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Query: CAS:50-67-9 (5-HT)
 31,727 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-HT) appears to play a modulatory role in the behavioral effects of cocaine, although the impact of 5-HT2C receptors in this control has not been fully established. The aim of the present study was to establish whether acute pretreatment with the selective 5-HT2C/2B antagonist SB 206553 (1, 2, and 4 mg/kg i.p.) altered hyperactivity induced by cocaine (15 mg/kg, i.p.) using an open field activity system which recorded central, peripheral, and rearing activity. Pretreatment with 1 and 2 mg/kg of SB 206553 attenuated cocaine-induced central and peripheral activity, respectively; rearing was also attenuated by the latter dose. However, the 4-mg/kg dose of SB 206553 significantly enhanced the effects of cocaine on peripheral activity. Based upon the present observations and an interpretation of previous research to implicate 5-HT2C receptor control of the dopamine (DA) mesoaccumbens pathways in behavior, a thorough and systematic analysis of the role of 5-HT2C (and 5-HT2B) receptors in psychostimulant-induced behaviors is warranted.
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PMID:Effects of the 5-HT2C/2B antagonist SB 206553 on hyperactivity induced by cocaine. 1032 25

1. Serotonin has been implicated as a mediator involved in migraine headache, an effect that may involve central 5-HT2B receptor activation. 5-HT2B receptor signal transduction in controversial. 2. Rat stomach fundus contraction to serotonin has been used as a model for 5-HT2B receptor activation. Serotonin-induced contractility involves intracellular calcium release and activation of protein kinase C without stimulation of phosphoinositide (PI) hydrolysis. 3. Since phospholipase D (PLD) activation results in phosphatidic acid production, which can release intracellular calcium and provide diacylglycerol for PKC activation, the purpose of this study was to determine whether the 5-HT2B receptor coupled to PLD activation using the rat stomach fundus as a model system. 4. Using phosphatidylethanol production to measure PLD activity, both bradykinin (0.01-1 microM) and phorbol dibutyrate (PDBu, 1 microM) stimulated PLD activity in rat stomach fundal strips, indicating that this tissue possesses an active PLD system. 5. Under identical conditions, 5-hydroxytryptamine (5-HT) failed to stimulate PLD activity over a concentration range (1 nM-1 microM) documented to induce 5-HT2B receptor-mediated contraction in rat stomach fundus. Thus, the 5-HT2B contractile receptor in rat stomach fundus is not coupled to PLD activation, whereas both bradykinin and phorbol ester do couple to PLD.
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PMID:Bradykinin and phorbol ester but not 5-HT2B receptor activation stimulate phospholipase D activity in the rat stomach fundus. 1039 Jul 27

In human brain tissues from patients dying with cerebral infarction, hypertensive encephalopathy, Alzheimer's disease, Huntington's disease, frontotemporal dementia, and Creutzfeldt-Jakob disease there is an activation of astrocytes. Such activated astrocytes display GFAP and strong 5-HT(2A), but not 5-HT(2B) or 5-HT(2C), receptor immunoreactivity; this 5-HT(2A) reaction has not been observed in normal, nonactivated astrocytes. It is suggested that an up-regulation of 5-HT(2A) receptors may be part of an early response reaction in astrocytes, possibly designed to maintain homeostasis or to induce secondary message pathways involving trophic factors or glycogenolysis.
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PMID:Activated astrocytes display increased 5-HT2a receptor expression in pathological states. 1041 57

Efforts to define precisely the role of 5-HT2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this deficiency, we developed a series of naphthylpyrimidines as potentially useful 5-HT2B receptor antagonists. RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine) was found to have nanomolar affinity for the 5-HT2B receptor (pKi = 9.5+/-0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. In cells expressing human recombinant 5-HT2B receptors, RS-127445 potently antagonized 5-HT-evoked formation of inositol phosphates (pK(B) = 9.5+/-0.1) and 5-HT-evoked increases in intracellular calcium (pIC50 = 10.4+/-0.1). RS-127445 also blocked 5-HT-evoked contraction of rat isolated stomach fundus (pA2 = 9.5+/-1.1) and (+/-)alpha-methyl-5-HT-mediated relaxation of the rat jugular vein (pA2 = 9.9+/-0.3). RS-127445 had no detectable intrinsic activity in these assays. In rats, the fraction of RS-127445 that was bioavailable via the oral or intraperitoneal routes was 14 and 60% respectively. Intraperitoneal administration of RS-127445 (5 mg kg(-1)) produced plasma concentrations predicted to fully saturate accessible 5-HT2B receptors for at least 4 h. In conclusion, RS-127445 is a selective, high affinity 5-HT2B receptor antagonist suitable for use is vivo. The therapeutic potential of this molecule is being further evaluated.
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PMID:RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist. 1045 51

1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B>5-HT2C>5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C>5-HT2B>5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A>5-HT2B>5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but <25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.
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PMID:Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. 1049 29

The involvement of 5-HT2 receptor subtypes in mediating a contraction response in the isolated intestine of Suncus murinus was investigated using DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane, a 5-HT2 receptor agonist) which produced a bell-shaped concentration response curve that was significantly (p < 0.05) reduced by methysergide (a 5-HT1/2 receptor antagonist, 1 microM) but not ketanserin (a 5-HT2A receptor antagonist, 1 microM), yohimbine (a 5-HT2B receptor antagonist, 1 microM) or a combination of ondansetron (a 5-HT3 receptor antagonist, 1 microM) plus SB204070 (8-amino-7-chloro(N-butyl-4-piperidyl) methylbenzo-1,4-dioxan-5-carboxylate hydrochloride, a 5-HT4 receptor antagonist, 1 nM). The contraction response to the lower concentrations of DOI (10 nM-0.3 microM) was reduced in the presence of SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole, a 5-HT2B/2C receptor antagonist, 1 microM), whilst conversely, the reducing response to the higher concentrations of DOI (1-30 microM) was prevented. A repeated challenge with 3 microM DOI produced a smaller response (desensitisation) and also reduced the response to 5-HT (5-hydroxytryptamine, 0.3 microM) that was inhibited by SB206553 (1 microM). Data indicate that 5-HT2C receptors are likely candidates to mediate the contractile response to DOI and demonstrate desensitisation to repeated challenges.
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PMID:Characterisation of 5-HT2 receptor subtypes in the Suncus murinus intestine. 1055 84

Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1-5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile.
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PMID:The biology of serotonin receptors: focus on migraine pathophysiology and treatment. 1056 26

We tested the hypothesis that 5-HT promotes the differentiation of enteric neurons by stimulating a developmentally regulated receptor expressed by crest-derived neuronal progenitors. 5-HT and the 5-HT(2) agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine(.)HCl (DOI) enhanced in vitro differentiation of enteric neurons, both in dissociated cultures of mixed cells and in cultures of crest-derived cells isolated from the gut by immunoselection with antibodies to p75(NTR). The promotion of in vitro neuronal differentiation by 5-HT and DOI was blocked by the 5-HT(1/2) antagonist methysergide, the pan-5-HT(2) antagonist ritanserin, and the 5-HT(2B/2C)-selective antagonist SB206553. The 5-HT(2A)-selective antagonist ketanserin did not completely block the developmental effects of 5-HT. 5-HT induced the nuclear translocation of mitogen-activated protein kinase. This effect was blocked by ritanserin. mRNA encoding 5-HT(2A) and 5-HT(2B) receptors was detected in the fetal bowel (stomach and small and large intestine), but that encoding the 5-HT(2C) receptor was not. mRNA encoding the 5-HT(2B) receptor and 5-HT(2B) immunoreactivity were found to be abundant in primordial [embryonic day 15 (E15)-E16] but not in mature myenteric ganglia. 5-HT(2B)-immunoreactive cells were found to be a subset of cells that expressed the neuronal marker PGP9.5. These data demonstrate for the first time that the 5-HT(2B) receptor is expressed in the small intestine as well as the stomach and that it is expressed by enteric neurons as well as by muscle. It is possible that by stimulating 5-HT(2B) receptors, 5-HT affects the fate of the large subset of enteric neurons that arises after the development of endogenous sources of 5-HT.
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PMID:Serotonin and the 5-HT(2B) receptor in the development of enteric neurons. 1062 7

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.
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PMID:Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors. 1063 Jul 30

The effects of injections i.c.v. of alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (BW723C86; 0.02 - 2 micromol kg(-1)), a 5-HT(2B) receptor agonist, on renal sympathetic and phrenic nerve activity, mean arterial blood pressure and heart rate were investigated in alpha-chloralose anaesthetized rats pretreated with a peripherally acting 5-HT(2) receptor antagonist. BW723C86 i.c.v. caused a dose-related increase in renal nerve activity reaching a maximum of 67+/-6%, which at the highest dose was associated with a small and maintained fall in mean arterial blood pressure of 7+/-3 mmHg. These changes were not associated with any significant changes in heart rate or phrenic nerve activity. BW723C86-evoked increases in renal nerve activity and hypotension were attenuated by pretreatment (i.c.v.) with SB204741 (300 nmol kg(-1); a 5-HT(2B) receptor antagonist) but not by the same dose (i.c.v.) of ketanserin (a 5-HT(2A) receptor antagonist) or RS102221 (a 5-HT(2C) receptor antagonist). None of these antagonists alone had any effect on the variables being measured. It is concluded that central 5-HT(2B) receptors may play a selective role in the control of sympathetic supply to the kidney, which could be important in the central mechanisms involved in blood volume regulation. British Journal of Pharmacology (2000) 129, 177 - 183
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PMID:Evidence that activation of central 5-HT(2B) receptors causes renal sympathoexcitation in anaesthetized rats. 1069 18


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