can be assessed by means of [I-123]IBZM SPECT. Studies on the typical neuroleptic haloperidol revealed an exponential dose response relationship measured by IBZM. Extrapyramidal side effects were presented by all patients below a threshold of the specific binding of IBZM below 0.4 (with one exception, norm value: >0.95). Also under treatment with the atypical neuroleptic clozapine an exponential dose response relationship was found. However, none of these patients showed extrapyramidal side effects. Recently introduced, new atypical neuroleptics such as risperidone and olanzapine again presented with an exponential relationship between daily dose and IBZM binding. The curves of the latter were in between the curves of haloperidol and clozapine. Extrapyramidal side effects were documented in a less number of patients treated with risperidone as compared to haloperidol, for olanzapine only one patient revealed these findings in our own patient group. The pharmacological profile of atypical neuroleptics shows - in addition to their binding to dopamine receptors - also high affinities to the receptors of other neurotransmitter systems, particularly the serotonergic system. Therefore, the lower incidence of extrapyramidal side effects seen by atypical in comparison to typical neuroleptics is at least in part most likely due to a complex interaction on a variety of neurotransmitter systems. (orig.) [de

5-HT_2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

DEFF Research Database (Denmark)

Klein, A B; Ultved, L; Adamsen, D

2014-01-01

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat st...... difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction....

Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease

Science.gov (United States)

Sagredo, Onintza; González, Sara; Aroyo, Ilia; Pazos, María Ruth; Benito, Cristina; Lastres-Becker, Isabel; Romero, Juan P.; Tolón, Rosa M.; Mechoulam, Raphael; Brouillet, Emmanuel; Romero, Julián; Fernández-Ruiz, Javier

2009-01-01

Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington’s disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB2 receptors were capable of protecting striatal projection neurons from malonate-induced death. That CB2 receptor agonists are neuroprotective was confirmed by using the selective CB2 receptor antagonist, SR144528, and by the observation that mice deficient in CB2 receptor were more sensitive to malonate than wild-type animals. CB2 receptors are scarce in the striatum in healthy conditions but they are markedly up-regulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB2 receptors in cells labelled with the marker of reactive microglia OX-42, and also in cells labelled with GFAP (a marker of astrocytes). We further showed that the activation of CB2 receptors significantly reduced the levels of tumor necrosis factor-α (TNF-α) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2 receptors would be up-regulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-α. Altogether our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. PMID:19115380

Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone

DEFF Research Database (Denmark)

D'Amico, Jessica M; Butler, Annie A; Héroux, Martin E

2017-01-01

that activation of 5-HT1Areceptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones. ABSTRACT: Intense serotonergic drive in the turtle spinal cord results in serotonin...... motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise....

Specific in vivo binding in the rat brain of [{sup 18}F]RP 62203: A selective 5-HT{sub 2A} receptor radioligand for positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

1996-02-01

In vivo pharmacokinetic and brain binding characteristics of [{sup 18}F]RP 62203, a selective high-affinity serotonergic 5-HT{sub 2A} receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 {+-} 0.07% injected dose/g, % ID/g and 0.08 {+-} 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT{sub 2A} receptor. Furthermore, specific [{sup 18}F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT{sub 2A} receptors, but not with known concentration profiles of dopaminergic D{sub 2} or adrenergic {alpha}{sub 1} receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT{sub 2A} antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [{sup 18}F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT{sub 2A} brain receptors in vivo with positron emission tomography.

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

Directory of Open Access Journals (Sweden)

Junlin eZhang

2013-05-01

Full Text Available Manipulation of serotonin (5HT during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM. Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days, OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs, these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals

DEFF Research Database (Denmark)

da Cunha-Bang, Sophie; Stenbæk, Dea Siggaard; Holst, Klaus

2013-01-01

age 47.0±18.7, range 23-86) to determine if trait aggression and trait impulsivity were related to frontal cortex 5-HT2A receptor binding (5-HT2AR) as measured with [(18)F]-altanserin PET imaging. Trait aggression and trait impulsivity were assessed with the Buss-Perry Aggression Questionnaire (AQ...... and the AQ or BIS-11 total scores. Also, there was no significant interaction between gender and frontal cortex 5-HT2AR in predicting trait aggression and trait impulsivity. This is the first study to examine how 5-HT2AR relates to trait aggression and trait impulsivity in a large sample of healthy......Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved. We investigated 94 healthy individuals (60 men, mean...

Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract.

Science.gov (United States)

Abe, Masayuki; Ito, Yoshihiko; Oyunzul, Luvsandorj; Oki-Fujino, Tomomi; Yamada, Shizuo

2009-04-01

Saw palmetto extract (SPE), used widely for the treatment of benign prostatic hyperplasia (BPH) has been shown to bind alpha(1)-adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. Major constituents of SPE are lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. The aim of this study was to investigate binding affinities of these fatty acids for pharmacologically relevant (alpha(1)-adrenergic, muscarinic and 1,4-DHP) receptors. The fatty acids inhibited specific [(3)H]prazosin binding in rat brain in a concentration-dependent manner with IC(50) values of 23.8 to 136 microg/ml, and specific (+)-[(3)H]PN 200-110 binding with IC(50) values of 24.5 to 79.5 microg/ml. Also, lauric acid, oleic acid, myristic acid and linoleic acid inhibited specific [(3)H]N-methylscopolamine ([(3)H]NMS) binding in rat brain with IC(50) values of 56.4 to 169 microg/ml. Palmitic acid had no effect on specific [(3)H]NMS binding. The affinity of oleic acid, myristic acid and linoleic acid for each receptor was greater than the affinity of SPE. Scatchard analysis revealed that oleic acid and lauric acid caused a significant decrease in the maximal number of binding sites (B(max)) for [(3)H]prazosin, [(3)H]NMS and (+)-[(3)H]PN 200-110. The results suggest that lauric acid and oleic acid bind noncompetitively to alpha(1)-adrenergic, muscarinic and 1,4-DHP calcium channel antagonist receptors. We developed a novel and convenient method of determining 5alpha-reductase activity using LC/MS. With this method, SPE was shown to inhibit 5alpha-reductase activity in rat liver with an IC(50) of 101 microg/ml. Similarly, all the fatty acids except palmitic acid inhibited 5alpha-reductase activity, with IC(50) values of 42.1 to 67.6 microg/ml. In conclusion, lauric acid, oleic acid, myristic acid, and linoleic acid, major constituents of SPE, exerted binding activities of alpha(1)-adrenergic, muscarinic and 1,4-DHP receptors and inhibited 5

Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

OpenAIRE

Hayashizaki, Seiji; Hirai, Shinobu; Ito, Yumi; Honda, Yoshiko; Arime, Yosefu; Sora, Ichiro; Okado, Haruo; Kodama, Tohru; Takada, Masahiko

2013-01-01

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization.

Science.gov (United States)

Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N; Leonard, Christopher S

2016-09-28

Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca(2+) release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca(2+) influx and Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

Neurobiology of D-1 dopamine receptors after neonatal-6-OHDA treatment: Relevance to Lesch-Nyhan disease

International Nuclear Information System (INIS)

Breese, G.R.; Duncan, G.E.; Mueller, R.A.; Napier, T.C.

1986-01-01

In the present work, experiments with neonatally and adult-6-OHDA-lesioned rats are described which examine the pharmacology of agonists and antagonists with specificity for D 1 and D 2 dopamine receptors. This work permits conclusions concerning the role of D 1 -dopamine receptors in behavior, about the interaction of D 1 receptors with D 2 -dopamine receptors, and about the importance of D 1 -dopamine receptors for the self-mutilation behavior (SMB) observed in rats treated neonatally with 6-OHDA when challenged with dopamine agonists as adults. The relationship of these findings to Lesch-Nyhan disease are also discussed

Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

Directory of Open Access Journals (Sweden)

Elizabeth Thomas Cox

2011-06-01

Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

International Nuclear Information System (INIS)

Hill, D.A.

1989-01-01

The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta 2 -adrenergic receptors (AR's) on peripheral blood lymphocytes, via [I 125 ]iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

Science.gov (United States)

Toshchakova, Valentina A.; Bakhtiari, Yalda; Kulikov, Alexander V.; Gusev, Sergey I.; Trofimova, Marina V.; Fedorenko, Olga Yu.; Mikhalitskaya, Ekaterina V.; Popova, Nina K.; Bokhan, Nikolay A.; Hovens, Johannes E.; Loonen, Anton J.M.; Wilffert, Bob; Ivanova, Svetlana A.

2018-01-01

Background Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed. PMID:29621775

The electrophysiological effects of the serotonin 1A receptor agonist buspirone in emotional face processing.

Science.gov (United States)

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

2015-04-01

Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT) receptor agonists impair emotional face processing. However, the specific contribution of the 5-HT1A receptor remains poorly understood. Here we investigated the spatiotemporal brain mechanisms underpinning the modulation of emotional face processing induced by buspirone, a partial 5-HT1A receptor agonist. In a psychophysical discrimination of emotional faces task, we observed that the discrimination fearful versus neutral faces were reduced, but not happy versus neutral faces. Electrical neuroimaging analyses were applied to visual evoked potentials elicited by emotional face images, after placebo and buspirone administration. Buspirone modulated response strength (i.e., global field power) in the interval 230-248ms after stimulus onset. Distributed source estimation over this time interval revealed that buspirone decreased the neural activity in the right dorsolateral prefrontal cortex that was evoked by fearful faces. These results indicate temporal and valence-specific effects of buspirone on the neuronal correlates of emotional face processing. Furthermore, the reduced neural activity in the dorsolateral prefrontal cortex in response to fearful faces suggests a reduced attention to fearful faces. Collectively, these findings provide new insights into the role of 5-HT1A receptors in emotional face processing and have implications for affective disorders that are characterized by an increased attention to negative stimuli. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Opioid regulation of mu receptor internalisation: relevance to the development of tolerance and dependence.

Science.gov (United States)

Lopez-Gimenez, Juan F; Milligan, Graeme

2010-11-01

Internalisation of the mu opioid receptor from the surface of cells is generally achieved by receptor occupancy with agonist ligands of high efficacy. However, in many situations the potent analgesic morphine fails to promote internalisation effectively and whether there is a direct link between this and the propensity for the sustained use of morphine to result in both tolerance and dependence has been studied intensely. Although frequently described as a partial agonist, this characteristic appears insufficient to explain the poor capacity of morphine to promote internalisation of the mu opioid receptor. Experiments performed using both transfected cell systems and ex vivo/in vivo models have provided evidence that when morphine can promote internalisation of the mu receptor there is a decrease in the development of tolerance and dependence. Although aspects of this model are controversial, such observations suggest a number of approaches to further enhance the use of morphine as an analgesic.

Phrenic motor neuron adenosine 2A receptors elicit phrenic motor facilitation.

Science.gov (United States)

Seven, Yasin B; Perim, Raphael R; Hobson, Orinda R; Simon, Alec K; Tadjalli, Arash; Mitchell, Gordon S

2018-04-15

Although adenosine 2A (A 2A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A 2A receptor siRNA injections. A 2A receptor siRNA injections selectively knocked down A 2A receptors in cholera toxin B-subunit-identified phrenic motor neurons, sparing cervical non-phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A 2A receptors relevant to A 2A receptor-induced phrenic motor facilitation. Upregulation of A 2A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury. Cervical spinal adenosine 2A (A 2A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A 2A receptors for pMF are unknown. This is an important question since the physiological outcome of A 2A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A 2A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A 2A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 ± 2%). Intrapleural siRNA injections were used to selectively knock down A 2A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A 2A receptor knock-down was verified by a ∼45% decrease in A 2A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, p

Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors.

Science.gov (United States)

Chipana, C; Camarasa, J; Pubill, D; Escubedo, E

2006-09-01

Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. Previous studies demonstrated the participation of alpha-7 nicotinic receptors (nAChR) in the neurotoxic effect of methamphetamine. The aim of this paper was to study the role of this receptor type in the acute effects and neurotoxicity of MDMA in mice. In vivo, methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist, significantly prevented MDMA-induced neurotoxicity at dopaminergic but not at serotonergic level, without affecting MDMA-induced hyperthermia. Glial activation was also fully prevented by MLA. In vitro, MDMA induced intrasynaptosomal reactive oxygen species (ROS) generation, which was calcium-, nitric-oxide synthase-, and protein kinase C-dependent. Also, the increase in ROS was prevented by MLA and alpha-bungarotoxin. Experiments with reserpine point to endogenous dopamine (DA) as the main source of MDMA-induced ROS. MLA also brought the MDMA-induced inhibition of [3H]DA uptake down, from 73% to 11%. We demonstrate that a coordinated activation of alpha-7 nAChR, blockade of DA transporter function and displacement of DA from intracellular stores induced by MDMA produces a neurotoxic effect that can be prevented by MLA, suggesting that alpha-7 nAChR have a key role in the MDMA neurotoxicity in mice; however, the involvement of nicotinic receptors containing the beta2 subunit cannot be conclusively ruled out.

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.

Serotonergic involvement in stress-induced vasopressin and oxytocin secretion

DEFF Research Database (Denmark)

Jørgensen, Henrik; Knigge, Ulrich; Kjaer, Andreas

2002-01-01

OBJECTIVE: To investigate the involvement of serotonin (5-hydroxytryptamine - 5-HT) receptors in mediation of stress-induced arginine vasopressin (AVP) and oxytocin (OT) secretion in male rats. DESIGN: Experiments on laboratory rats with control groups. METHODS: Different stress paradigms were...... the swim stress-induced OT response. CONCLUSION: 5-HT(2A), 5-HT(2C) and possibly 5-HT(3) and 5-HT(4) receptors, but not 5-HT(1A) receptors, are involved in the restraint stress-induced AVP secretion. 5-HT does not seem to be involved in the dehydration- or hemorrhage-induced AVP response. The restraint...... stress-induced OT response seems to be mediated via 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. The dehydration and hemorrhage-induced OT responses are at least mediated by the 5-HT(2A) and 5-HT(2C) receptors. The 5-HT(3) and 5-HT(4) receptors are not involved in stress-induced OT secretion....

The effect of tryptophan supplemented diets on brain serotonergic activity and plasma cortisol under undisturbed and stressed conditions in grouped-housed Nile tilapia Oreochromis niloticus

DEFF Research Database (Denmark)

Martins, C.I.M.; Silva, P.I.M.; Costas, B.

2013-01-01

-term supplementation with TRP supplemented diets changes brain serotonergic activity and the stress response associated with slaughter handling in grouped-housed Nile tilapia Oreochromis niloticus. Adult fish (n. =. 108, 490.6. ±. 4.0. g, 12 individuals per tank) were exposed to one of the three treatments...

Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats.

Science.gov (United States)

Li, Chen; Kirby, Lynn G

2016-01-01

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Stressors and stress hormones can inhibit the dorsal raphe nucleus (DRN)-5-HT system, which composes the majority of forebrain-projecting 5-HT. This inhibition is mediated via stimulation of GABA synaptic activity at DRN-5-HT neurons. Using swim stress-induced reinstatement of morphine conditioned place-preference, recent data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Moreover, GABAA receptor-mediated inhibition of the serotonergic DRN is required for this reinstatement. In our current experiment, we tested the hypothesis that GABAergic sensitization of DRN-5-HT neurons is a neuroadaptation elicited by multiple classes of abused drugs across multiple models of stress-induced relapse by applying a chemical stressor (yohimbine) to induce reinstatement of previously extinguished cocaine self-administration in Sprague-Dawley rats. Whole-cell patch-clamp recordings of GABA synaptic activity in DRN-5-HT neurons were conducted after the reinstatement. Behavioral data indicate that yohimbine triggered reinstatement of cocaine self-administration. Electrophysiology data indicate that 5-HT neurons in the cocaine group exposed to yohimbine had increased amplitude of inhibitory postsynaptic currents compared to yoked-saline controls exposed to yohimbine or unstressed animals in both drug groups. These data, together with previous findings, indicate that interaction between psychostimulant or opioid history and chemical or physical stressors may increase postsynaptic GABA receptor density and/or sensitivity in DRN-5-HT neurons. Such mechanisms may result in serotonergic hypofunction and consequent dysphoric mood states which confer vulnerability to stress-induced drug reinstatement. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy.

Science.gov (United States)

Choudhury, Sabanum; Borah, Anupom

2015-07-01

Liver diseases lead to a complex syndrome characterized by neurological, neuro-psychiatric and motor complications, called hepatic encephalopathy, which is prevalent in patients and animal models of acute, sub-chronic and chronic liver failure. Although alterations in GABAergic, glutamatergic, cholinergic and serotonergic neuronal functions have been implicated in HE, the molecular mechanisms that lead to HE in chronic liver disease (CLD) is least illustrated. Due to hepatocellular failure, levels of ammonia and homocysteine (Hcy), in addition to others, are found to increase in the brain as well as plasma. Hcy, a non-protein forming amino acid and an excitotoxin, activates ionotropic glutamate (n-methyl-d-aspartate; NMDA) receptors, and thereby leads to influx of Ca(2+) into neurons, which in turn activates several pathways that trigger oxidative stress, inflammation and apoptosis, collectively called excitotoxicity. Elevated levels of Hcy in the plasma and brain, a condition called Hyperhomocysteinemia (HHcy), and the resultant NMDA receptor-mediated excitotoxicity has been implicated in several diseases, including Parkinson's disease and Alzheimer's disease. Although, hyperammonemia has been shown to cause excitotoxicity, the role of HHcy in the development of behavioral and neurochemical alterations that occur in HE has not been illustrated yet. It is hypothesized that CLD-induced HHcy plays a major role in the development of HE through activation of NMDA receptors. It is further hypothesized that HHcy synergizes with hyperammonemia to activate NMDA receptor in the brain, and thereby cause oxidative stress, inflammation and apoptosis, and neuronal loss that leads to HE. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task.

Science.gov (United States)

Meneses, Alfredo

2004-12-06

There is an important debate regarding the functional role of the 5-HT(1A) and 5-HT(7) receptor in memory systems. Hence, the objective of this paper is to investigate the function of serotonin (5-hydroxytryptamine, 5-HT) in memory consolidation, utilising an autoshaping Pavlovian/instrumental learning test. Specific antagonists at 5-HT(1A) (WAY 100635) and 5-HT(7) (SB-269970 or DR 4004) receptors administered i.p. or s.c.) after training, significantly decreased the improvement of performance produced by the 5-HT(1A/7) agonist 8-OH-DPAT to levels lower than controls'. These same antagonists attenuated the decreased level of performance produced by mCPP, although they decrease the performance levels after p-chloroamphetamine (PCA) lesion of the 5-HT system, which has no effect on its own on the conditioned response. Moreover, SB-269970 or DR 4004 reversed amnesia induced by scopolamine and dizocilpine. These data confirm a role for 5-HT(1A) and 5-HT(7) receptors in memory formation and support the hypothesis that serotonergic, cholinergic, and glutamatergic systems interact in cognitively impaired animals. These findings support a potential role for both 5-HT(1A) and 5-HT(7) receptors in the pathophysiology and/or treatment of schizophrenia, cognitive deficits and the mechanism of action of atypical antipsychotic drugs.

The Association between Use of Serotonergic Antidepressants and Perioperative Bleeding during Total Hip Arthroplasty - A Cohort Study

DEFF Research Database (Denmark)

Dall, M.; Primdahl, A.; Damborg, F.

2014-01-01

on the observed blood loss and the need for blood transfusions among this group. We compared the blood loss between users of SA, users of non-serotonergic antidepressants (NSA) and non-users, while adjusting for potential confounders using multivariate linear regression. We indentified 1318 patients...... that underwent a THA in the study period. The average volume of surgical bleeding was 350 ml. The adjusted incremental blood loss associated with use of SA and NSA was 93, 95% confidence interval (38-147) ml and -50 (-125 to 25) ml compared with non-use. Only 48 subjects (3.6%) had transfusions. Use of SA...

Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice

Directory of Open Access Journals (Sweden)

Flóra Gölöncsér

2017-10-01

Full Text Available Serotonergic and glutamatergic neurons of median raphe region (MRR play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7 are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate but not GABA in vivo. Similar optical stimulation (OS significantly increased [3H]5-HT and [3H]glutamate release in acute MRR and hippocampal slices. We examined spatial and temporal patterns of [3H]5-HT release and the interaction between the serotonin and glutamate systems. Whilst [3H]5-HT release from MRR neurons was [Ca2+]o-dependent and sensitive to TTX, CNQX and DL-AP-5, release from hippocampal terminals was not affected by the latter drugs. Hippocampal [3H]5-HT released by electrical but not OS was subject to modulation by 5- HT1B/D receptors agonist sumatriptan (1 μM, whereas the selective 5-HT1A agonist buspirone (0.1 μM was without effect. [3H]5-HT released by electrical and optical stimulation was decreased in mice genetically deficient in P2rx7s, and after perfusion with selective P2rx7 antagonists, JNJ-47965567 (0.1 μM, and AZ-10606120 (0.1 μM. Optical and electrical stimulation elevated the extracellular level of ATP. Our results demonstrate for the

Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry

Directory of Open Access Journals (Sweden)

Ross A. McDevitt

2014-09-01

Full Text Available The dorsal raphe nucleus (DRN contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA. Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.

A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C)

DEFF Research Database (Denmark)

Brasch-Andersen, Charlotte; Møller, Malik U; Christiansen, Lene

2011-01-01

the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin.......047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief...... with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated...

OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding.

Science.gov (United States)

Pittenger, Christopher; Adams, Thomas G; Gallezot, Jean-Dominique; Crowley, Michael J; Nabulsi, Nabeel; James Ropchan; Gao, Hong; Kichuk, Stephen A; Simpson, Ryan; Billingslea, Eileen; Hannestad, Jonas; Bloch, Michael; Mayes, Linda; Bhagwagar, Zubin; Carson, Richard E

2016-05-15

Obsessive-compulsive disorder (OCD) is characterized by impaired sensorimotor gating, as measured using prepulse inhibition (PPI). This effect may be related to abnormalities in the serotonin (5-HT) system. 5-HT1B agonists can impair PPI, produce OCD-like behaviors in animals, and exacerbate OCD symptoms in humans. We measured 5-HT1B receptor availability using (11)C-P943 positron emission tomography (PET) in unmedicated, non-depressed OCD patients (n=12) and matched healthy controls (HC; n=12). Usable PPI data were obtained from 20 of these subjects (10 from each group). There were no significant main effects of OCD diagnosis on 5-HT1B receptor availability ((11)C-P943 BPND); however, the relationship between PPI and (11)C-P943 BPND differed dramatically and significantly between groups. 5-HT1B receptor availability in the basal ganglia and thalamus correlated positively with PPI in controls; these correlations were lost or even reversed in the OCD group. In cortical regions there were no significant correlations with PPI in controls, but widespread positive correlations in OCD patients. Positive correlations between 5-HT1B receptor availability and PPI were consistent across diagnostic groups only in two structures, the orbitofrontal cortex and the amygdala. Differential associations of 5-HT1B receptor availability with PPI in patients suggest functionally important alterations in the serotonergic regulation of cortical/subcortical balance in OCD. Copyright © 2016 Elsevier B.V. All rights reserved.

Pindolol antagonises G-protein activation at both pre- and postsynaptic serotonin 5-HT1A receptors: a.

Science.gov (United States)

Newman-Tancredi, A; Chaput, C; Touzard, M; Millan, M J

2001-04-01

The arylalkylamine, pindolol, may potentiate the clinical actions of antidepressant agents. Although it is thought to act via blockade of 5-HT1A autoreceptors, its efficacy at these sites remains controversial. Herein, we evaluated the actions of pindolol at 5-HT1A autoreceptors and specific populations of postsynaptic 5-HT1A receptors employing [35S]GTPgammaS autoradiography, a measure of receptor-mediated G-protein activation. Both 8-OH-DPAT (1 microM) and 5-HT (10 microM) elicited a pronounced increase in [35S]GTPyS binding in the dorsal raphe nucleus, which contains serotonergic cell bodies bearing 5-HT1A autoreceptors. Pindolol abolished their actions. In the dentate gyrus, lateral septum and entorhinal cortex, structures enriched in postsynaptic 5-HT1A receptors, 8-OH-DPAT (1 microM) and 5-HT (10 microM) also elicited a marked increase in [35S]GTPgammaS binding which was likewise blocked by pindolol. The antagonism of 5-HT-induced [35S]GTPgammaS labelling in the dentate gyrus was shown to be concentration-dependent, yielding a pIC50 of 5.82. Pindolol did not, itself, affect [35S]GTPgammaS binding in any brain region examined. In conclusion, these data suggest that, as characterised by [35S]GTPgammaS autoradiography, and compared with 5-HT and 8-OH-DPAT, pindolol possesses low efficacy at both pre- and postsynaptic 5-HT1A receptors.

Epilepsy, E/I balance and GABAA receptor plasticity

Directory of Open Access Journals (Sweden)

Jean-Marc Fritschy

2008-03-01

Full Text Available GABAA receptors mediate most of the fast inhibitory transmission in the CNS. They form heteromeric complexes assembled from a large family of subunit genes. The existence of multiple GABAA receptor subtypes differing in subunit composition, localization and functional properties underlies their role for fi ne-tuning of neuronal circuits and genesis of network oscillations. The differential regulation of GABAA receptor subtypes represents a major facet of homeostatic synaptic plasticity and contributes to the excitation/inhibition (E/I balance under physiological conditions and upon pathological challenges. The purpose of this review is to discuss recent fi ndings highlighting the signifi cance of GABAA receptor heterogeneity for the concept of E/I balance and its relevance for epilepsy. Specifi cally, we address the following issues: (1 role for tonic inhibition, mediated by extrasynaptic GABAA receptors, for controlling neuronal excitability; (2 signifi cance of chloride ion transport for maintenance of the E/I balance in adult brain; and (3 molecular mechanisms underlying GABAA receptor regulation (traffi cking, posttranslational modifi cation, gene transcription that are important for homoeostatic plasticity. Finally, the relevance of these fi ndings is discussed in light of the involvement of GABAA receptors in epileptic disorders, based on recent experimental studies of temporal lobe epilepsy (TLE and absence seizures and on the identifi cation of mutations in GABAA receptor subunit genes underlying familial forms of epilepsy.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology.

Science.gov (United States)

De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-11-23

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors.

Feeding motivation as a personality trait in Nile tilapia (Oreochromis niloticus): role of serotonergic neurotransmission

DEFF Research Database (Denmark)

Silva, P.I.M.; Martins, C.I.M.; Höglund, Erik

2014-01-01

Consistent individual variation in behaviour and physiology (i.e. animal personality or coping style) has emerged as a central topic in many biological disciplines. Yet, underlying mechanisms of crucial personality traits like feeding behaviour in novel environments remain unclear. Comparative...... to determine to what degree brain 5-hydroxytryptamine (5-HT, serotonin) activity pertains to this aspect of animal personality, as a correlate to feed anticipatory behaviour and recovery of feed intake after transfer to a novel environment. Crucial to the definition of animal personality, a strong degree...... of individual consistency in different measures of feeding behaviour (feeding latency and feeding score), was demonstrated. Furthermore, low serotonergic activity in the hypothalamus was highly correlated with a personality characterized by high feeding motivation, with feeding motivation represented...

Antidepressant-like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems.

Science.gov (United States)

Can, Özgür Devrim; Turan, Nazlı; Demir Özkay, Ümide; Öztürk, Yusuf

2017-12-01

This study was planned to examine the antidepressant potency of gallic acid (30 and 60mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. Administration of gallic acid at 60mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity. The anti-immobility effect observed in the TST was abolished with pre-treatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100mg/kg i.p. administered for 4-consecutive days), ketanserin (a 5-HT2A/2C antagonist; 1mg/kg i.p.), ondansetron (a 5-HT3 antagonist; 0.3mg/kg i.p.), α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100mg/kg i.p.), phentolamine (non-selective alpha-adrenoceptor antagonist; 5mg/kg i.p.), SCH 23390 (a dopamine D1 antagonist; 0.05mg/kg s.c.), and sulpiride (a dopamine D2/D3 antagonist; 50mg/kg i.p.). However, NAN 190 (a 5-HT1A antagonist; 0.5mg/kg i.p.) and propranolol (a non-selective β-adrenoceptor antagonist; 5mg/kg i.p.) pre-treatments were ineffective at reversing the antidepressant-like effects of gallic acid. The results of the present study indicate that gallic acid seems to have a dual mechanism of action by increasing not only serotonin but also catecholamine levels in synaptic clefts of the central nervous system. Further alpha adrenergic, 5-HT2A/2C and 5-HT3 serotonergic, and D1, D2, and D3 dopaminergic receptors also seem to be involved in this antidepressant-like activity. Copyright © 2017 Elsevier Inc. All rights reserved.

Distribution and morphology of cholinergic, putative catecholaminergic and serotonergic neurons in the brain of the Egyptian rousette flying fox, Rousettus aegyptiacus.

Science.gov (United States)

Maseko, Busisiwe C; Bourne, James A; Manger, Paul R

2007-11-01

Over the past decade much controversy has surrounded the hypothesis that the megachiroptera, or megabats, share unique neural characteristics with the primates. These observations, which include similarities in visual pathways, have suggested that the megabats are more closely related to the primates than to the other group of the Chiropteran order, the microbats, and suggests a diphyletic origin of the Chiroptera. To contribute data relevant to this debate, we used immunohistochemical techniques to reveal the architecture of the neuromodulatory systems of the Egyptian rousette (Rousettus aegypticus), an echolocating megabat. Our findings revealed many similarities in the nuclear parcellation of the cholinergic, putative catecholaminergic and serotonergic systems with that seen in other mammals including the microbat. However, there were 11 discrete nuclei forming part of these systems in the brain of the megabat studied that were not evident in an earlier study of a microbat. The occurrence of these nuclei align the megabat studied more closely with primates than any other mammalian group and clearly distinguishes them from the microbat, which aligns with the insectivores. The neural systems investigated are not related to such Chiropteran specializations as echolocation, flight, vision or olfaction. If neural characteristics are considered strong indicators of phylogenetic relationships, then the data of the current study strongly supports the diphyletic origin of Chiroptera and aligns the megabat most closely with primates in agreement with studies of other neural characters.

Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

Directory of Open Access Journals (Sweden)

Tomoko eSoga

2015-11-01

Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without Acetylsalicylic Acid in Major Depressive Disorder.

Science.gov (United States)

Zdanowicz, Nicolas; Reynaert, Christine; Jacques, Denis; Lepiece, Brice; Dubois, Thomas

2017-09-01

Antidepressant medication efficacy remains a major research challenge. Here, we explored four questions: whether noradrenergic antidepressants are more effective than serotonergic antidepressants; whether the addition of 100 mg acetylsalicylic acid (ASA) changes antidepressant efficacy; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA; and whether serum levels of brain-derived neurotrophic factor (BDNF) are clinically informative. In a two-year study, forty people with major depressive disorder were randomly assigned to groups that received an SSRI (escitalopram) or an SNRI (duloxetine), each group received concomitant ASA (100 mg) or a placebo. Sociodemographic data were recorded and patients under went regular assessments with the Hamilton depression scale (HDS) and clinical global impression (CGI) scale. Serum levels of BDNF were measured four times per year. There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA. However, subgroup comparisons revealed that the duloxetine + ASA (DASA) subgroup showed a more rapid improvement in HDS score as early as 2 months (t=-3.114, p=0.01), in CGI score at 5 months (t=-2.119, p=0.05), and a better remission rate (χ 2 =6.296, p 0.012) than the escitalopram + placebo (EP) subgroup. Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup (t=3.713; p=0.002). This suggest two hypotheses: either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone, or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants. Further research is needed to test these hypotheses.

Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

Science.gov (United States)

Barwell, James; Gingell, Joseph J; Watkins, Harriet A; Archbold, Julia K; Poyner, David R; Hay, Debbie L

2012-05-01

The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats.

Science.gov (United States)

Ma, Jingyi; Stan Leung, L

2017-10-01

Decreased GABA B receptor function is proposed to mediate some symptoms of schizophrenia. In this study, we tested the effect of CGP7930, a GABA B receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15 min prior to ketamine (3 mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection. CGP7930 at doses of 1 mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1 mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65-100 Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3 mM/1 μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5 mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1 mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABA B receptor function in vivo. CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.

Implication of 5-HT(2B) receptors in the serotonin syndrome.

Science.gov (United States)

Diaz, Silvina Laura; Maroteaux, Luc

2011-09-01

The serotonin (5-HT) syndrome occurs in humans after antidepressant overdose or combination of drugs inducing a massive increase in extracellular 5-HT. Several 5-HT receptors are known to participate in this syndrome in humans and animal models. The 5-HT(2B) receptor has been proposed as a positive modulator of serotonergic activity, but whether it is involved in 5-HT syndrome has not yet been studied. We analyzed here, a putative role of 5-HT(2B) receptors in this disorder by forced swimming test (FST) and behavioral assessment in the open field. In FST, genetic (5-HT(2B)(-/-) mice) or pharmacological (antagonist RS127445 at 0.5 mg/kg) ablation of 5-HT(2B) receptors facilitated selective 5-HT reuptake inhibitors (SSRI)-induced increase of immobility time as well as expression of other symptoms related to 5-HT syndrome like hind limb abduction and Straub tail. Increase in immobility was also developed in FST by both wild type (WT) and 5-HT(2B)(-/-) mice after the administration of 5-HT(1A), 5-HT(2A) or 5-HT(2C) receptor agonists, 8-OH-DPAT (5 mg/kg), DOI (1 mg/kg), or WAY161503 (5 mg/kg), respectively. In contrast, the 5-HT(2B) receptor agonist BW723C86 (3 mg/kg) or 5-HT(1B) receptor agonist CGS12066A (2 mg/kg) decreased immobility time in both genotypes. The 5-HT syndrome induced by fluoxetine at high doses was blocked in WT and 5-HT(2B)(-/-) mice by administration of 5-HT(1A) and 5-HT(2C) receptor antagonists (WAY100635 0.5 mg/kg and SB242084 0.5 mg/kg) but not by the 5-HT(2A) receptor antagonist MDL100907 (1 mg/kg). By behavioral assessment, we confirmed that 5-HT(2B)(-/-) mice were more prone to develop 5-HT syndrome symptoms after administration of high dose of SSRIs or the 5-HT precursor 5-Hydroxytryptophan, 5-HTP, even if increases in 5-HT plasma levels were similar in both genotypes. This evidence suggests that the presence of 5-HT(2B) receptors hinders acute 5-HT toxicity once high levels of 5-HT are attained. Therefore, differential agonism

Getting a Handle on Neuropharmacology by Targeting Receptor-Associated Proteins.

Science.gov (United States)

Maher, Michael P; Matta, Jose A; Gu, Shenyan; Seierstad, Mark; Bredt, David S

2017-12-06

Targeted therapy for neuropsychiatric disorders requires selective modulation of dysfunctional neuronal pathways. Receptors relevant to CNS disorders typically have associated proteins discretely expressed in specific neuronal pathways; these accessory proteins provide a new dimension for drug discovery. Recent studies show that targeting a TARP auxiliary subunit of AMPA receptors selectively modulates neuronal excitability in specific forebrain pathways relevant to epilepsy. Other medicinally important ion channels, gated by glutamate, γ-aminobutyric acid (GABA), and acetylcholine, also have associated proteins, which may be druggable. This emerging pharmacology of receptor-associated proteins provides a new approach for improving drug efficacy while mitigating side effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Stress and Cognition: the relevance of timing, steroid receptors and sex differences

NARCIS (Netherlands)

Cornelisse, S.

2013-01-01

In response to a stressful situation the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are activated, eventually leading to the release of catecholamines and corticosteroids. These stress hormones bind to different receptors in the brain (in case of corticosteroids,

Diverse roles of extracellular calcium-sensing receptor in the central nervous system

DEFF Research Database (Denmark)

Bandyopadhyay, Sanghamitra; Tfelt-Hansen, Jacob; Chattopadhyay, Naibedya

2010-01-01

The G-protein-coupled calcium-sensing receptor (CaSR), upon activation by Ca(2+) or other physiologically relevant polycationic molecules, performs diverse functions in the brain. The CaSR is widely expressed in the central nervous system (CNS) and is characterized by a robust increase in its...... to astrocytic or neuronal lineages. In adult CNS, CaSR has broad relevance in maintaining local ionic homeostasis. CaSR shares an evolutionary relationship with the metabotropic glutamate receptor and forms heteromeric complexes with the type B-aminobutyric acid receptor subunits that affects its cell surface...

Serotonin and decision making processes.

Science.gov (United States)

Homberg, Judith R

2012-01-01

Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5-HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT(2A) agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT(2A) antagonists and 5-HT(2C) agonists decrease impulsivity. 5-HT(6) antagonists univocally affect decision making processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mode of Action and Human Relevance Analysis for Nuclear Receptor-Mediated Liver Toxicity: A Case Study with Phenobarbital as a Model Constitutive Androstane Receptor (CAR) Activator

Science.gov (United States)

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key nuclear receptors involved in the regulation of cellular responses. to exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non­ genotoxic i...

Pattern of distribution of serotonergic fibers to the amygdala and extended amygdala in the rat.

Science.gov (United States)

Linley, Stephanie B; Olucha-Bordonau, Francisco; Vertes, Robert P

2017-01-01

As is well recognized, serotonergic (5-HT) fibers distribute widely throughout the forebrain, including the amygdala. Although a few reports have examined the 5-HT innervation of select nuclei of the amygdala in the rat, no previous report has described overall 5-HT projections to the amygdala in the rat. Using immunostaining for the serotonin transporter, SERT, we describe the complete pattern of distribution of 5-HT fibers to the amygdala (proper) and to the extended amygdala in the rat. Based on its ontogenetic origins, the amygdala was subdivided into two major parts, pallial and subpallial components, with the pallial component further divided into superficial and deep nuclei (Olucha-Bordonau et al. 2015). SERT + fibers were shown to distributed moderately to densely to the deep and cortical pallial nuclei, but, by contrast, lightly to the subpallial nuclei. Specifically, 1) of the deep pallial nuclei, the lateral, basolateral, and basomedial nuclei contained a very dense concentration of 5-HT fibers; 2) of the cortical pallial nuclei, the anterior cortical and amygdala-cortical transition zone rostrally and the posteromedial and posterolateral nuclei caudally contained a moderate concentration of 5-HT fibers; and 3) of the subpallial nuclei, the anterior nuclei and the rostral part of the medial (Me) nuclei contained a moderate concentration of 5-HT fibers, whereas caudal regions of Me as well as the central nuclei and the intercalated nuclei contained a sparse/light concentration of 5-HT fibers. With regard to the extended amygdala (primarily the bed nucleus of stria terminalis; BST), on the whole, the BST contained moderate numbers of 5-HT fibers, spread fairly uniformly throughout BST. The findings are discussed with respect to a critical serotonergic influence on the amygdala, particularly on the basal complex, and on the extended amygdala in the control of states of fear and anxiety. J. Comp. Neurol. 525:116-139, 2017. © 2016 Wiley Periodicals, Inc. �

Relevance of the NR4A sub-family of nuclear orphan receptors in trophoblastic BeWo cell differentiation.

Science.gov (United States)

Malhotra, Sudha Saryu; Gupta, Satish Kumar

2017-01-01

Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub-family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH. A similar significant increase was observed at the respective protein levels after 2 and 48 h of treatment with forskolin, hCG or GnRH. Silencing Nor-1, Nurr-1 or Nur-77 individually did not show any effect on forskolin-, hCG- and/or GnRH-mediated BeWo cell fusion and/or hCG secretion. After silencing any one member of the NR4A sub-family, an increase in the transcript levels of the other sub-family members was observed, indicating a compensatory effect due to their functional redundancy. Simultaneously silencing all three NR4A sub-family members significantly downregulated forskolin- and hCG-mediated BeWo cell fusion and/or hCG secretion. However, a considerable amount of cell death occurred after forskolin or hCG treatment as compared to the control siRNA-transfected cells. These results suggest that the NR4A sub-family of nuclear orphan receptors has a role in trophoblastic cell differentiation.

The expression and role of serotonin receptor 5HTR2A in canine osteoblasts and an osteosarcoma cell line.

Science.gov (United States)

Bracha, Shay; Viall, Austin; Goodall, Cheri; Stang, Bernadette; Ruaux, Craig; Seguin, Bernard; Chappell, Patrick E

2013-12-12

The significance of the serotonergic system in bone physiology and, more specifically, the importance of the five hydroxytryptamine receptor 2A (5HTR2A) in normal osteoblast proliferation have been previously described; however the role of serotonin in osteosarcoma remains unclear. Particularly, the expression and function of 5HTR2A in canine osteosarcoma has not yet been studied, thus we sought to determine if this indoleamine modulates cellular proliferation in vitro. Using real time quantitative reverse transcription PCR and immunoblot analyses, we explored receptor expression and signaling differences between non-neoplastic canine osteoblasts (CnOb) and an osteosarcoma cell line (COS). To elucidate specific serotonergic signaling pathways triggered by 5HTR2A, we performed immunoblots for ERK and CREB. Finally, we compared cell viability and the induction of apoptosis in the presence 5HTR2A agonists and antagonists. 5HTR2A was overexpressed in the malignant cell line in comparison to normal cells. In CnOb cells, ERK phosphorylation (ERK-P) decreased in response to both serotonin and a specific 5HTR2A antagonist, ritanserin. In contrast, ERK-P abundance increased in COS cells following either treatment. While endogenous CREB was undetectable in CnOb, CREB was observed constitutively in COS, with expression and exhibited increased CREB phosphorylation following escalating concentrations of ritanserin. To determine the influence of 5HTR2A signaling on cell viability we challenged cells with ritanserin and serotonin. Our findings confirmed that serotonin treatment promoted cell viability in malignant cells but not in normal osteoblasts. Conversely, ritanserin reduced cell viability in both the normal and osteosarcoma cells. Further, ritanserin induced apoptosis in COS at the same concentrations associated with decreased cell viability. These findings confirm the existence of a functional 5HTR2A in a canine osteosarcoma cell line. Results indicate that intracellular

Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections

Directory of Open Access Journals (Sweden)

Antonietta Messina

2018-02-01

Full Text Available IntroductionSleep and migraine share a common pathophysiological substrate, although the underlying mechanisms are unknown. The serotonergic and orexinergic systems are both involved in the regulation of sleep/wake cycle, and numerous studies show that both are involved in the migraine etiopathogenesis. These two systems are anatomically and functionally interconnected. Our hypothesis is that in migraine a dysfunction of orexinergic projections on the median raphe (MR nuclei, interfering with serotonergic regulation, may cause Non-Rapid Eye Movement parasomnias, such as somnambulism.Hypothesis/theoryActing on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would lead to a higher release of serotonin. The activation of serotonergic receptors located on the walls of large cerebral vessels would lead to abnormal vasodilatation and consequently increase transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. As a consequence, there is activation of sensory nerve endings at the level of hard vessels in the meninges, with release of pro-inflammatory peptides (e.g., substance P and CGRP. Within this hypothetical frame, the released serotonin could also interact with trigeminovascular afferents to activate and/or facilitate the release of the neuropeptide at the level of the trigeminal ganglion. The dysregulation of the physiological negative feedback of serotonin on the orexinergic neurons, in turn, would contribute to an alteration of the whole system, altering the sleep–wake cycle.ConclusionSerotonergic neurons of the MR nuclei receive an excitatory input from hypothalamic orexin/hypocretin neurons and reciprocally inhibit orexin/hypocretin neurons through the serotonin 1A receptor (or 5-HT1A receptor. Considering this complex system, if there is an alteration it may facilitate the pathophysiological mechanisms involved in the migraine, while it may produce

Serotonergic modulation of nicotine-induced kinetic tremor in mice

Directory of Open Access Journals (Sweden)

Naofumi Kunisawa

2017-06-01

Full Text Available We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT, significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT1A antagonist. In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI, significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT2 antagonist. The 5-HT3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT3 antagonist or SB-258585 (5-HT6 antagonist. These results suggest that postsynaptic 5-HT1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT2 receptors have an inhibitory modulatory role in induction of nicotine tremor.

Perinatal serotonergic activity: A decisive factor in the control of food intake

Directory of Open Access Journals (Sweden)

Isabeli Lins PINHEIRO

Full Text Available ABSTRACT The serotoninergic system controls key events related to proper nervous system development. The neurotransmitter serotonin and the serotonin transporter are critical for this control. Availability of these components is minutely regulated during the development period, and the environment may affect their action on the nervous system. Environmental factors such as undernutrition and selective serotonin reuptake inhibitors may increase the availability of serotonin in the synaptic cleft and change its anorectic action. The physiological responses promoted by serotonin on intake control decrease when requested by acute stimuli or stress, demonstrating that animals or individuals develop adaptations in response to the environmental insults they experience during the development period. Diseases, such as anxiety and obesity, appear to be associated with the body’s response to stress or stimulus, and require greater serotonergic system action. These findings demonstrate the importance of the level of serotonin in the perinatal period to the development of molecular and morphological aspects of food intake control, and its decisive role in understanding the possible environmental factors that cause diseases in adulthood.

Calcium is the switch in the moonlighting dual function of the ligand-activated receptor kinase phytosulfokine receptor 1

KAUST Repository

Muleya, Victor

2014-09-23

Background: A number of receptor kinases contain guanylate cyclase (GC) catalytic centres encapsulated in the cytosolic kinase domain. A prototypical example is the phytosulfokine receptor 1 (PSKR1) that is involved in regulating growth responses in plants. PSKR1 contains both kinase and GC activities however the underlying mechanisms regulating the dual functions have remained elusive. Findings: Here, we confirm the dual activity of the cytoplasmic domain of the PSKR1 receptor. We show that mutations within the guanylate cyclase centre modulate the GC activity while not affecting the kinase catalytic activity. Using physiologically relevant Ca2+ levels, we demonstrate that its GC activity is enhanced over two-fold by Ca2+ in a concentration-dependent manner. Conversely, increasing Ca2+ levels inhibits kinase activity up to 500-fold at 100 nM Ca2+. Conclusions: Changes in calcium at physiological levels can regulate the kinase and GC activities of PSKR1. We therefore propose a functional model of how calcium acts as a bimodal switch between kinase and GC activity in PSKR1 that could be relevant to other members of this novel class of ligand-activated receptor kinases.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

Science.gov (United States)

2013-01-01

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

Acetylcholine receptors in the human retina

International Nuclear Information System (INIS)

Hutchins, J.B.; Hollyfield, J.G.

1985-01-01

Evidence for a population of acetylcholine (ACh) receptors in the human retina is presented. The authors have used the irreversible ligand 3 H-propylbenzilylcholine mustard ( 3 H-PrBCM) to label muscarinic receptors. 3 H- or 125 I-alpha-bungarotoxin (alpha-BTx) was used to label putative nicotinic receptors. Muscarinic receptors are apparently present in the inner plexiform layer of the retina. Autoradiographic grain densities are reduced in the presence of saturating concentrations of atropine, quinuclidinyl benzilate or scopolamine; this indicates that 3 H-PrBCM binding is specific for a population of muscarinic receptors in the human retina. Binding sites for radiolabeled alpha-BTx are found predominantly in the inner plexiform layer of the retina. Grain densities are reduced in the presence of d-tubocurarine, indicating that alpha-BTx may bind to a pharmacologically relevant nicotinic ACh receptor. This study provides evidence for cholinergic neurotransmission in the human retina

Different serotonin receptor types participate in 5-hydroxytryptophan-induced gonadotropins and prolactin release in the female infantile rat.

Science.gov (United States)

Lacau-Mengido, I M; Libertun, C; Becú-Villalobos, D

1996-05-01

Serotonin (5-HT) receptors can be classified into at least three, possibly up to seven, classes of receptors. They comprise the 5-HT1, 5-HT2, and 5-HT3 classes, the "uncloned' 5-HT4 receptor and the recombinant receptors 5-ht5, 5-ht6 and 5-ht7. We investigated the role of different serotonin receptor types in a neuroendocrine response to the activation of the serotonergic system. Female immature rats were chosen as an experimental model as it has been shown that during the 3rd week of life, and not at later developmental stages, 5-hydroxytryptophan (5-HTP, a serotonin precursor) induces gonadotropin release in females and not in males. Besides, at this age, serotonin releases prolactin in both sexes. 5-HTP (50 mg/kg) released prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as expected. Ketanserin (5-HT2A antagonist) and methysergide (5-HT2C antagonist) blocked 5-HTP-induced prolactin release, but did not block the LH or FSH responses. Ondansetron (5-HT3 receptor antagonist) did not modify prolactin response to 5-HTP, whereas it blocked 5-HTP-induced LH and FSH release. Propranolol (5-HT1 and beta-adrenergic antagonist) blocked prolactin, LH and FSH release induced by 5-HTP. The 5-HT2C agonist 1-(3-chlorophenyl)piperazine dihydrochloride released prolactin, without modifying LH or FSH release. Methyl-quipazine and phenylbiguanide (5-HT3 agonists) increased both LH and FSH levels, without altering prolactin secretion. The present experiments indicate that serotonin acting at the 5-HT3 receptor mediates LH and FSH release in infantile female rats, whereas 5-HT2C or 2A receptor types participate in the release of prolactin at this age. 5-HT1 receptor type may be involved in the release of the three hormones, though a beta-adrenergic component of the response cannot be discarded.

Serotonergic modulation of spinal motor control

DEFF Research Database (Denmark)

Perrier, Jean-Francois Marie; Cotel, Florence

2015-01-01

Serotonin (5-HT) is a monoamine that powerfully modulates spinal motor control by acting on intrasynaptic and extrasynaptic receptors. Here we review the diversity of 5-HT actions on locomotor and motoneuronal activities. Two approaches have been used on in vitro spinal cord preparations: either...

Immunohistochemical assessment of oestrogen and progesterone receptors

DEFF Research Database (Denmark)

Grabau, D A; Thorpe, S M; Knoop, A

2000-01-01

Two different methods to determine steroid receptors were analysed with respect to their ability to estimate prognosis in primary breast cancer patients. The immunohistochemical assay (IHA) was compared with the dextran-coated charcoal (DCC) method of receptor determination. A random sample of 28...... distinction between benign and malignant tissue is possible using the IHAmethod. Thus, IHAresults appear to be more clinically relevant....

Serotonergic modulation of nicotine-induced kinetic tremor in mice.

Science.gov (United States)

Kunisawa, Naofumi; Iha, Higor A; Nomura, Yuji; Onishi, Misaki; Matsubara, Nami; Shimizu, Saki; Ohno, Yukihiro

2017-06-01

We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh) receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT 1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT 1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT 2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT 2 antagonist). The 5-HT 3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT 3 antagonist) or SB-258585 (5-HT 6 antagonist). These results suggest that postsynaptic 5-HT 1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT 2 receptors have an inhibitory modulatory role in induction of nicotine tremor. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

Science.gov (United States)

Papakosta, Vassiliki-Maria; Kalogerakou, Stamatina; Kontis, Dimitris; Anyfandi, Eleni; Theochari, Eirini; Boulougouris, Vasileios; Papadopoulos, Sokrates; Panagis, George; Tsaltas, Eleftheria

2013-04-15

The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. Copyright © 2013 Elsevier B.V. All rights reserved.

Chemokines and their receptors in central nervous system disease

NARCIS (Netherlands)

Biber, K; de Jong, EK; van Weering, HRJ; Boddeke, HWGM

Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

Science.gov (United States)

Li, Yan; Pehrson, Alan L; Oosting, Ronald S; Gulinello, Maria; Olivier, Berend; Sanchez, Connie

2017-07-15

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT 1A receptor agonist), CP-94253 (a 5-HT 1B receptor agonist), or ondansetron (a 5-HT 3 receptor antagonist). These selective ligands were chosen to simulate vortioxetine's direct modulation of these receptors. Paroxetine was also included in the male study. Acute and repeated treatment with vortioxetine at doses corresponding to clinical levels (based on serotonin transporter occupancy) had minimal effects on sexual behavior in male and female rats. High dose vortioxetine plus flesinoxan (to mimic predicted clinical levels of 5-HT 1A receptor occupancy by vortioxetine) facilitated male rat sexual behavior (acutely) while inhibiting female rat proceptive behavior (both acutely and after 14 days treatment). The selective serotonin reuptake inhibitor, paroxetine, inhibited male sexual behavior after repeated administration (7 and 14 days). Flesinoxan alone facilitated male sexual behavior acutely while inhibiting female rat proceptive behavior after repeated administration (7 and 14 days). CP-94253 inhibited sexual behavior in both male and female rats after repeated administration. Ondansetron had no effect on sexual behavior. These findings underline the complex serotonergic regulation of sexual behavior and indicate that the low sexual side effects of vortioxetine found in clinical studies are likely associated with its direct modulation of serotonin receptors. Copyright © 2017. Published by Elsevier Ltd.

Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding.

Science.gov (United States)

Kanagarajadurai, Karuppiah; Malini, Manoharan; Bhattacharya, Aditi; Panicker, Mitradas M; Sowdhamini, Ramanathan

2009-12-01

The serotonergic system has been implicated in emotional and cognitive function. In particular, 5-HT(2A) (5-hydroxytrytamine receptor 2A) is attributed to a number of disorders like schizophrenia, depression, eating disorders and anxiety. 5-HT(2A), being a GPCR (G-protein coupled receptor), is important in the pharmaceutical industry as a proven target for these disorders. Despite their extensive clinical importance, the structural studies of this protein is lacking due to difficulties in determining its crystal structure. We have performed sequence analysis and molecular modeling of 5-HT(2A) that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor. The analysis also revealed a set of residues specific to the receptor which distinguishes them from other members of the subclass and their orthologs. Further, starting from the model structure of human 5-HT(2A) receptor, docking studies were attempted to envisage how it might interact with eight of its ligands (such as serotonin, dopamine, DOI, LSD, haloperidol, ketanserin, risperidone and clozapine). The binding studies of dopamine to 5-HT(2A) receptor can bring up better understanding in the etiology of a number of neurological disorders involving both these two receptors. Our sequence analysis and study of interactions of this receptor with other ligands reveal additional residue hotspots such as Asn 363 and Tyr 370. The function of these residues can be further analyzed by rational design of site-directed mutagenesis. Two distinct binding sites are identified which could play important roles in ligand binding and signaling.

Serotonergic stimulation of the rat hypothalamo-pituitary-adrenal axis

DEFF Research Database (Denmark)

Mikkelsen, Jens D; Hay-Schmidt, Anders; Kiss, Alexander

2004-01-01

Acute stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by selective serotonin reuptake inhibitors (SSRIs) is mediated by several postsynaptic 5-HT receptor subtypes. Activation of 5-HT(1A) and 5-HT(2A) receptors increases plasma corticosterone levels, and it is likely that these recept...

Transmitter receptors reveal segregation of the arcopallium/amygdala complex in pigeons (Columba livia).

Science.gov (United States)

Herold, Christina; Paulitschek, Christina; Palomero-Gallagher, Nicola; Güntürkün, Onur; Zilles, Karl

2018-02-15

At the beginning of the 20th century it was suggested that a complex group of nuclei in the avian posterior ventral telencephalon is comparable to the mammalian amygdala. Subsequent findings, however, revealed that most of these structures share premotor characteristics, while some indeed constitute the avian amygdala. These developments resulted in 2004 in a change of nomenclature of these nuclei, which from then on were named arcopallial or amygdala nuclei and referred to as the arcopallium/amygdala complex. The structural basis for the similarities between avian and mammalian arcopallial and amygdala subregions is poorly understood. Therefore, we analyzed binding site densities for glutamatergic AMPA, NMDA and kainate, GABAergic GABA A , muscarinic M 1 , M 2 and nicotinic acetylcholine (nACh; α 4 β 2 subtype), noradrenergic α 1 and α 2 , serotonergic 5-HT 1A and dopaminergic D 1/5 receptors using quantitative in vitro receptor autoradiography combined with a detailed analysis of the cyto- and myelo-architecture. Our approach supports a segregation of the pigeon's arcopallium/amygdala complex into the following subregions: the arcopallium anterius (AA), the arcopallium ventrale (AV), the arcopallium dorsale (AD), the arcopallium intermedium (AI), the arcopallium mediale (AM), the arcopallium posterius (AP), the nucleus posterioris amygdalopallii pars basalis (PoAb) and pars compacta (PoAc), the nucleus taeniae amgygdalae (TnA) and the area subpallialis amygdalae (SpA). Some of these subregions showed further subnuclei and each region of the arcopallium/amygdala complex are characterized by a distinct multi-receptor density expression. Here we provide a new detailed map of the pigeon's arcopallium/amygdala complex and compare the receptor architecture of the subregions to their possible mammalian counterparts. © 2017 Wiley Periodicals, Inc.

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats.

Science.gov (United States)

Ulak, Güner; Mutlu, Oguz; Akar, Füruzan Yildiz; Komsuoğlu, F Ipek; Tanyeri, Pelin; Erden, B Faruk

2008-10-01

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.

Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice.

Science.gov (United States)

Palotai, Miklós; Telegdy, Gyula; Tanaka, Masaru; Bagosi, Zsolt; Jászberényi, Miklós

2014-11-01

Little is known about the action of neuropeptide AF (NPAF) on anxiety and depression. Only our previous study provides evidence that NPAF induces anxiety-like behavior in rats. Therefore, the aim of the present study was to investigate the action of NPAF on depression-like behavior and the underlying neurotransmissions in mice. In order to determine whether there are species differences between rats and mice, we have investigated the action of NPAF on anxiety-like behavior in mice as well. A modified forced swimming test (mFST) and an elevated plus maze test (EPMT) were used to investigate the depression and anxiety-related behaviors, respectively. Mice were treated with NPAF 30min prior to the tests. In the mFST, the animals were pretreated with a non-selective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2/D3/D4 dopamine receptor antagonist, haloperidol, a α1/α2β-adrenergic receptor antagonist, prazosin or a non-selective β-adrenergic receptor antagonist, propranolol 30min before the NPAF administration. In the mFST, NPAF decreased the immobility time and increased the climbing and swimming times. This action was reversed completely by methysergide and partially by atropine, whereas cyproheptadine, haloperidol, prazosin and propranolol were ineffective. In the EPMT, NPAF decreased the time spent in the arms (open/open+closed). Our results demonstrate that NPAF induces anti-depressant-like behavior in mice, which is mediated, at least in part, through 5HT2-serotonergic and muscarinic cholinergic neurotransmissions. In addition, the NPAF-induced anxiety is species-independent, since it develops also in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

d-Lysergic Acid Diethylamide (LSD as a Model of Psychosis: Mechanism of Action and Pharmacology

Directory of Open Access Journals (Sweden)

Danilo De Gregorio

2016-11-01

Full Text Available d-Lysergic Acid Diethylamide (LSD is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1 and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA mechanism or acting on TAAR1 receptors.

Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms

DEFF Research Database (Denmark)

Srinivasan, Supriya; Sadegh, Leila; Elle, Ida C

2008-01-01

We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat...... feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses...

Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

DEFF Research Database (Denmark)

Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian

2013-01-01

Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine...... about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure...... but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure...

Antidepressant induced sexual dysfunction Part 1: epidemiology ...

African Journals Online (AJOL)

Adele

Abstract. Sexual dysfunction is a common side effect of treatment with antidepressants, particularly those with a predominantly .... free of serotonergic effects or have highly selective receptor .... received little attention in the current literature.

Serotonin and brain function: a tale of two receptors.

Science.gov (United States)

Carhart-Harris, R L; Nutt, D J

2017-09-01

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.

Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: a translational link to humans.

Science.gov (United States)

Neill, Joanna C; Harte, Michael K; Haddad, Peter M; Lydall, Emma S; Dwyer, Dominic M

2014-05-01

Negative symptoms of schizophrenia remain an unmet clinical need as they are common, persistent, respond poorly to existing treatments and lead to disability. Blunted affect, alogia, asociality, anhedonia and avolition are regarded as key negative symptoms despite DSM-IV-TR specifying a more limited range. The key to development of improved therapies is improved animal models that mimic the human condition in terms of behaviour and pathology and that predict efficacy of novel treatments in patients. Accumulating evidence shows that NMDA receptor (NMDAR) antagonists mimic cognitive deficits of relevance to schizophrenia in animals, along with associated pathological changes. This review examines evidence for the ability of NMDAR antagonists to mimic anhedonia and asociality, two negative symptoms of schizophrenia, in animals. The use of various species, paradigms and treatment regimens are reviewed. We conclude that sub-chronic treatment with NMDAR antagonists, typically PCP, induces social withdrawal in animals but not anhedonia. NMDAR antagonists have further effects in paradigms such as motivational salience that may be useful for mimicking other aspects of negative symptoms but these require further development. Sub-chronic treatment regimens of NMDAR antagonists also have some neurobiological effects of relevance to negative symptoms. It is our view that a sub-chronic treatment regime with NMDAR antagonists, particularly PCP, with animals tested following a wash-out period and in a battery of tests to assess certain behaviours of relevance to negative symptoms and social withdrawal (the animal equivalent of asociality) is valuable. This will enhance our understanding of the psycho and neuropathology of specific negative symptom domains and allow early detection of novel pharmacological targets. © 2013 Elsevier B.V. and ECNP All rights reserved.

Dimer-based model for heptaspanning membrane receptors.

Science.gov (United States)

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferré, Sergi; Fuxe, Kjell; Cortés, Antonio; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2005-07-01

The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our two-state-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

Directory of Open Access Journals (Sweden)

John D. Chan

2016-12-01

Full Text Available 5-hydroxytryptamine (5-HT is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL, prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex

Directory of Open Access Journals (Sweden)

Martha Canto-Bustos

2017-09-01

Full Text Available Motoneurons, the final common path of the Central Nervous System (CNS, are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons’ membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control.

Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn

Science.gov (United States)

Leszczyńska, Anna N.; Majczyński, Henryk; Wilczyński, Grzegorz M.; Sławińska, Urszula; Cabaj, Anna M.

2015-01-01

Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3–4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers. PMID

Modulation of the intrinsic properties of motoneurons by serotonin

DEFF Research Database (Denmark)

Perrier, Jean-François; Rasmussen, Hanne Borger; Christensen, Rasmus Kordt

2013-01-01

Serotonin (5-HT) is one of the main transmitters in the nervous system. Serotonergic neurons in the raphe nuclei in the brainstem innervate most parts of the central nervous system including motoneurons in the spinal cord and brainstem. This review will focus on the modulatory role that 5-HT exerts...... a sustained depolarization and an amplification of synaptic inputs. Under pathological conditions, such as after a spinal cord injury, the promotion of persistent inward currents by serotonin and/or the overexpression of autoactive serotonergic receptors may contribute to motoneuronal excitability, muscle...

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y12 receptor.

Science.gov (United States)

Cunningham, Margaret R; Aungraheeta, Riyaad; Mundell, Stuart J

2017-07-05

Genetic variations in G protein-coupled receptor (GPCR) genes can disrupt receptor function in a wide variety of human genetic diseases, including platelet bleeding disorders. Platelets are critical for haemostasis with inappropriate platelet activation leading to the development of arterial thrombosis, which can result in heart attack and stroke whilst decreased platelet activity is associated with an increased risk of bleeding. GPCRs expressed on the surface of platelets play key roles in regulating platelet activity and therefore function. Receptors include purinergic receptors (P2Y 1 and P2Y 12 ), proteinase-activated receptor (PAR1 and PAR4) and thromboxane receptors (TPα), among others. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis. With the advance of genomic technologies, there has been a substantial increase in the identification of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms (SNPs) and insertion or deletions that have the potential to alter GPCR expression or function. A number of defects in platelet GPCRs that disrupt receptor function have now been characterized in patients with mild bleeding disorders. This review will focus on rare, function-disrupting variants of platelet GPCRs with particular emphasis upon mutations in the P2Y 12 receptor gene that affect receptor traffic to modulate platelet function. Further this review will outline how the identification and characterization of function-disrupting GPCR mutations provides an essential link in translating our detailed understanding of receptor traffic and function in cell line studies into relevant human biological systems. Copyright © 2017. Published by Elsevier B.V.

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease.

Science.gov (United States)

Kwakowsky, Andrea; Milne, Michael R; Waldvogel, Henry J; Faull, Richard L

2016-12-17

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

Sex differences and serotonergic mechanisms in the behavioural effects of psilocin.

Science.gov (United States)

Tylš, Filip; Páleníček, Tomáš; Kadeřábek, Lukáš; Lipski, Michaela; Kubešová, Anna; Horáček, Jiří

2016-06-01

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology - sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms - the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.

Structural Analysis of Botulinum Neurotoxin Type G Receptor Binding

Energy Technology Data Exchange (ETDEWEB)

Schmitt, John; Karalewitz, Andrew; Benefield, Desire A.; Mushrush, Darren J.; Pruitt, Rory N.; Spiller, Benjamin W.; Barbieri, Joseph T.; Lacy, D. Borden (Vanderbilt); (MCW)

2010-10-19

Botulinum neurotoxin (BoNT) binds peripheral neurons at the neuromuscular junction through a dual-receptor mechanism that includes interactions with ganglioside and protein receptors. The receptor identities vary depending on BoNT serotype (A-G). BoNT/B and BoNT/G bind the luminal domains of synaptotagmin I and II, homologous synaptic vesicle proteins. We observe conditions under which BoNT/B binds both Syt isoforms, but BoNT/G binds only SytI. Both serotypes bind ganglioside G{sub T1b}. The BoNT/G receptor-binding domain crystal structure provides a context for examining these binding interactions and a platform for understanding the physiological relevance of different Syt receptor isoforms in vivo.

Alterations in serotonin receptor-induced contractility of bovine lateral saphenous vein in cattle grazing endophyte-infected tall fescue.

Science.gov (United States)

Klotz, J L; Brown, K R; Xue, Y; Matthews, J C; Boling, J A; Burris, W R; Bush, L P; Strickland, J R

2012-02-01

As part of a 2-yr study documenting the physiologic impact of grazing endophyte-infected tall fescue on growing cattle, 2 experiments were conducted to characterize and evaluate effects of grazing 2 levels of toxic endophyte-infected tall fescue pastures on vascular contractility and serotonin receptors. Experiment 1 examined vasoconstrictive activities of 5-hydroxytryptamine (5HT), α-methylserotonin (ME5HT; a 5HT(2) receptor agonist), d-lysergic acid (LSA), and ergovaline (ERV) on lateral saphenous veins collected from steers immediately removed from a high-endophyte-infected tall fescue pasture (HE) or a low-endophyte-infected mixed-grass (LE) pasture. Using the same pastures, Exp. 2 evaluated effects of grazing 2 levels of toxic endophyte-infected tall fescue on vasoconstrictive activities of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), BW 723C86 (BW7), CGS-12066A (CGS), and 5-carboxamidotryptamine hemiethanolate maleate (5CT), agonists for 5HT(2A),( 2B), 5HT(1B), and 5HT(7) receptors, respectively. One-half of the steers in Exp. 2 were slaughtered immediately after removal from pasture, and the other one-half were fed finishing diets for >91 d before slaughter. For Exp. 1, maximal contractile intensities were greater (P 91 d. Experiment 1 demonstrated that grazing of HE pastures for 89 to 105 d induces functional alterations in blood vessels, as evidenced by reduced contractile capacity and altered serotonergic receptor activity. Experiment 2 demonstrated that grazing HE pastures alters vascular responses, which may be mediated through altered serotonin receptor activities, and these alterations may be ameliorated by the removal of ergot alkaloid exposure as demonstrated by the absence of differences in finished steers.

Serotonin 6 receptor controls Alzheimer's disease and depression.

Science.gov (United States)

Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

2015-09-29

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.

Effects of interaction of an early experience of reward through maternal contact or its denial with social stress during adolescence on the serotonergic system and the stress responsiveness of adult female rats.

Science.gov (United States)

Raftogianni, A; Diamantopoulou, A; Alikaridis, F; Stamatakis, A; Stylianopoulou, F

2012-05-03

Experiences during critical periods, such as the neonatal and adolescence, play a critical role in determining adult stress-coping behavior. Based on the aforementioned we developed an experimental protocol, which included a neonatal experience and a social stress during adolescence. The serotonergic system is known as an important modulator of coping ability and, in general, emotional balance in both normal and pathological states, such as depression and anxiety, for which females are more vulnerable. Thus in the present work we used female rats and determined 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and 5-hydroxytryptamine receptor type 1A (5-HT(1A)) receptor levels in the prefrontal cortex (PFC) and the amygdala (AMY). During postnatal days 10-13 (PND 10-13) rat pups were exposed to a T-maze, one arm of which lead to the mother. One group of animals was allowed contact with the mother (rewarded-receiving expected reward (RER)), whereas the other was denied the expected reward (DER). High performance liquid chromatography (HPLC) analysis revealed that in both the PFC and in AMY, adult RER animals had higher basal 5-HT levels. Furthermore, in the AMY of this group of animals, higher levels of 5-HT(1A) receptors were detected by Western blot analysis. In adulthood rats were exposed to the Forced Swimming Test/Stress (FST/S). RER animals not exposed to the adolescent stress exhibited longer immobility time during both the first and second day of FST. Corticosterone levels following the FST fell faster in the DER animals. Adolescent stress affected the responses to the adult FSS only in the DER animals, which had decreased 5-HT in the AMY and increased immobility time on both days of the FST, compared with the DER, not stressed in adolescence. The phenotype of the DER animals is in line with the "match-mismatch" hypothesis, which states that if two events during critical periods of life "match" in being mildly stressful, their interaction can be adaptive. Copyright

Evaluation and comparison of antinociceptive activity of aspartame with sucrose.

Science.gov (United States)

Rani, Seema; Gupta, Mahesh C

2012-01-01

Artificial sweeteners are low-calorie substances used to sweeten a wide variety of foods. At present they are used increasingly not only by diabetics, but also by the general public as a mean of controlling the weight. This study was carried out to evaluate and compare antinociceptive activity of the artificial sweeteners, aspartame and sucrose and to study the mechanisms involved in this analgesic activity. Forty eight white albino Wistar rats were divided into two groups of 24 rats each. Group 1 received sucrose and group 2 received aspartame solution ad libitum for 14 days as their only source of liquid. On 14(th) day, both groups of rats were divided into 3 subgroups having 8 rats each. Group Ia and IIa served as control. Group Ib and IIb were given naloxone and Ic and IIc received ketanserin, the opioid and serotonergic receptor antagonists, respectively. Tail withdrawal latencies (tail flick analgesiometer) and paw licking/jumping latencies (Eddy's hot plate method) were increased significantly in both aspartame and sucrose group. The analgesia produced by aspartame was comparable with sucrose. The opioid receptor antagonist naloxone and the 5-HT(2A/2C) serotonergic receptor antagonist ketanserin partly reversed the antinociceptive effect of these sweeteners. Thus, the artificial sweetening agent aspartame showed antinociceptive activity like sucrose in rats. Reduction in antinociceptive activity of aspartame and sucrose by opioid and serotoninergic antagonists demonstrate the involvement of both opioid and serotonergic system.

Playing it safe but losing anyway--serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion.

Science.gov (United States)

Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2013-08-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has been implicated in processing negative outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to a negative outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopram had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to negative outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to negative outcomes in left amygdala. Critically, these pharmacological effects were restricted to negative outcomes that were caused by low-risk decisions and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of negative outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of negative outcomes in goal-directed behaviors. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Retraction: Borroto-Escuela et al., The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity.

Science.gov (United States)

2013-07-10

The Journal of Neuroscience has received a report describing an investigation by the Karolinska Institutet, which found substantial data misrepresentation in the article "The Existence of FGFR1-5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity" by Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudó , Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, and Kjell Fuxe, which appeared on pages 6295-6303 of the May 2, 2012 issue. Because the results cannot be considered reliable, the editors of The Journal are retracting the paper.

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.

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

Science.gov (United States)

Stenbæk, Dea Siggaard; Dam, Vibeke Høyrup; Fisher, Patrick MacDonald; Hansen, Nanna; Hjordt, Liv Vadskjær; Frokjaer, Vibe Gedsoe

2017-01-01

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.

Novel G Protein-Coupled Oestrogen Receptor GPR30 Shows Changes in mRNA Expression in the Rat Brain over the Oestrous Cycle

Directory of Open Access Journals (Sweden)

Emma J. Spary

2012-02-01

Full Text Available Oestrogen influences autonomic function via actions at classical nuclear oestrogen receptors α and β in the brain, and recent evidence suggests the orphan G protein-coupled receptor GPR30 may also function as a cytoplasmic oestrogen receptor. We investigated the expression of GPR30 in female rat brains throughout the oestrous cycle and after ovariectomy to determine whether GPR30 expression in central autonomic nuclei is correlated with circulating oestrogen levels. In the nucleus of the solitary tract (NTS, ventrolateral medulla (VLM and periaqueductal gray (PAG GPR30 mRNA, quantified by real-time PCR, was increased in proestrus and oestrus. In ovariectomised (OVX rats, expression in NTS and VLM appeared increased compared to metoestrus, but in the hypothalamic paraventricular nucleus and PAG lower mRNA levels were seen in OVX. GPR30-like immunoreactivity (GPR30-LI colocalised with Golgi in neurones in many brain areas associated with autonomic pathways, and analysis of numbers of immunoreactive neurones showed differences consistent with the PCR data. GPR30-LI was found in a variety of transmitter phenotypes, including cholinergic, serotonergic, catecholaminergic and nitrergic neurones in different neuronal groups. These observations support the view that GPR30 could act as a rapid transducer responding to oestrogen levels and thus modulate the activity of central autonomic pathways.

Drosophila olfactory receptors as classifiers for volatiles from disparate real world applications

International Nuclear Information System (INIS)

Nowotny, Thomas; De Bruyne, Marien; Warr, Coral G; Berna, Amalia Z; Trowell, Stephen C

2014-01-01

Olfactory receptors evolved to provide animals with ecologically and behaviourally relevant information. The resulting extreme sensitivity and discrimination has proven useful to humans, who have therefore co-opted some animals’ sense of smell. One aim of machine olfaction research is to replace the use of animal noses and one avenue of such research aims to incorporate olfactory receptors into artificial noses. Here, we investigate how well the olfactory receptors of the fruit fly, Drosophila melanogaster, perform in classifying volatile odourants that they would not normally encounter. We collected a large number of in vivo recordings from individual Drosophila olfactory receptor neurons in response to an ecologically relevant set of 36 chemicals related to wine (‘wine set’) and an ecologically irrelevant set of 35 chemicals related to chemical hazards (‘industrial set’), each chemical at a single concentration. Resampled response sets were used to classify the chemicals against all others within each set, using a standard linear support vector machine classifier and a wrapper approach. Drosophila receptors appear highly capable of distinguishing chemicals that they have not evolved to process. In contrast to previous work with metal oxide sensors, Drosophila receptors achieved the best recognition accuracy if the outputs of all 20 receptor types were used. (paper)

Sex Hormone Receptor Repertoire in Breast Cancer

Directory of Open Access Journals (Sweden)

Gerald M. Higa

2013-01-01

Full Text Available Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy, the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression.

Science.gov (United States)

Hadjighassem, Mahmoud R; Austin, Mark C; Szewczyk, Bernadeta; Daigle, Mireille; Stockmeier, Craig A; Albert, Paul R

2009-08-01

Altered expression of serotonin-1A (5-HT1A) receptors, both presynaptic in the raphe nuclei and post-synaptic in limbic and cortical target areas, has been implicated in mood disorders such as major depression and anxiety. Within the 5-HT1A receptor gene, a powerful dual repressor element (DRE) is regulated by two protein complexes: Freud-1/CC2D1A and a second, unknown repressor. Here we identify human Freud-2/CC2D1B, a Freud-1 homologue, as the second repressor. Freud-2 distribution was examined with Northern and Western blot, reverse transcriptase polymerase chain reaction, and immunohistochemistry/immunofluorescence; Freud-2 function was examined by electrophoretic mobility shift, reporter assay, and Western blot. Freud-2 RNA was widely distributed in brain and peripheral tissues. Freud-2 protein was enriched in the nuclear fraction of human prefrontal cortex and hippocampus but was weakly expressed in the dorsal raphe nucleus. Freud-2 immunostaining was co-localized with 5-HT1A receptors, neuronal and glial markers. In prefrontal cortex, Freud-2 was expressed at similar levels in control and depressed male subjects. Recombinant hFreud-2 protein bound specifically to 5' or 3' human DRE adjacent to the Freud-1 site. Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. Furthermore, small interfering RNA knockdown of endogenous hFreud-2 expression de-repressed 5-HT1A promoter activity and increased levels of 5-HT1A receptor protein in SK-N-SH cells. Human Freud-2 binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons.

A Physiologic Role for Serotonergic Transmission in Adult Rat Taste Buds

Science.gov (United States)

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

A physiologic role for serotonergic transmission in adult rat taste buds.

Directory of Open Access Journals (Sweden)

Luc Jaber

Full Text Available Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells and was once thought to be essential to neurotransmission (now understood as purinergic. However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers

A physiologic role for serotonergic transmission in adult rat taste buds.

Science.gov (United States)

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

Structural and Molecular Modeling Features of P2X Receptors

Directory of Open Access Journals (Sweden)

Luiz Anastacio Alves

2014-03-01

Full Text Available Currently, adenosine 5'-triphosphate (ATP is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors.

Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity.

Science.gov (United States)

Howerton, Alexis R; Roland, Alison V; Fluharty, Jessica M; Marshall, Anikò; Chen, Alon; Daniels, Derek; Beck, Sheryl G; Bale, Tracy L

2014-06-01

Women are twice as likely as men to suffer from stress-related affective disorders. Corticotropin-releasing factor (CRF) is an important link between stress and mood, in part through its signaling in the serotonergic dorsal raphe (DR). Development of CRF receptor-1 (CRFr1) antagonists has been a focus of numerous clinical trials but has not yet been proven efficacious. We hypothesized that sex differences in CRFr1 modulation of DR circuits might be key determinants in predicting therapeutic responses and affective disorder vulnerability. Male and female mice received DR infusions of the CRFr1 antagonist, NBI 35965, or CRF and were evaluated for stress responsivity. Sex differences in indices of neural activation (cFos) and colocalization of CRFr1 throughout the DR were examined. Whole-cell patch-clamp electrophysiology assessed sex differences in serotonin neuron membrane characteristics and responsivity to CRF. Males showed robust behavioral and hypothalamic-pituitary-adrenal axis responses to DR infusion of NBI 35965 and CRF, whereas females were minimally responsive. Sex differences were also found for both CRF-induced DR cFos and CRFr1 co-localization throughout the DR. Electrophysiologically, female serotonergic neurons showed blunted membrane excitability and divergent inhibitory postsynaptic current responses to CRF application. These studies demonstrate convincing sex differences in CRFr1 activity in the DR, where blunted female responses to NBI 35965 and CRF suggest unique stress modulation of the DR. These sex differences might underlie affective disorder vulnerability and differential sensitivity to pharmacologic treatments developed to target the CRF system, thereby contributing to a current lack of CRFr1 antagonist efficacy in clinical trials. © 2013 Published by Society of Biological Psychiatry on behalf of Society of Biological Psychiatry.

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

Science.gov (United States)

Kwakowsky, Andrea; Milne, Michael R.; Waldvogel, Henry J.; Faull, Richard L.

2016-01-01

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. PMID:27999310

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Andrea Kwakowsky

2016-12-01

Full Text Available The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2 on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease.

Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus.

Science.gov (United States)

Schmidt, S D; Furini, C R G; Zinn, C G; Cavalcante, L E; Ferreira, F F; Behling, J A K; Myskiw, J C; Izquierdo, I

2017-07-01

The process of memory formation is complex and highly dynamic. During learning, the newly acquired information is found in a fragile and labile state. Through a process known as consolidation, which requires specific mechanisms such as protein synthesis, the memory trace is stored and stabilized. It is known that when a consolidated memory is recalled, it again becomes labile and sensitive to disruption. To be maintained, this memory must undergo an additional process of restabilization called reconsolidation, which requires another phase of protein synthesis. Memory consolidation has been studied for more than a century, while the molecular mechanisms underlying the memory reconsolidation are starting to be elucidated. For this, is essential compare the participation of important neurotransmitters and its receptors in both processes in brain regions that play a central role in the fear response learning. With focus on serotonin (5-HT), a well characterized neurotransmitter that has been strongly implicated in learning and memory, we investigated, in the CA1 region of the dorsal hippocampus, whether the latest discovered serotonergic receptors, 5-HT 5A , 5-HT 6 and 5-HT 7 , are involved in the consolidation and reconsolidation of contextual fear conditioning (CFC) memory. For this, male rats with cannulae implanted in the CA1 region received immediately after the training or reactivation session, or 3h post-reactivation of the CFC, infusions of agonists or antagonists of the 5-HT 5A , 5-HT 6 and 5-HT 7 receptors. After 24h, animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of the hippocampus the 5-HT 5A , 5-HT 6 and 5-HT 7 serotonin receptors participate in the reconsolidation of the CFC memory 3h post-reactivation. Additionally, the results suggest that the 5-HT 6 and 5-HT 7 receptors also participate in the consolidation of the CFC memory. Copyright © 2017 Elsevier Inc. All rights reserved.

Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

DEFF Research Database (Denmark)

Dejgaard, Anders; Liggett, S B; Christensen, N J

1991-01-01

In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... densities (and binding affinities), measured with 3H-labelled yohimbine, and adrenaline-induced suppression of cyclic AMP contents did not differ among the three groups. Thus, in contrast to idiopathic autonomic failure, there is no generalized increase in adrenergic receptors in autonomic failure due...

FCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance

Directory of Open Access Journals (Sweden)

Giuseppe Sconocchia

2017-04-01

Full Text Available For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient’s immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient’s immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA-specific monoclonal antibodies (mAbs, T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv, which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16. Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available

Sensorimotor Gating in Neurotensin-1 Receptor Null Mice

Science.gov (United States)

Feifel, D.; Pang, Z.; Shilling, P.D.; Melendez, G.; Schreiber, R.; Button, D.

2009-01-01

BACKGROUND Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist, PD149163, known to increase PPI in rats. METHODS Baseline PPI and acoustic startle response were measured in WT and NT1 knockout KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days. RESULTS Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice. CONCLUSIONS The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists. PMID:19596359

Test-retest reliability of [{sup 11}C]AZ10419369 binding to 5-HT{sub 1B} receptors in human brain

Energy Technology Data Exchange (ETDEWEB)

Nord, Magdalena; Finnema, Sjoerd J.; Schain, Martin; Halldin, Christer; Farde, Lars [Karolinska Institutet, Center for Psychiatric Research, R5:00, Karolinska University Hospital, Department of Clinical Neuroscience, Stockholm (Sweden)

2014-02-15

[{sup 11}C]AZ10419369 is a recently developed 5-HT{sub 1B} receptor radioligand that is sensitive to changes in endogenous serotonin concentrations in the primate brain. Thus, [{sup 11}C] AZ10419369 may serve as a useful tool in clinical studies of the pathophysiology and pharmacological treatment of diseases related to the serotonin system, such as depression and anxiety disorders. The aim of this study was to evaluate the test-retest reliability of [{sup 11}C]AZ10419369. Eight men were examined with PET and [{sup 11}C] AZ10419369 twice on the same day. The binding potentials (BP{sub ND}) of [{sup 11}C]AZ10419369 in selected serotonergic projection areas and in the raphe nuclei (RN) were determined using the simplified reference tissue model, and for comparison also using a wavelet-aided parametric imaging approach. The BP{sub ND} values obtained from the first and second PET scans were compared by means of descriptive statistics, difference, absolute variability and intraclass correlation coefficient. Similar BP{sub ND} values were obtained with the two methods. The absolute mean differences in BP{sub ND} between PET 1 and PET 2 were less than 3 % in all serotonergic projection regions. Absolute variabilities were low in cortical regions (5 - 7 %), low to moderate (7 - 14 %) in subcortical regions, but higher (20 %) in the RN. The BP{sub ND} of [{sup 11}C]AZ10419369 is highly reproducible in cortical regions and satisfactory in subcortical projection areas. The variability in the RN is higher. Thus larger sample sizes or larger divergences are required to assess a potential difference between subjects or between experimental conditions in this region. (orig.)

Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder.

Science.gov (United States)

Pintsuk, Julia; Borroto-Escuela, Dasiel O; Pomierny, Bartosz; Wydra, Karolina; Zaniewska, Magdalena; Filip, Malgorzata; Fuxe, Kjell

2016-05-01

In the current study behavioral and biochemical experiments were performed to study changes in the allosteric A2AR-D2R interactions in the ventral and dorsal striatum after cocaine self-administration versus corresponding yoked saline control. By using ex vivo [(3)H]-raclopride/quinpirole competition experiments, the effects of the A2AR agonist CGS 21680 (100 nM) on the KiH and KiL values of the D2-like receptor (D2-likeR) were determined. One major result was a significant reduction in the D2-likeR agonist high affinity state observed with CGS 21680 after cocaine self-administration in the ventral striatum compared with the yoked saline group. The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR-D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor-receptor interaction. In contrast, in the dorsal striatum the CGS 21680-induced antagonistic modulation in the D2-likeR agonist high affinity state was abolished after cocaine self-administration versus the yoked saline group probably due to a local dysfunction/disruption of the A2AR-D2-like R heteroreceptor complexes. Such a change in the dorsal striatum in cocaine self-administration can contribute to the development of either locomotor sensitization, habit-forming learning and/or the compulsive drug seeking by enhanced D2-likeR protomer signaling. Potential differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes, including differential recruitment of sigma 1 receptor, in the ventral and dorsal striatum may explain the differential regional changes observed in the A2A-D2-likeR interactions after cocaine self-administration. Copyright © 2016 Elsevier Inc. All rights reserved.

Measuring serotonin synthesis : From conventional methods to PET tracers and their (pre)clinical implications

NARCIS (Netherlands)

Visser, Anniek K. D.; van Waarde, Aren; Willemsen, Antoon T. M.; Bosker, Fokko J.; Luiten, Paul G. M.; den Boer, Johan A.; Kema, Ido P.; Dierckx, Rudi A. J. O.

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

Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT(1B)-like receptor.

Science.gov (United States)

Moloney, G P; Martin, G R; Mathews, N; Milne, A; Hobbs, H; Dodsworth, S; Sang, P Y; Knight, C; Williams, M; Maxwell, M; Glen, R C

1999-07-15

The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like receptor antagonist with a plasma elimination half-life of approximately 4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N-benzylcarboxamide group and its close proximity to the 3-side chain.

Predicting Subtype Selectivity for Adenosine Receptor Ligands with Three-Dimensional Biologically Relevant Spectrum (BRS-3D)

Science.gov (United States)

He, Song-Bing; Ben Hu; Kuang, Zheng-Kun; Wang, Dong; Kong, De-Xin

2016-11-01

Adenosine receptors (ARs) are potential therapeutic targets for Parkinson’s disease, diabetes, pain, stroke and cancers. Prediction of subtype selectivity is therefore important from both therapeutic and mechanistic perspectives. In this paper, we introduced a shape similarity profile as molecular descriptor, namely three-dimensional biologically relevant spectrum (BRS-3D), for AR selectivity prediction. Pairwise regression and discrimination models were built with the support vector machine methods. The average determination coefficient (r2) of the regression models was 0.664 (for test sets). The 2B-3 (A2B vs A3) model performed best with q2 = 0.769 for training sets (10-fold cross-validation), and r2 = 0.766, RMSE = 0.828 for test sets. The models’ robustness and stability were validated with 100 times resampling and 500 times Y-randomization. We compared the performance of BRS-3D with 3D descriptors calculated by MOE. BRS-3D performed as good as, or better than, MOE 3D descriptors. The performances of the discrimination models were also encouraging, with average accuracy (ACC) 0.912 and MCC 0.792 (test set). The 2A-3 (A2A vs A3) selectivity discrimination model (ACC = 0.882 and MCC = 0.715 for test set) outperformed an earlier reported one (ACC = 0.784). These results demonstrated that, through multiple conformation encoding, BRS-3D can be used as an effective molecular descriptor for AR subtype selectivity prediction.

Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

Science.gov (United States)

Gelband, C H; Sumners, C; Lu, D; Raizada, M K

1998-02-27

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

AUGMENTATIVE EFFECT OF PROSTAGLANDIN E1 ON PENTOBARBITAL HYPNOSIS MEDIATED BY 5-HT IN CHICKS

Directory of Open Access Journals (Sweden)

Amalendu Chanda

2012-01-01

Full Text Available Prostaglandins (PG are present in different tissues specially in brain tissues endowed with different central nervous system activities. Similarly, 5-hydroxytryptamine (5-HT a biogenic amine with its presence in different central and peripheral tissues as neurotransmitter plays an important role in the regulation of physiological functions specially hypnosis, convulsions, analgesia in rats, mice, cats and chicks etc. Pentobarbitone (PB induced sleep appear to be a serotonergic modulator activity in different animals. PGE1 potentiates the pentobarbitone hypnosis also mediated through serotonin. In the present study, PGE1 induced sleeping time in chicks was evaluated. Drugs affecting 5-HT synthesis, metabolism and receptor activity modulate the potentiating response, while adrenergic receptor antagonists did not showed any response. This study suggest that PGE1 potentiate PB induced sleep through serotonergic signaling pathway as PGE1 increased 5-HT synthesis rate in chick brain.

Development of 99mTc agents for imaging central neural system receptors

International Nuclear Information System (INIS)

2004-01-01

Radiopharmaceuticals that bind to central neural system (CNS) receptors in vivo are potentially useful for understanding the pathophysiology of anumber of neurological and psychiatric disorders, their diagnosis and treatment. Carbon-11 labelled compounds and positron emission tomography(PET) imaging have played a vital role in establishing the usefulness of imaging the dopaminergic, cholinergic, serotonergic and benzodiazapine receptors, and relating the receptor density to disease status. Since the use of 11C agents is constrained due to their 20 min half-life, various radiohalogenated analogues based on the structure of 11C compounds have been successfully developed, providing comparable information. Iodine- 123 is the most widely employed of these radioisotopes; it has a longer, 13 h, half-life. Through the use of 123I, there has been a steady growth in CNS receptor imaging studies employing single photon emission computerized tomography (SPECT). SPECT, as compared with PET, has slightly inferior image resolution but has the advantage of being readily available worldwide. However, the 123I radiopharmaceutical is expensive and the distribution system outside of the major markets is not well developed for its supply on a routine basis. The ideal radioisotope for SPECT imaging is 99mTc, due to its low cost per dose, availability through commercially available generator systems and physical decay characteristics. Over 80% of all diagnostic nuclear medicine imaging studies worldwide are conducted using this radioisotope. Development of 99mTc radiopharmaceuticals for imaging CNS receptors is therefore of considerable importance. On the basis of the recommendations of a consultants meeting, the International Atomic Energy Agency (IAEA) initiated in 1996 a Co-ordinated Research Project (CRP) on Development of Agents for Imaging CNS Receptors based on 99mTc. At that time there were no 99mTc CNS receptor imaging radiopharmaceuticals available even though work on

Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats.

Science.gov (United States)

Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

2015-08-01

Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation.

Receptor-Mediated Melanoma Targeting with Radiolabeled α-Melanocyte-Stimulating Hormone: Relevance of the Net Charge of the Ligand

Directory of Open Access Journals (Sweden)

Alex N. Eberle

2017-04-01

Full Text Available A majority of melanotic and amelanotic melanomas overexpress melanocortin type 1 receptors (MC1Rs for α-melanocyte-stimulating hormone. Radiolabeled linear or cyclic analogs of α-MSH have a great potential as diagnostic or therapeutic tools for the management of malignant melanoma. Compounds such as [111In]DOTA-NAP-amide exhibit high affinity for the MC1R in vitro, good tumor uptake in vivo, but they may suffer from relatively high kidney uptake and retention in vivo. We have shown previously that the introduction of negative charges into radiolabeled DOTA-NAP-amide peptide analogs may enhance their excretion and reduce kidney retention. To address the question of where to place negative charges within the ligand, we have extended these studies by designing two novel peptides, Ac-Nle-Asp-His-d-Phe-Arg-Trp-Gly-Lys(DOTA-d-Asp-d-Asp-OH (DOTA-NAP-d-Asp-d-Asp with three negative charges at the C-terminal end (overall net charge of the molecule −2 and DOTA-Gly-Tyr(P-Nle-Asp-His-d-Phe-Arg-Trp-NH2 (DOTA-Phospho-MSH2-9 with two negative charges in the N-terminal region (net charge −1. The former peptide showed markedly reduced receptor affinity and biological activity by >10-fold compared to DOTA-NAP-amide as reference compound, and the latter peptide displayed similar bioactivity and receptor affinity as the reference compound. The uptake by melanoma tumor tissue of [111In]DOTA-Phospho-MSH2-9 was 7.33 ± 0.47 %ID/g 4 h after injection, i.e., almost equally high as with [111In]DOTA-NAP-amide. The kidney retention was 2.68 ± 0.18 %ID/g 4 h after injection and hence 44% lower than that of [111In]DOTA-NAP-amide. Over an observation period from 4 to 48 h, the tumor-to-kidney ratio of [111In]DOTA-Phospho-MSH2-9 was 35% more favorable than that of the reference compound. In a comparison of DOTA-NAP-d-Asp-d-Asp, DOTA-Phospho-MSH2-9 and DOTA-NAP-amide with five previously published analogs of DOTA-NAP-amide that altogether cover a range

Progestin potency – Assessment and relevance to choice of oral contraceptives

Directory of Open Access Journals (Sweden)

Norman Goldstuck

2011-12-01

Conclusions: Newer progestins are more receptor selective and potency is less relevant than it was with older progestins. Epidemiological studies of progestin potency and its role in disease generally use out of date information. There is still confusion about the relationship of dose and potency in some studies. The use of the EPA can help eliminate this.

Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

Directory of Open Access Journals (Sweden)

Chui-Mian Zeng

2018-05-01

Full Text Available Frizzled receptors (FZDs are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs that serve as receptors for secreted Wingless-type (WNT ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.

Multiple actions of iontophoretically applied serotonin on motorneurones in the turtle spinal cord in vitro

DEFF Research Database (Denmark)

Skydsgaard, Morten Arnika; Hounsgaard, J

1996-01-01

The effects of focal activation of serotonergic receptors in motorneurones were investigated in a slice preparation of the turtle spinal cord. The test response to glutamate evoked from a dendrite by iontophoresis was attenuated by serotonin or 8-hydroxy-dipropyl-aminotetralin (8-OH-DPAT) applied...

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...

[Functional organization and structure of the serotonergic neuronal network of terrestrial snail].

Science.gov (United States)

Nikitin, E S; Balaban, P M

2011-01-01

The extension of knowledge how the brain works requires permanent improvement of methods of recording of neuronal activity and increase in the number of neurons recorded simultaneously to better understand the collective work of neuronal networks and assemblies. Conventional methods allow simultaneous intracellular recording up to 2-5 neurons and their membrane potentials, currents or monosynaptic connections or observation of spiking of neuronal groups with subsequent discrimination of individual spikes with loss of details of the dynamics of membrane potential. We recorded activity of a compact group of serotonergic neurons (up to 56 simultaneously) in the ganglion of a terrestrial mollusk using the method of optical recording of membrane potential that allowed to record individual action potentials in details with action potential parameters and to reveal morphology of the neurons rcorded. We demonstrated clear clustering in the group in relation with the dynamics of action potentials and phasic or tonic components in the neuronal responses to external electrophysiological and tactile stimuli. Also, we showed that identified neuron Pd2 could induce activation of a significant number of neurons in the group whereas neuron Pd4 did not induce any activation. However, its activation is delayed with regard to activation of the reacting group of neurons. Our data strongly support the concept of possible delegation of the integrative function by the network to a single neuron.

Too little sleep gradually desensitizes the serotonin 1A receptor system

NARCIS (Netherlands)

Roman, Viktor; Walstra, Irene; Luiten, PGM; Meerlo, P

2005-01-01

Study Objectives: In our 24-hour society, frequently disrupted and restricted sleep is a rapidly increasing problem that may contribute to the development of diseases such as depression. One of the proposed neurobiological mechanisms underlying depression is a disturbance in the brain's serotonergic

Interleukin-6 receptor pathways in coronary heart disease

DEFF Research Database (Denmark)

Sarwar, Nadeem; Butterworth, Adam S; Freitag, Daniel F

2012-01-01

Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied ...

Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs

Directory of Open Access Journals (Sweden)

Kai Yang

2014-02-01

Full Text Available G Protein Coupled Receptors (GPCRs are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs, which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity.

Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding

DEFF Research Database (Denmark)

Perfalk, Erik; Cunha-Bang, Sofi da; Holst, Klaus K

2017-01-01

The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4...... positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum...... and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p=0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our...

The neuroprotection of cannabidiol against MPP⁺-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease.

Science.gov (United States)

Santos, Neife Aparecida Guinaim; Martins, Nádia Maria; Sisti, Flávia Malvestio; Fernandes, Laís Silva; Ferreira, Rafaela Scalco; Queiroz, Regina Helena Costa; Santos, Antônio Cardozo

2015-12-25

Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Elimination of a ligand gating site generates a supersensitive olfactory receptor.

Science.gov (United States)

Sharma, Kanika; Ahuja, Gaurav; Hussain, Ashiq; Balfanz, Sabine; Baumann, Arnd; Korsching, Sigrun I

2016-06-21

Olfaction poses one of the most complex ligand-receptor matching problems in biology due to the unparalleled multitude of odor molecules facing a large number of cognate olfactory receptors. We have recently deorphanized an olfactory receptor, TAAR13c, as a specific receptor for the death-associated odor cadaverine. Here we have modeled the cadaverine/TAAR13c interaction, exchanged predicted binding residues by site-directed mutagenesis, and measured the activity of the mutant receptors. Unexpectedly we observed a binding site for cadaverine at the external surface of the receptor, in addition to an internal binding site, whose mutation resulted in complete loss of activity. In stark contrast, elimination of the external binding site generated supersensitive receptors. Modeling suggests this site to act as a gate, limiting access of the ligand to the internal binding site and thereby downregulating the affinity of the native receptor. This constitutes a novel mechanism to fine-tune physiological sensitivity to socially relevant odors.

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand.

Science.gov (United States)

Buhot, Marie-Christine; Wolff, Mathieu; Benhassine, Narimane; Costet, Pierre; Hen, René; Segu, Louis

2003-01-01

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."

Modulation of formalin-induced pain-related behaviour by clonidine and yohimbine in the Speke's hinged tortoise (Kiniskys spekii)

DEFF Research Database (Denmark)

Makau, C M; Towett, P K; Abelson, K S P

2017-01-01

The study was designed to investigate the involvement of noradrenergic and serotonergic receptor systems in the modulation of formalin-induced pain-related behaviour in the Speke's hinged tortoise. Intradermal injection of 100 μL of formalin at a dilution of 12.5% caused pain-related behaviour (h...

Xenobiotics and the Glucocorticoid Receptor

International Nuclear Information System (INIS)

Gulliver, Linda S M

2017-01-01

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

Xenobiotics and the Glucocorticoid Receptor

Energy Technology Data Exchange (ETDEWEB)

Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

2017-03-15

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid

The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction.

Science.gov (United States)

Filip, M; Zaniewska, M; Frankowska, M; Wydra, K; Fuxe, K

2012-01-01

Drug addiction is a serious brain disorder with somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Illegal (e.g., psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking and relapse. One of the hallmarks of drugs that are abused by humans is that they have different mechanisms of action to increase dopamine (DA) neurotransmission within the mesolimbic circuitry of the brain and indirectly activate DA receptors. Among the DA receptors, D(2) receptors are linked to drug abuse and addiction because their function has been proven to be correlated with drug reinforcement and relapses. The recognition that D(2) receptors exist not only as homomers but also can form heteromers, such as with the adenosine (A)(2A) receptor, that are pharmacologically and functionally distinct from their constituent receptors, has significantly expanded the range of potential drug targets and provided new avenues for drug design in the search for novel drug addiction therapies. The aim of this review is to bring current focus on A(2A) receptors, their physiology and pharmacology in the central nervous system, and to discuss the therapeutic relevance of these receptors to drug addiction. We concentrate on the contribution of A(2A) receptors to the effects of different classes of drugs of abuse examined in preclinical behavioral experiments carried out with pharmacological and genetic tools. The consequences of chronic drug treatment on A(2A) receptor-assigned functions in preclinical studies are also presented. Finally, the neurochemical mechanism of the interaction between A(2A) receptors and drugs of abuse in the context of the heteromeric A(2A)-D(2) receptor complex is discussed. Taken together, a significant amount of experimental analyses provide evidence that targeting A(2A) receptors may offer innovative translational strategies

Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans

NARCIS (Netherlands)

Brunham, Liam R.; Tietjen, Ian; Bochem, Andrea E.; Singaraja, Roshni R.; Franchini, Patrick L.; Radomski, Chris; Mattice, Maryanne; Legendre, Annick; Hovingh, G. Kees; Kastelein, John J. P.; Hayden, Michael R.

2011-01-01

The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C).

Estrogen, Estrogen Receptor and Lung Cancer

Directory of Open Access Journals (Sweden)

Li-Han Hsu

2017-08-01

Full Text Available Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR, and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.

In vivo assessment of dopamine D-2 and serotonin S-2 receptors measured by C-11 N-methylspiperone (NMSP) in manic-depressive illness

International Nuclear Information System (INIS)

Wong, D.F.; Pearlson, G.; Wagner, H.N. Jr.

1985-01-01

The hypothesis has been suggested that either the dopaminergic or serotonergic neurotransmitter systems may be involved in manic-depressive illness (MD). The authors have studied 16 subjects with C-11 NMSP PET imaging. Two had never received neuroleptics; 4 were drug free for 1 month at the time of scanning; of these 3 were acutely manic; the rest were on stable lithium treatment. The dopamine and serotonin binding was estimated by the 43 min. caudate/cerebellum (Ca/Cb) and frontal/cerebellum (FC/Cb) ratios, respectively. No statistically significant difference was detected when compared to 44 age and sex matched controls. Based upon the variance in the normal data and the average age of the patient group studied, the probability of detecting a difference of >30% between patients and normals is >0.8. Hence, identification of receptor abnormalities if present will be improved with increased sample size of both normals and patients

Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice.

Science.gov (United States)

Browne, Caleb J; Ji, Xiaodong; Higgins, Guy A; Fletcher, Paul J; Harvey-Lewis, Colin

2017-10-01

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT 2C receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT 2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT 2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT 2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT 2C receptor ligands may have important implications when considering the 5-HT 2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

Plasticity of Signaling by Spinal Estrogen Receptor α, κ-Opioid Receptor, and Metabotropic Glutamate Receptors over the Rat Reproductive Cycle Regulates Spinal Endomorphin 2 Antinociception: Relevance of Endogenous-Biased Agonism.

Science.gov (United States)

Liu, Nai-Jiang; Murugaiyan, Vijaya; Storman, Emiliya M; Schnell, Stephen A; Kumar, Arjun; Wessendorf, Martin W; Gintzler, Alan R

2017-11-15

We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous μ-opioid receptor (MOR) ligand] induces antinociception that varies with stage of the rat estrous cycle: minimal during diestrus and prominent during proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies that enable spinal EM2 antinociception. We now report that in female rats, increased spinal dynorphin release and κ-opioid receptor (KOR) signaling, as well as the emergence of glutamate-activated metabotropic glutamate receptor 1 (mGluR 1 ) signaling, are critical to the transition from an EM2 nonresponsive state (during diestrus) to an analgesically responsive state (during proestrus). Differential signaling by mGluR 1 , depending on its activation by membrane estrogen receptor α (mERα; during diestrus) versus glutamate (during proestrus), concomitant with the ebb and flow of spinal dynorphin/KOR signaling, functions as a switch, preventing or promoting, respectively, spinal EM2 antinociception. Importantly, EM2 and glutamate-containing varicosities appose spinal neurons that express MOR along with mGluRs and mERα, suggesting that signaling mechanisms regulating analgesic effectiveness of intrathecally applied EM2 also pertain to endogenous EM2. Regulation of spinal EM2 antinociception by both the nature of the endogenous mGluR 1 activator (i.e., endogenous biased agonism at mGluR 1 ) and changes in spinal dynorphin/KOR signaling represent a novel mechanism for modulating analgesic responsiveness to endogenous EM2 (and perhaps other opioids). This points the way for developing noncanonical pharmacological approaches to pain management by harnessing endogenous opioids for pain relief. SIGNIFICANCE STATEMENT The current prescription opioid abuse epidemic underscores the urgency to develop alternative pharmacotherapies for managing pain. We find that the magnitude of spinal endomorphin 2 (EM2) antinociception not only

Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity

Directory of Open Access Journals (Sweden)

Jonathan eShelton

2015-01-01

Full Text Available Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6 induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg. Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15 or advance (CT22 wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light-induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals.

Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

DEFF Research Database (Denmark)

Dejgaard, Anders; Liggett, S B; Christensen, N J

1991-01-01

In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... by measuring these in a group of subjects with well-documented adrenergic denervation hypersensitivity, patients with diabetic autonomic neuropathy. Mononuclear leukocyte beta 2-adrenergic receptor densities (and binding affinities), measured with 125I-labelled pindolol, and isoproterenol-stimulated cyclic AMP...... accumulation, in samples from patients with insulin-dependent diabetes mellitus (IDDM) with diabetic autonomic neuropathy (n = 8), were no different from those in samples from patients with IDDM without neuropathy (n = 8), or from non-diabetic subjects (n = 8). In addition, platelet alpha 2-adrenergic receptor...

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Science.gov (United States)

Navarro, Gemma; Borroto-Escuela, Dasiel; Angelats, Edgar; Etayo, Íñigo; Reyes-Resina, Irene; Pulido-Salgado, Marta; Rodríguez-Pérez, Ana I; Canela, Enric I; Saura, Josep; Lanciego, José Luis; Labandeira-García, José Luis; Saura, Carlos A; Fuxe, Kjell; Franco, Rafael

2018-01-01

Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB 1 and CB 2 receptors, which may form heteromeric complexes (CB 1 -CB 2 Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB 1 and circa 20 fold for CB 2 ), whereas receptor levels were similar for CB 1 and markedly upregulated for CB 2 ; CB 1 -CB 2 Hets were also upregulated. Unlike in resting cells, CB 2 receptors became robustly coupled to G i in activated cells, in which CB 1 -CB 2 Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß 1-42 ). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP Sw,Ind ) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP Sw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB 1 -CB 2 Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB 1 -CB 2 Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB 1 -CB 2 heteroreceptor complex in activated microglia have potential as targets in the

Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

DEFF Research Database (Denmark)

Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine

2010-01-01

in the MCF7 cells of the isoflavonoid mixture and coumestrol was supported by an observed increase in progesterone receptor protein expression as well as a decreased ER expression. Overall, the results support that nutrition-relevant concentrations of PEs both alone and in mixtures possess various endocrine...

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.

Hearing loss alters serotonergic modulation of intrinsic excitability in auditory cortex.

Science.gov (United States)

Rao, Deepti; Basura, Gregory J; Roche, Joseph; Daniels, Scott; Mancilla, Jaime G; Manis, Paul B

2010-11-01

Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 μM) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that

5-HT radioligands for human brain imaging with PET and SPECT

DEFF Research Database (Denmark)

Paterson, Louise M; Kornum, Birgitte R; Nutt, David J

2013-01-01

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used...

Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance.

Science.gov (United States)

Dinis-Oliveira, Ricardo Jorge

2017-02-01

Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT) 2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.

Lu AA21004, a novel multimodal antidepressantwith activity exerted through serotonergic targets

DEFF Research Database (Denmark)

Mork, A.; Pehrson, A.; Montezinho, L. C. P.

2012-01-01

Background: Lu AA21004 is a multimodal antidepressant that functions as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we investigated preclinical effects of Lu AA21004 1) on target occupancies, 2...... (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (ACh), histamine (Hist)] were measured by microdialysis. Antidepressant potential was assessed in the forced swim test using Flinders Sensitive Line (FSL) rats. Moreover, effects of Lu AA21004 on acquisition, consolidation and recall...

The Determinations of Estrogen and Progesterone Receptor in Breast Cancer Cell by Radioimmunoassay Method

International Nuclear Information System (INIS)

Kim, Chi Yeul

1981-01-01

The estrogen and progesterone receptors which are bound to the cytoplasmic protein of cancer cells were measured in 20 patients with the early breast cancer by means of radioimmunoassay using charcoal. 1) The patients with estrogen receptor positive were 13 (65%) of 20 cases and with progestrone receptor positive were 7 cases (35%) in the early breast cancer. 2) Coexistence of estrogen and progesterone receptor positive was noted in 7 cases (35%). The cases of estrogen receptor positive and progesterone receptor negative were 6 cases (33.3%), while there were no cases of estrogen receptor negative with progesterone receptor positive. 3) Coincidence of estrogen and progesterone negative was noticed in 7 cases (35%). Conclusively it is considered that the measurement of estrogen and progesterone receptors has relevance as predictive value, in the response to hormonal manipulations and chemotherapy for breast cancer patients.

TRAIL death receptors and cancer therapeutics

International Nuclear Information System (INIS)

Huang Ying; Sheikh, M. Saeed

2007-01-01

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also known as Apo2L is an apoptotic molecule that belongs to the tumor necrosis factor superfamily of cytokines. It mediates its apoptotic effects via its cognate death receptors including DR4 and DR5. Agonistic monoclonal antibodies have also been developed that selectively activate TRAIL death receptors to mediate apoptosis. Multiple clinically relevant agents also upregulate the expression of TRAIL death receptors, and cooperate with TRAIL as well as DR4 and DR5-specific agonistic antibodies to exhibit tumor cell killing. TRAIL is currently in phase I clinical trials, whereas DR4 and DR5-specific agonistic antibodies have been tested in phase I and II studies. Thus, TRAIL has clearly distinguished itself from the other family members including TNF-alpha and FasL both of which could not make it to the clinic due to their toxic nature. It is therefore, evident that the future of TRAIL-based therapeutic approaches looks brighter

A Review on Ubiquitination of Neurotrophin Receptors: Facts and Perspectives

Science.gov (United States)

Sánchez-Sánchez, Julia; Arévalo, Juan Carlos

2017-01-01

Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination. Additional studies are needed that focus on the ubiquitination of TrkB, TrkC, and p75NTR in order to further understand the role of ubiquitination in their physiological and pathological functions. Here we review what is currently known regarding the ubiquitination of neurotrophin receptors and its physiological and pathological relevance. PMID:28335430

Antagonism of a (+)N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs.

Science.gov (United States)

Glennon, R A; Young, R; Herndon, J L

1993-08-01

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+)N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at sigma- and phencyclidine (PCP) receptors. Although the low-affinity sigma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands--(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)--antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone display modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither establish a role for sigma involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that sigma-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.

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.

[Clinical relevance of ESR1 circulating mutations detection in hormone receptor positive metastatic breast cancer].

Science.gov (United States)

Clatot, Florian; Perdrix, Anne; Sefrioui, David; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2018-01-01

If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials. This review will present the acquired ESR1 mutations, as well as the methods used for their detection in blood and the potential clinical impact of this approach for hormone receptor positive breast cancer management. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

DEFF Research Database (Denmark)

Tfelt-Hansen, Peer C; Olesen, Jes

2012-01-01

Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

Pharmacological Profile of Nociceptin/Orphanin FQ Receptors Interacting with G-Proteins and β-Arrestins 2.

Directory of Open Access Journals (Sweden)

D Malfacini

Full Text Available Nociceptin/orphanin FQ (N/OFQ controls several biological functions by selectively activating an opioid like receptor named N/OFQ peptide receptor (NOP. Biased agonism is emerging as an important and therapeutically relevant pharmacological concept in the field of G protein coupled receptors including opioids. To evaluate the relevance of this phenomenon in the NOP receptor, we used a bioluminescence resonance energy transfer technology to measure the interactions of the NOP receptor with either G proteins or β-arrestin 2 in the absence and in presence of increasing concentration of ligands. A large panel of receptor ligands was investigated by comparing their ability to promote or block NOP/G protein and NOP/arrestin interactions. In this study we report a systematic analysis of the functional selectivity of NOP receptor ligands. NOP/G protein interactions (investigated in cell membranes allowed a precise estimation of both ligand potency and efficacy yielding data highly consistent with the known pharmacological profile of this receptor. The same panel of ligands displayed marked differences in the ability to promote NOP/β-arrestin 2 interactions (evaluated in whole cells. In particular, full agonists displayed a general lower potency and for some ligands an inverted rank order of potency was noted. Most partial agonists behaved as pure competitive antagonists of receptor/arrestin interaction. Antagonists displayed similar values of potency for NOP/Gβ1 or NOP/β-arrestin 2 interaction. Using N/OFQ as reference ligand we computed the bias factors of NOP ligands and a number of agonists with greater efficacy at G protein coupling were identified.

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

Science.gov (United States)

Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

2016-08-01

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.

Science.gov (United States)

Hadjighassem, Mahmoud R; Galaraga, Kimberly; Albert, Paul R

2011-01-01

The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation.

Science.gov (United States)

Collins, Anne L; Aitken, Tara J; Greenfield, Venuz Y; Ostlund, Sean B; Wassum, Kate M

2016-11-01

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

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

International Nuclear Information System (INIS)

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

1985-01-01

In the presence of a 30 nM prazosin mask, [ 3 H]-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ([ 3 H]WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [ 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 [ 3 H]WB4101-binding sites in the presence of 30 nM prazosin and [ 3 H] lysergic acid diethylamide ([ 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 [ 3 H]WB4101 is significantly lower than the Bmax of [ 3 H]LSD in various brain regions. WB4101 competition for [ 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 [ 3 H]WB4101 binding derived from saturation experiments. This suggests that [ 3 H]WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by [ 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 [ 3 H]WB4101 but compete for multiple [ 3 H]LSD 5-HT1 binding sites. These data indicate that [ 3 H]WB4101 selectively labels the 5-HT1A serotonin receptor, whereas [ 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 [ 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 [ 3 H]WB4101 binding

Structure and function of the IFNγ receptor on human mononuclear phagocytes

International Nuclear Information System (INIS)

Schreiber, R.D.; Celada, A.

1986-01-01

Human mononuclear phagocytes bear a receptor that binds 125 I-IFNγ in a saturable, reversible and specific manner. The receptor consists minimally of a 70 kD polypeptide chain and its expression (5000/cell) and binding affinity (Ka=10 9 M -1 ) are unaffected by cellular activation or differentiation. The receptor's biological relevance was validated by correlating receptor occupancy with induction of a cellular response. 50% maximal induction of Fc receptors on U937 was effected by 0.8 nM IFNγ; the same concentration needed to half saturate U937 IFNγ receptors. Ligand-receptor interaction displayed species specificity but not cellular specificity. The receptors on U937 and human fibroblasts displayed identical ligand binding affinities (1.5-1.8 x 10 9 M -1 ). At 37 0 C, IFNγ bound to U937 in a biphasic manner. The high affinity binding component was due to ligand internalization since purified cell membranes and paraformaldehyde fixed cells displayed only the lower Ka and ligand internalization could be directly demonstrated. Using lysosomotropic amines, the internalized IFNγ-IFNγ receptor complex was tracked into an acid compartment where dissociation occurred. Free intracellular IFNγ was then degraded while free receptor entered an intracellular pool and eventually recycled back to the cell surface

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...

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

Science.gov (United States)

Bucci, Ines; Giuliani, Cesidio; Napolitano, Giorgio

2017-01-01

Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and fetal

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

Directory of Open Access Journals (Sweden)

Ines Bucci

2017-06-01

Full Text Available Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH receptor (TSHR antibodies (TRAbs are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs, blocking (TBAbs, or neutral (N-TRAbs depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and

Anti-NMDA (a-NMDAR) receptor encephalitis related to acute consumption of metamphetamine: Relevance of differential diagnosis.

Science.gov (United States)

Iriondo, O; Zaldibar-Gerrikagoitia, J; Rodríguez, T; García, J M; Aguilera, L

2017-03-01

A 19-year-old male came to the Emergency Room of our hospital due to an episode of dystonic movements and disorientation 4 days after consuming methamphetamine, which evolved to a catatonic frank syndrome and eventually to status epilepticus. Definitive diagnosis was anti-NMDA receptor encephalitis, an acute inflammation of the limbic area of autoimmune origin in which early diagnosis and treatment are key elements for the final outcome. In this case, initial normal tests and previous methamphetamine poisoning delayed diagnosis, because inhaled-methamphetamine poisoning causes similar clinical symptoms to anti-NMDA receptor encephalitis. Methamphetamine poisoning may have caused an immune response in the patient, bringing on the progress of the pathology. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer

International Nuclear Information System (INIS)

Berasain, Carmen; Latasa, María Ujue; Urtasun, Raquel; Goñi, Saioa; Elizalde, María; Garcia-Irigoyen, Oihane; Azcona, María; Prieto, Jesús; Ávila, Matías A.

2011-01-01

Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling systems are emerging as mechanisms of targeted therapy resistance. The identification of such interactions is therefore of particular relevance to improve therapeutic efficacy. Among the different signaling pathways activated in hepatocarcinogenesis the epidermal growth factor receptor (EGFR) system plays a prominent role, being recognized as a “signaling hub” where different extracellular growth and survival signals converge. EGFR can be transactivated in response to multiple heterologous ligands through the physical interaction with multiple receptors, the activity of intracellular kinases or the shedding of EGFR-ligands. In this article we review the crosstalk between the EGFR and other signaling pathways that could be relevant to liver cancer development and treatment

Why relevance theory is relevant for lexicography

DEFF Research Database (Denmark)

Bothma, Theo; Tarp, Sven

2014-01-01

This article starts by providing a brief summary of relevance theory in information science in relation to the function theory of lexicography, explaining the different types of relevance, viz. objective system relevance and the subjective types of relevance, i.e. topical, cognitive, situational...... that is very important for lexicography as well as for information science, viz. functional relevance. Since all lexicographic work is ultimately aimed at satisfying users’ information needs, the article then discusses why the lexicographer should take note of all these types of relevance when planning a new...... dictionary project, identifying new tasks and responsibilities of the modern lexicographer. The article furthermore discusses how relevance theory impacts on teaching dictionary culture and reference skills. By integrating insights from lexicography and information science, the article contributes to new...

Study of nerve fibers nature reinforcing duodenal contractions by electrical stimulation of sympathetic nerve

Directory of Open Access Journals (Sweden)

Sveshnikov D.S.

2011-09-01

Full Text Available The subject of the article is to investigate the mechanism of increased reactions by electrical stimulation of the sympathetic nerve. Materials and methods: Experiments on dogs have shown that stimulant reactions during blockade of a-adrenergic by phentolamine and (3-adrenergic receptors with propranolol were completely eliminated by lizer-gol —the blocker of 5-HT12-receptors. Results: Infusion of lizergol did not influence on duodenal motor activity and the function of the vagus nerve. Conclusion: Effector neuron is found out to be serotonergic and its action is provided by 5-HT1 2 receptors

Oligomerisation of C. elegans Olfactory Receptors, ODR-10 and STR-112, in Yeast

KAUST Repository

Tehseen, Muhammad; Liao, Chunyan; Dacres, Helen; Dumancic, Mira; Trowell, Stephen; Anderson, Alisha

2014-01-01

It is widely accepted that vertebrate G-Protein Coupled Receptors (GPCRs) associate with each other as homo- or hetero-dimers or higher-order oligomers. The C. elegans genome encodes hundreds of olfactory GPCRs, which may be expressed in fewer than a dozen chemosensory neurons, suggesting an opportunity for oligomerisation. Here we show, using three independent lines of evidence: co-immunoprecipitation, bioluminescence resonance energy transfer and a yeast two-hybrid assay that nematode olfactory receptors (ORs) oligomerise when heterologously expressed in yeast. Specifically, the nematode receptor ODR-10 is able to homo-oligomerise and can also form heteromers with the related nematode receptor STR-112. ODR-10 also oligomerised with the rat I7 OR but did not oligomerise with the human somatostatin receptor 5, a neuropeptide receptor. In this study, the question of functional relevance was not addressed and remains to be investigated.

Oligomerisation of C. elegans Olfactory Receptors, ODR-10 and STR-112, in Yeast

KAUST Repository

Tehseen, Muhammad

2014-09-25

It is widely accepted that vertebrate G-Protein Coupled Receptors (GPCRs) associate with each other as homo- or hetero-dimers or higher-order oligomers. The C. elegans genome encodes hundreds of olfactory GPCRs, which may be expressed in fewer than a dozen chemosensory neurons, suggesting an opportunity for oligomerisation. Here we show, using three independent lines of evidence: co-immunoprecipitation, bioluminescence resonance energy transfer and a yeast two-hybrid assay that nematode olfactory receptors (ORs) oligomerise when heterologously expressed in yeast. Specifically, the nematode receptor ODR-10 is able to homo-oligomerise and can also form heteromers with the related nematode receptor STR-112. ODR-10 also oligomerised with the rat I7 OR but did not oligomerise with the human somatostatin receptor 5, a neuropeptide receptor. In this study, the question of functional relevance was not addressed and remains to be investigated.

The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms?

Science.gov (United States)

Goodman, Neil

2002-01-01

This article aims to explore, through established scientific research and documented accounts of personal experience, the similarities between religious mystical experiences and some effects of D-lysergic diethylamide or LSD. LSD predominantly works upon the serotonergic (serotonin-using neurons) diffuse neuromodulatory system, which projects its axons to virtually all areas of the brain including the neocortex. By its normal action it modulates awareness of the environmental surroundings and filters a high proportion of this information before it can be processed, thereby only allowing the amount of information that is necessary for survival. LSD works to open this filter, and so an increased amount of somatosensory data is processed with a corresponding increase in what is deemed important. This article describes the effects and actions of LSD, and due to the similarities with the nondrug-induced mystical experience the author proposes that the two could have common modes of action upon the brain. This could lead to avenues of research into mysticism and a wealth of knowledge on consciousness and how we perceive the universe.

Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling

DEFF Research Database (Denmark)

Lam, Henrik Rye; Plenge, P.; Jørgensen, O.S.

2001-01-01

Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, an...

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Directory of Open Access Journals (Sweden)

Petra eAmchova

2014-03-01

Full Text Available Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed higher voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 µg/kg/infusion. To this aim, olfactory-bulbectomized (OBX and sham-operated (SHAM Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous (FR-1 schedule of reinforcement in 2h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behaviour after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg, did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2 reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats.

Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region

Directory of Open Access Journals (Sweden)

Paul eGrzesik

2015-09-01

Full Text Available The human lutropin/choriogonadotropin receptor (LHCGR can be activated by binding two slightly different gonadotropic glycoprotein hormones, choriogonadotropin (CG - secreted by the placenta, and lutropin (LH - produced by the pituitary. They induce different signaling profiles at the LHCGR. This cannot be explained by binding to the receptor's leucine-rich repeat domain (LRRD, as this binding is similar for the two hormones. We therefore speculate that there are previously unknown differences in the hormone/receptor interaction at the extracellular hinge region, which might help to understand functional differences between the two hormones. We have therefore performed a detailed study of the binding and action of LH and CG at the LHCGR hinge region. We focused on a primate-specific additional exon in the hinge region, which is located between LRRD and the serpentine domain. The segment of the hinge region encoded by exon10 was previously reported to be only relevant to hLH signaling, as the exon10-deletion receptor exhibits decreased hLH signaling, but unchanged hCG signaling. We designed an advanced homology model of the hormone/LHCGR complex, followed by experimental characterization of relevant fragments in the hinge region. In addition, we examined predictions of a helical exon10-encoded conformation by block-wise polyalanine (helix supporting mutations. These helix preserving modifications showed no effect on hormone induced signaling. However, introduction of a structure-disturbing double-proline mutant LHCGR-Q303P/E305P within the exon10-helix has, in contrast to exon10 deletion, no impact on hLH, but only on hCG signaling. This opposite effect on signaling by hLH and hCG can be explained by distinct sites of hormone interaction in the hinge region s. In conclusion, our analysis provides details of the differences between hLH- and hCG-induced signaling that are mainly determined in the L2-beta loop of the hormones and in the hinge region

Genetic polymorphisms in the serotonergic system are associated with circadian manifestations of bruxism.

Science.gov (United States)

Oporto, G H; Bornhardt, T; Iturriaga, V; Salazar, L A

2016-11-01

Bruxism (BRX) is a condition of great interest for researchers and clinicians in dental and medical areas. BRX has two circadian manifestations; it can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, WB). However, it can be suffered together. Recent investigations suggest that central nervous system neurotransmitters and their genes could be involved in the genesis of BRX. Serotonin is responsible for the circadian rhythm, maintaining arousal, regulating stress response, muscle tone and breathing. Thus, serotonin could be associated with BRX pathogenesis. The aim of this work was to evaluate the frequency of genetic polymorphisms in the genes HTR1A (rs6295), HTR2A (rs1923884, rs4941573, rs6313, rs2770304), HTR2C (rs17260565) and SLC6A4 (rs63749047) in subjects undergoing BRX treatment. Patients included were classified according to their diagnosis in awake bruxism (61 patients), sleep bruxism (26 patients) and both (43 patients). The control group included 59 healthy patients with no signs of BRX. Data showed significant differences in allelic frequencies for the HTR2A rs2770304 polymorphism, where the C allele was associated with increased risk of SB (odds ratio = 2·13, 95% confidence interval: 1·08-4·21, P = 0·03). Our results suggest that polymorphisms in serotonergic pathways are involved in sleep bruxism. Further research is needed to clarify and increase the current understanding of BRX physiopathology. © 2016 John Wiley & Sons Ltd.

Functional relevance of aromatic residues in the first transmembrane domain of P2X receptors

Czech Academy of Sciences Publication Activity Database

Jindřichová, Marie; Vávra, Vojtěch; Obšil, Tomáš; Stojilkovic, S. S.; Zemková, Hana

2009-01-01

Roč. 109, č. 3 (2009), s. 923-934 ISSN 0022-3042 R&D Projects: GA MŠk(CZ) LC554; GA AV ČR(CZ) IAA5011408; GA AV ČR(CZ) IAA500110702; GA AV ČR(CZ) IAA500110910 Institutional research plan: CEZ:AV0Z50110509 Keywords : purinergic receptors * gating * transmembrane domain Subject RIV: FH - Neuro logy Impact factor: 3.999, year: 2009

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice.

Science.gov (United States)

Otsuka, Tsuyoshi; Kawai, Misato; Togo, Yuki; Goda, Ryosei; Kawase, Takahiro; Matsuo, Haruka; Iwamoto, Ayaka; Nagasawa, Mao; Furuse, Mitsuhiro; Yasuo, Shinobu

2014-02-01

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. Copyright © 2013 Elsevier Ltd. All rights reserved.

The discovery of tropane-derived CCR5 receptor antagonists.

Science.gov (United States)

Armour, Duncan R; de Groot, Marcel J; Price, David A; Stammen, Blanda L C; Wood, Anthony; Perros, Manos; Burt, Catherine

2006-04-01

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms.

Directory of Open Access Journals (Sweden)

Olle Eriksson

Full Text Available To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD and asymptomatic controls.Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women.Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP, radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs: the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain".There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001. Menstrual phase changes in this asymmetry (premenstrual-follicular correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006. The PMD group showed a strong inverse correlation between phase changes (premenstrual-follicular in plasma levels of estradiol and phase changes in the laterality (dx/sin of radiotracer activity in the dorsolateral prefrontal ROI (rs = -0.635; 0.027. The control group showed no such correlation.Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral

Relevance of genetically determined host factors to the prognosis of meningococcal disease.

Science.gov (United States)

Domingo, P; Muñiz-Diaz, E; Baraldès, M A; Arilla, M; Barquet, N; Pericas, R; Juárez, C; Madoz, P; Vázquez, G

2004-08-01

To assess the relevance of genetically determined host factors for the prognosis of meningococcal disease, Fc gamma receptor IIA (FcgammaRIIA), the tumor necrosis factor alpha (TNF-alpha) gene promoter region, and plasminogen-activator-inhibitor-1 (PAI-1) gene polymorphisms were studied in 145 patients with meningococcal disease and in 290 healthy controls matched by sex. Distribution of FcgammaRIIA, TNF-alpha, and PAI-1 alleles was not significantly different between patients and controls. Patients with the FcgammaRIIA-R/R 131 allotype scored > or =1 point in the Barcelona prognostic system more frequently than patients with other allotypes (odds ratio, 18.6; 95% confidence interval, 7.1-49.0, PFc gamma receptor IIA polymorphism was associated with markers of disease severity, but TNF-alpha and PAI-1 polymorphisms were not.

Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

Directory of Open Access Journals (Sweden)

Fabrizio Fierro

2017-09-01

Full Text Available Human G-protein coupled receptors (hGPCRs constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

DEFF Research Database (Denmark)

Noehr-Jensen, L; Zwisler, S; Larsen, F

2009-01-01

PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels...... of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0......-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype...

Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

DEFF Research Database (Denmark)

Wellendorph, Petrine; Goodman, M W; Burstein, E S

2002-01-01

The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct...... receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known...... revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor...

NMDA Receptors in Glial Cells: Pending Questions.

Science.gov (United States)

Dzamba, David; Honsa, Pavel; Anderova, Miroslava

2013-05-01

Glutamate receptors of the N-methyl-D-aspartate (NMDA) type are involved in many cognitive processes, including behavior, learning and synaptic plasticity. For a long time NMDA receptors were thought to be the privileged domain of neurons; however, discoveries of the last 25 years have demonstrated their active role in glial cells as well. Despite the large number of studies in the field, there are many unresolved questions connected with NMDA receptors in glia that are still a matter of debate. The main objective of this review is to shed light on these controversies by summarizing results from all relevant works concerning astrocytes, oligodendrocytes and polydendrocytes (also known as NG2 glial cells) in experimental animals, further extended by studies performed on human glia. The results are divided according to the study approach to enable a better comparison of how findings obtained at the mRNA level correspond with protein expression or functionality. Furthermore, special attention is focused on the NMDA receptor subunits present in the particular glial cell types, which give them special characteristics different from those of neurons - for example, the absence of Mg(2+) block and decreased Ca(2+) permeability. Since glial cells are implicated in important physiological and pathophysiological roles in the central nervous system (CNS), the last part of this review provides an overview of glial NMDA receptors with respect to ischemic brain injury.

Serotonergic and dopaminergic activities of rigidified (R)-aporphine derivatives.

Science.gov (United States)

Linnanen, T; Brisander, M; Mohell, N; Johansson, A M

2001-02-12

Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.

Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

Science.gov (United States)

Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

2006-11-01

In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory.

Science.gov (United States)

Moraga-Amaro, Rodrigo; González, Hugo; Ugalde, Valentina; Donoso-Ramos, Juan Pablo; Quintana-Donoso, Daisy; Lara, Marcelo; Morales, Bernardo; Rojas, Patricio; Pacheco, Rodrigo; Stehberg, Jimmy

2016-04-01

Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

Perirhinal Cortex Muscarinic Receptor Blockade Impairs Taste Recognition Memory Formation

Science.gov (United States)

Gutierrez, Ranier; De la Cruz, Vanesa; Rodriguez-Ortiz, Carlos J.; Bermudez-Rattoni, Federico

2004-01-01

The relevance of perirhinal cortical cholinergic and glutamatergic neurotransmission for taste recognition memory and learned taste aversion was assessed by microinfusions of muscarinic (scopolamine), NMDA (AP-5), and AMPA (NBQX) receptor antagonists. Infusions of scopolamine, but not AP5 or NBQX, prevented the consolidation of taste recognition…

Toll-like receptor mRNA expression is selectively increased in the colonic mucosa of two animal models relevant to irritable bowel syndrome.

Directory of Open Access Journals (Sweden)

Declan P McKernan

2009-12-01

Full Text Available Irritable bowel syndrome (IBS is largely viewed as a stress-related disorder caused by aberrant brain-gut-immune communication and altered gastrointestinal (GI homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stress-induced IBS-like symptoms.In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensitivity; the stress-sensitive Wistar-Kyoto (WKY rat and the maternally separated (MS rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains.These data suggest that both early life stress (MS and a genetic predisposition (WKY to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS.

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology in Drosophila melanogaster.

Science.gov (United States)

Majeed, Zana R; Abdeljaber, Esraa; Soveland, Robin; Cornwell, Kristin; Bankemper, Aubrey; Koch, Felicitas; Cooper, Robin L

2016-01-01

Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs) in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity.

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology in Drosophila melanogaster

Directory of Open Access Journals (Sweden)

Zana R. Majeed

2016-01-01

Full Text Available Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity.

5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

Directory of Open Access Journals (Sweden)

Minal Jaggar

2017-12-01

Full Text Available Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC and hippocampus in 5-HT2A receptor knockout (5-HT2A−/− and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2, trophic factors (Bdnf, Igf1 and immediate early genes (IEGs (Arc, Fos, Fosb, Egr1-4 in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. Keywords: 5-HT2A−/− mice, Prefrontal cortex, Hippocampus, Gene expression, Sexual dimorphism, Despair

Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer

OpenAIRE

Xie, Xin; Rui, Wenbin; He, Wei; Shao, Yuan; Sun, Fukang; Zhou, Wenlong; Wu, Yuxuan; Zhu, Yu

2017-01-01

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase which utilizes collagen as a ligand to regulate the interaction between cancer cells and tumor stroma. However, the clinical relevance of DDR1 expression in bladder cancer as well as its molecular regulation have not been previously investigated. Here, we assessed the role of DDR1 in bladder cancer. The DDR1 levels in bladder cancer specimens were examined by Western blot, compared to the paired adhesive normal controls. The eff...

Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

Directory of Open Access Journals (Sweden)

Berit eBrogaard

2013-10-01

Full Text Available Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia.

Science.gov (United States)

Brogaard, Berit

2013-01-01

Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

Identification of a cys-ser substitution in the 5-HT{sub 2C} (HTR2C) receptor gene and allelic association to violent behavior and alcoholism

Energy Technology Data Exchange (ETDEWEB)

Lappalainen, J.; Ozaki, N.; Goldman, D. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

1994-09-01

Several lines of evidence suggest that brain serotonergic functions, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist, are abnormal in some individuals with alcoholism and aggressive behaviors. The aim of the present study was to identify coding sequence variants in the human 5-HT{sub 2C} receptor gene which may cause abnormal or variant function of this receptor. Using SSCP analysis, a non-conservative cys-ser substitution was found in the 5-HT{sub 2C} receptor (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}). The polymorphism was typed in CEPH families to genetically map the gene. To test for association of the variant to alcoholism, violent behavior and serotonin function, the 5-HT{sub 2C} genotypes of 151 non-related Finnish male alcoholic violent offenders and impulsive fire setters and 127 Finnish psychiatrically interviewed healthy male volunteers were determined. CSF 5-HIAA concentrations were available for 74 alcoholic violent offenders and 25 healthy volunteers. Linkage analysis placed the 5-HT{sub 2C} gene on Xq21, a region that has been previously shown to contain genes for several mental retardation syndromes. The 5-HT{sub 2Ccys}/5-HT{sub 2Cser} genotype frequencies in alcoholic violent offenders and controls differed significantly (0.90/0.10 and 0.82/0.18, respectively, P=0.048). The association was found to be strongest in the violent offenders who did not fulfill the criteria for antisocial personality disorder (5-HT{sub 2Ccys}/5-HT{sub 2Cser} 0.93/0.07, p=0.021). No association was found between CSF 5-HIAA concentrations and 5-HT{sub 2C} genotype. These results implicate a 5-HT{sub 2C} receptor amino acid substitution in predisposition to alcohol abuse and violent behavior in a subgroup of alcoholics.

The 5-HT₁A receptor C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation.

Science.gov (United States)

Janssen, Paddy K C; van Schaik, R; Zwinderman, Aeilko H; Olivier, Berend; Waldinger, Marcel D

2014-06-01

Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 min, and has been postulated as a neurobiological dysfunction related to diminished serotonergic neurotransmission with 5-HT₁A receptor hyperfunction and 5-HT₂C hypofunction. To investigate the relationship between 5-HT₁A receptor gene (HTR₁A)-C(1019)G promoter polymorphism and IELT in men with LPE. This polymorphism is known to increase 5-HT1A receptor expression. A prospective study was conducted in 54 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for HTR₁A gene polymorphism. Allele frequencies and genotypes of C and G variants of HTR₁A polymorphism were determined. Association between CC, CG, and GG genotypes and the IELT in men with LPE were investigated. IELT measured by stopwatch, HTR₁A polymorphism. In this cohort of men with LPE, the geometric mean IELT was 23.8 s. Of the 54 men, the CC, CG and GG genotype frequency for the C(1019)G polymorphism of the 5-HT₁A gene was 33%, 43% and 24%, respectively. The geometric mean IELT for the CC, CG and GG genotypes were 14.5, 27.7 and 36.0 s, respectively (p=0.019). Compared to GG and CG genotypes, men with CC genotype had a 250% and 190% shorter ejaculation time, respectively. HTR₁A gene polymorphism is associated with the IELT in men with LPE. Men with CC genotype have shorter IELTs than men with GG and CG genotypes. Copyright © 2014 Elsevier Inc. All rights reserved.

Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.

Science.gov (United States)

Prüss, H; Leubner, J; Wenke, N K; Czirják, G Á; Szentiks, C A; Greenwood, A D

2015-08-27

Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut's encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut's cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed.

AMP is an adenosine A1 receptor agonist.

Science.gov (United States)

Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

2012-02-17

Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

Neurotensin receptors in human neoplasms: high incidence in Ewing's sarcomas.

Science.gov (United States)

Reubi, J C; Waser, B; Schaer, J C; Laissue, J A

1999-07-19

Receptors for regulatory peptides, such as somatostatin or vasoactive intestinal peptide (VIP), expressed at high density by neoplastic cells, can be instrumental for tumor diagnosis and therapy. Little is known about the expression of neurotensin receptors in human tumors. In the present study, 464 human neoplasms of various types were investigated for their neurotensin receptor content by in vitro receptor autoradiography on tissue sections using 125I-[Tyr3]-neurotensin as radioligand. Neurotensin receptors were identified and localized in tumor cells of 11/17 Ewing's sarcomas, 21/40 meningiomas, 10/23 astrocytomas, 5/13 medulloblastomas, 7/24 medullary thyroid cancers and 2/8 small cell lung cancers. They were rarely found in non-small cell lung cancers and breast carcinomas; they were absent in prostate, ovarian, renal cell and hepatocellular carcinomas, neuroendocrine gut tumors, pituitary adenomas, schwannomas, neuroblastomas and lymphomas. When present, the receptors bound with nanomolar affinity neurotensin and acetyl-neurotensin-(8-13), with lower affinity neuromedin N, diethylenetriamine penta-acetic acidneurotensin-(8-13) and SR 48692, but not neurotensin-(1-11). They were all of the NT1 type, without high affinity for levocabastine. Further, in 2 receptor-positive Ewing's sarcomas, neurotensin mRNA was detected by in situ hybridization techniques. Since neurotensin is known to stimulate cell proliferation, the presence of neurotensin receptors in human neoplasia may be of biological relevance, possibly as an integrative part of an autocrine feedback mechanism of tumor growth stimulation.

Melatonin receptors: latest insights from mouse models

Science.gov (United States)

Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

2014-01-01

Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

Coupling of g proteins to reconstituted monomers and tetramers of the M2 muscarinic receptor.

Science.gov (United States)

Redka, Dar'ya S; Morizumi, Takefumi; Elmslie, Gwendolynne; Paranthaman, Pranavan; Shivnaraine, Rabindra V; Ellis, John; Ernst, Oliver P; Wells, James W

2014-08-29

G protein-coupled receptors can be reconstituted as monomers in nanodiscs and as tetramers in liposomes. When reconstituted with G proteins, both forms enable an allosteric interaction between agonists and guanylyl nucleotides. Both forms, therefore, are candidates for the complex that controls signaling at the level of the receptor. To identify the biologically relevant form, reconstituted monomers and tetramers of the purified M2 muscarinic receptor were compared with muscarinic receptors in sarcolemmal membranes for the effect of guanosine 5'-[β,γ-imido]triphosphate (GMP-PNP) on the inhibition of N-[(3)H]methylscopolamine by the agonist oxotremorine-M. With monomers, a stepwise increase in the concentration of GMP-PNP effected a lateral, rightward shift in the semilogarithmic binding profile (i.e. a progressive decrease in the apparent affinity of oxotremorine-M). With tetramers and receptors in sarcolemmal membranes, GMP-PNP effected a vertical, upward shift (i.e. an apparent redistribution of sites from a state of high affinity to one of low affinity with no change in affinity per se). The data were analyzed in terms of a mechanistic scheme based on a ligand-regulated equilibrium between uncoupled and G protein-coupled receptors (the "ternary complex model"). The model predicts a rightward shift in the presence of GMP-PNP and could not account for the effects at tetramers in vesicles or receptors in sarcolemmal membranes. Monomers present a special case of the model in which agonists and guanylyl nucleotides interact within a complex that is both constitutive and stable. The results favor oligomers of the M2 receptor over monomers as the biologically relevant state for coupling to G proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.