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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Recent neurochemical studies of the properties of 5-hydroxytryptamine (5-HT) pathways arising from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) have measured extracellular 5-HT in brain regions with reported preferential DRN or MRN 5-HT inputs. Here, we have tested whether electrical stimulation of the DRN and MRN releases 5-HT in rat forebrain regions in a pattern that fits the reported distribution of DRN/MRN pathways. The effect on extracellular 5-HT of electrical stimulation (5 Hz, 300 µA, 20 min) of the DRN, and then MRN, was determined in six regions of the anaesthetised rat. Stimulation of the DRN evoked a short-lasting but clear-cut release of 5-HT (+70–100%) in regions (frontal cortex, dorsal striatum, globus pallidus, and ventral hippocampus) reported to receive a 5-HT projection from the DRN. Regions receiving an MRN innervation (dorsal hippocampus, medial septum, and ventral hippocampus) released 5-HT (+70–100%) in response to MRN stimulation. Regions reported to receive a preferential DRN innervation (frontal cortex, dorsal striatum, and globus pallidus) did not respond to MRN stimulation. Of two regions (dorsal hippocampus and medial septum) reported to receive a preferential MRN innervation, one did not respond to DRN stimulation (dorsal hippocampus) although the other (medial septum) did. In summary, electrical stimulation of the DRN and MRN released 5-HT in a regionally specific pattern. With the exception of one region (medial septum), this pattern of release bears a strong relationship to the distribution of 5-HT projections from the DRN and MRN reported by anatomical studies. The combination of raphe stimulation with microdialysis may be a useful way to study the in vivo neurochemistry of DRN/MRN 5-HT pathways.
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Archives of Biochemistry and Biophysics 252 (1987), S. 409-417 
    ISSN: 0003-9861
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Archives of Biochemistry and Biophysics 246 (1986), S. 52-62 
    ISSN: 0003-9861
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 137 (1986), S. 61-68 
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Key words Anxiety ; Conditioning ; Frontal cortex ; Hypothalamus ; Microdialysis ; Noradrenaline ; Shuttle-box
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Extracellular noradrenaline concentration in the rat forebrain is increased by aversive environmental stimuli. This study investigated whether conditioned cues for such stimuli have the same effect. Methods: After training rats to associate a tone (conditioned cue) with transfer from a neutral zone to a brightly lit zone of a light/dark shuttle-box (unconditioned stimulus), microdialysis probes were implanted into the frontal cortex and hypothalamus under halothane anaesthesia. Changes in extracellular noradrenaline concentration were then monitored on exposure to the tone alone. Parallel experiments monitored rats’ behaviour in the light arena. Results: A single exposure to the light arena increased extracellular noradrenaline in the frontal cortex and the hypothalamus but neither a single, nor repeated, exposure to the tone alone had any effect. After conditioning trials, the tone alone increased extracellular noradrenaline in the frontal cortex but not the hypothalamus, whilst the tone+transfer to the light arena resulted in a prolonged increase in extracellular noradrenaline in both brain regions. The time that rats spent within the light arena was also prolonged. Conclusions: Noradrenergic neurones in the frontal cortex, but not the hypothalamus, respond to conditioned cues for aversive environmental stimuli. However, prolongation of the noradrenergic response in both brain regions could contribute to the behavioural adaptation to such unconditioned stimuli.
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  • 6
    ISSN: 1432-2072
    Keywords: Key words Frontal cortex ; Hypothalamus ; Light/dark shuttle-box ; Microdialysis in vivo ; Novelty ; Stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Although physically aversive stimuli induce functional changes in central noradrenergic neurones, little is known about the noradrenergic response to environmentally aversive stimuli. Objectives: The first aim was to characterise environmental features that are perceived as stressful by rats. The second was to investigate whether changes in the concentration of extracellular noradrenaline are induced by these environmental features. Methods: A light/dark shuttle-box was used to test rats’ behavioural response to a range of stimuli (novelty, bright light, and the presence of an unfamiliar rat), either before or after microdialysis probe implantation. Changes in the concentration of extracellular noradrenaline in the frontal cortex and hypothalamus in vivo were then evaluated on exposure to these same test conditions. Results: Naive rats spent less time in a brightly-lit test arena than a dark one. However, the behavioural response to the light arena was attenuated by the presence of an unfamiliar rat. Probe implantation intensified the response to the light arena but did not affect behaviour in the dark arena. In the microdialysis studies, there was no change in the concentration of extracellular noradrenaline on transfer of rats to the dark arena but there was an increase in both the frontal cortex (+45%) and hypothalamus (+75%) on exposure to the light arena. A similar increase was induced in both brain regions when the light arena contained an unfamiliar rat. Conclusions: Implantation of a microdialysis probe modifies the behavioural responses to certain environmental stimuli. Regardless of this, the extent to which rats perceive a novel environment as aversive is not the only determinant of the noradrenergic response to such stimuli. However, differences in stimulus controllability in the microdialysis and the behavioural experiments could influence the apparent intensity of the stress.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 339-346 
    ISSN: 1432-1912
    Keywords: 5-HT1A receptor ; Microdialysis ; 8-OHDPAT ; Buspirone ; Ipsapirone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Electrophysiological measurements of 5-HT neuronal activity report that repeated administration of 5-HT1A receptor agonists leads to desensitization of the 5-HT1A autoreceptor but this has not yet been detected in measurements of brain 5-HT synthesis or metabolism. Here we have determined the effect of repeated administration of 5-HT1A receptor agonists on brain 5-HT release using microdialysis. 2. Acute administration of the 5-HT1A receptor agonists buspirone (0.1–5 mg/kg s.c.) and ipsapirone (0.03–3 mg/kg s.c.) caused a dose-dependent decrease in 5-HT output in ventral hippocampus of the chloral hydrate anaesthetized rat. 3. The 5-HT response to buspirone (0.1 and 0.5 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was significantly inhibited by pre-treatment with the 5-HT1/β-adrenoceptor antagonist pindolol (8–16 mg/kg s.c.). The 5-HT response to buspirone (0.1 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was not blocked by pretreatment with a combination of the β1 and β2-adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg/kg s.c.). 4. The effect of an acute challenge of buspirone (0.5 mg/kg s.c.) on 5-HT output in ventral hippocampus was not attenuated in rats treated twice daily for 14 days with 0.5 or 5 mg/kg s.c. buspirone compared to saline-injected controls. Similarly, the decrease in 5-HT induced by an acute challenge of ipsapirone (0.5 mg/kg s.c.) was not attenuated in rats treated twice daily for 14 days with 5 mg/kg s.c. ipsapirone. 5. In further experiments it was shown that the decrease in 5-HT induced in both ventral hippocampus and striatum by an acute challenge of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 mg/kg s.c.), was not attenuated in rats treated twice daily for 14 days with 1 mg/kg s.c. 8-OH-DPAT. 6. Basal levels of 5-HT in hippocampal and striatal microdialysates of animals treated repeatedly with the 5-HT1A receptor agonists were not consistently altered relative to treatment controls. 7. In agreement with earlier studies measuring regional brain 5-HT synthesis and metabolism, the present microdialysis measurements of 5-HT release indicate that the inhibitory effect of 5-HT1A receptor agonists on presynaptic 5-HT function is maintained in rats treated repeatedly with the same drugs.
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  • 8
    ISSN: 1432-2323
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Cette étude a eu pour but de déterminer les caractères fonctionnels des adénomes thyroïdiens, des nodules adénomateux (colloïdes), des nodules hyperfonctionnels et du parenchyme thyroïdien normal par rapport à la présence des récepteurs TSH, des taux d'adénylate cyclase et de la réaction de l'adénylate cyclase aux stimuli spécifiques: NaF, GTPγS [guanosine 5′-0-(3 thiotriphosphatate)], PGE1 et TSH. Un certain nombre de spécimens de thyroïdectomies [11 de parenchyme normal, 7 d'adénomes, 8 de nodules adénomateux (colloïde), 5 de nodules hyperfonctionnels] furent plongés dans du nitrogène liquide et conservés à 90°C. Les explorations furent effectuées sur les membranes plasmatiques purifiées partiellement. La liaison entre récepteur et125I-TSH fut analysée et mesurée. L'activité de l'adénylate cyclase fut appréciée au niveau du même fragment tissulaire par conversion de (α-32P) ATP en cAMP. L'affinité haute ou basse des récepteurs TSH fut constatée chez les nodules adénomateux (colloïdes), les nodules hyperfonctionnels et le parenchyme thyroïdien normal. Les adénomes thyroïdiens avaient une affinité réceptrice haute normale et une affinité réceptrice basse normale ou diminuée. L'activité d'adénylate cyclase était légèrement augmentée. Tous les groupes accusaient une activité adénylate cyclase augmentée à la stimulation par le NaF, la réponse étant de 60% plus importante pour l'adénome thyroïdien que pour le tissu thyroïdien normal. Tous les tissus réagissaient à la stimulation par PGE1, la réaction étant le double pour le tissu thyroïdien normal par rapport à l'adénome thyroïdien. La réponse de l'adénylate cyclase des nodules adénomateux (colloïde) et des nodules hyperfonctionnels était différente de celle de l'adénome et comparable à celle du parenchyme normal. La réponse de l'adénylate cyclase à la stimulation par la TSH était quatre fois plus importante pour l'adénome thyroïdien et deux fois plus pour les nodules thyroïdiens colloïdes par rapport au parenchyme thyroïdien normal. Ces constatations permettent d'affirmer sur le plan clinique que les adénomes thyroïdiens sensibles à la TSH ne régressent pas nécessairement avec la suppression de l'action de la TSH. Cependant les nodules hyperfonctionnels au stade de début qui présentent des taux de TSH normaux peuvent voir leur croissance et leur caractère hyperfonctionnel supprimés ou retardés par la suppression de la TSH.
    Abstract: Resumen El estudio fue designado para examinar las características funcionales de los adenomas tiroideos, los nódulos adenomatosos (coloides), los nódulos hiperfuncionantes y el parenquima tiroideo normal en relación con la presencia de receptores de TSH, niveles de adenilato ciclasa y la respuesta de la adenilato ciclasa a estímulos específicos, tales como NaF (fluoruro sódico), GPTγS [guanosino 5′0-(3-tiotrifosfatato)], PGE1 y TSH. Alícuotas de especímenes de pacientes sometidos a tiroidectomía [11 tiroides normales, 7 adenomas, 8 nódulos adenomatosos (coloides), 5 nódulos hiperfuncionantes] fueron sumergidos en nitrógeno líquido y almacenados a 90°C. Los estudios fueron realizados sobre membranas plasmáticas parcialmente purificadas. La capacidad de ligación de125I de los receptores de TSH fue cuantificada y analizada de acuerdo al método de Scatchard. La actividad de la adenilato ciclasa fue determinada en la misma fracción tisular por medio de la conversión de ATP (α-32P) a cAMP. Se encontraron receptores de TSH de alta y baja afinidad en los nódulos adenomatosos (coloides), en los nódulos hiperfuncionantes y en el parénquima tiroideo normal. Los adenomas tiroideos exhibieron receptores de alta afinidad en cantidades normales; los receptores de baja afinidad estuvieron presentes en niveles normales o disminuidos. La actividad basal de adenilato ciclasa apareció ligeramente aumentada en los adenomas tiroideos. Todos los grupos demostraron respuesta de la adenilato ciclasa al NaF, con los adenomas tiroideos un 60% más susceptibles que el parénquima tiroideo normal (p〈0,005). Todos los tejidos respondieron a la PGE1, el parénquima tiroideo normal siendo doblemente sensible que los adenomas tiroideos. La respuesta de adenilato ciclasa de los nódulos adenomatosos (coloides) y de los nódulos hiperfuncionantes fue diferente de la de los adenomas y comparable a la del parénquima tiroideo normal. La respuesta de adenilato ciclasa a TSH apareció cuatro veces mayor en los adenomas tiroideos y doblemente mayor en los nódulos adenomatos (coloides) que la del parénquima tiroideo normal. Como implicación clínica de estos hallazgos aparece el que los adenomas tiroideos, siendo sensibles a TSH, no necesariamente habrán de regresar con la deprivación de TSH, en tanto que los nódulos hiperfuncionantes en las etapas tempranas de su desarrollo con niveles normales de TSH pueden ser inhibidos o retardados en su crecimiento y función por medio de la supresión de TSH.
    Notes: Abstract This study was designed to examine the functional characteristics of thyroid adenomas, adenomatous (colloid) nodules, hyperfunctioning nodules, and normal thyroid parenchyma with respect to the presence of TSH receptors, levels of adenylate cyclase, and the responsiveness of adenylate cyclase to specific stimuli, e.g., NaF (sodium fluoride), GTPγS [guanosine 5′-0-(3-thiotriphosphatate)], PGE1, and TSH. Aliquots of specimens from patients undergoing thyroidectomy [11 normal thyroids, 7 adenomas, 8 adenomatous (colloid) nodules, 5 hyperfunctioning nodules] were immersed in liquid nitrogen and stored at 90°C. Studies were performed on partially purified plasma membranes. Receptor binding of125I-TSH was quantitated and analyzed according to Scatchard. Adenylate cyclase activity was assayed in the same tissue fraction by conversion of (α-32P) ATP to cAMP. High- and low-affinity TSH receptors were present in adenomatous (colloid) nodules, hyperfunctioning nodules, and normal thyroid parenchyma. The thyroid adenomas had high-affinity receptors in normal quantities; low-affinity receptors were present at normal or decreased levels. The basal adenylate cyclase activity was slightly increased in thyroid adenomas. All groups had adenylate cyclase response to NaF with the thyroid adenomas being 60% more responsive than normal thyroid parenchyma (p 〈0.005). All tissues responded to PGE1, with normal thyroid parenchyma being twice as responsive as thyroid adenomas. The adenylate cyclase response of adenomatous (colloid) nodules and hyperfunctioning nodules was distinct from that of adenomas and comparable to that of normal thyroid parenchyma. The adenylate cyclase response to TSH was fourfold in thyroid adenomas and twofold in adenomatous (colloid) nodules compared to normal thyroid parenchyma.
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  • 9
    Publication Date: 2014-07-24
    Description: Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1 H )-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity ( K i 〈 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, h α 1B -, and h α 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and h α 1B/2C -adrenoceptors. Brexpiprazole also had affinity ( K i 〈 5 nM) for hD 3 - , h5-HT 2B -, h5-HT 7 -, h α 1A -, and h α 1D -adrenergic receptors, moderate affinity for hH 1 ( K i = 19 nM), and low affinity for hM 1 receptors ( K i 〉 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
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  • 10
    Publication Date: 2014-07-24
    Description: Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1 H )-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT 1A ) and D 2/3 receptors, combined with potent antagonist effects on 5-HT 2A , α 1B -, and α 2C -adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED 50 = 6.0 mg/kg), apomorphine- or d -amphetamine-induced hyperactivity (ED 50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED 50 = 2.9) in rats at clinically relevant D 2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED 50 = 20) well above clinically relevant D 2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D 2 occupancies. In the NOR test, the 5-HT 1A agonist buspirone and the 5-HT 2A antagonist M100907 [( R )-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT 1A antagonist WAY100635 ( N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT 1A, D 2 , and 5-HT 2A receptors, with possible modulating activity through additional monoamine receptors.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
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