Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

The present study investigated whether serotonin (5-HT) agonists could inhibit the ability of arginine-vasopressin (AVP) to induce a form of scent marking called flank marking by their actions in the medial preoptic-anterior hypothalamus (MPOA-AH). DOI, a 5-HT2A,2B,2C receptor agonist, did not inhibit AVP-induced flank marking, but mCPP a 5-HT2A antagonist and 5-HT2B,2C agonist inhibited AVP-induced flank marking. In addition, the finding that 8-OH-DPAT, CGS-12066A and SC53116 also inhibited AVP-induced flank marking suggests that 5-HT could also inhibit flank marking by acting through 5-HT1A, 5-HT7, 5-HT1B and/or 5-HT4 receptor subtypes. These data support the hypothesis that 5-HT acts within the MPOA-AH to inhibit the ability of AVP to induce flank marking.
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PMID:Serotonin and vasopressin interact in the hypothalamus to control communicative behavior. 1200 93

Interactions of serotonin (5-HT) with different specific 5-HT receptors that can coexist in the same blood vessel sometimes generate opposite effects. The aim of this study was to characterize the functional role of previously described mRNAs for 5-HT receptors in the rat aorta (5-HT(2A), 5-HT(2B), 5-HT(1B), 5-HT(7)) as well as to study the known 5-HT(2A) receptor-mediated constrictor response and investigate the influences of endothelium and preconstriction on the tissue in that response. A slight endothelium- and concentration-dependent relaxant effect was observed for 5-HT in aorta precontracted with either 5 microM phenylephrine (PE) or 1 microM prostaglandin F2alpha (PGF2alpha) in the presence of 0.3 microM ketanserin. EC50 values for 5-HT and alpha-methyl-5-HT relaxant responses after PE were 43.10 +/- 4.00 and 57.11 +/- 8.01 nM, respectively. pK(B) values for antagonists cyproheptadine and rauwolscine were 8.92 +/- 0.22 and 7.15 +/- 0.12, respectively. In nonprecontracted tissues, the contractile potency of 5-HT was higher in the absence of endothelium (EC50, degreesM): 2.60 +/- 0.28 and 4.12 +/- 0.21 in the absence and in the presence of endothelium, respectively. The differences were statistically significant (p<0.05). In precontracted tissues, the differences in EC50 values (2.22 +/- 0.40 and 4.65 +/- 0.60 microM without and with endothelium, respectively) were also statistically significant (p<0.05). pK(B) values for the 5-HT(2A) antagonist ketanserin were similar under all conditions tested. In conclusion, under our experimental conditions there are two functional 5-HT receptors in rat aorta: 5-HT(2A) contractile receptor in smooth muscle and a high-affinity relaxant receptor that mediates a very slight response and the pharmacology of which could be compatible with an endothelial 5-HT(2B) receptor.
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PMID:Functional characterization of serotonin receptors in rat isolated aorta. 1203 97

A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and (-) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and (-)-norfenfluramine. Fenfluramines and norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)-MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders.
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PMID:Therapeutic and adverse actions of serotonin transporter substrates. 1216 29

Arterial hyperresponsiveness to serotonin (5-hydroxytryptamine, 5-HT) is observed in experimental models and human forms of hypertension. Presently, we test the hypothesis that the 5-HT(2B) receptor is up-regulated and necessary for maintaining elevated blood pressure in a rat made hypertensive by the nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine (LNNA; 0.5 g/l). After 2 weeks of treatment, thoracic aorta were removed from LNNA hypertensive (systolic blood pressure = 189 +/- 5 mm Hg) and sham normotensive rats (121 +/- 1 mm Hg), denuded, and mounted into isolated tissue baths for measurement of isometric contraction. In sham tissues, 5-HT-induced contraction was mediated by the 5-HT(2A) receptor as evidence by a parallel rightward shift in response to 5-HT by the 5-HT(2A/2C) receptor antagonist ketanserin (10 nM) and lack of shift by the 5-HT(2B) receptor antagonist 6-methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole hydrochloride (LY272015) (10 nM). In contrast, LY272015 produced a 4-fold rightward shift to 5-HT in aorta from LNNA hypertensive rats, and blockade by ketanserin did not occur at low concentrations of 5-HT. Maximal contraction to the 5-HT(2B) receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride was significantly greater in LNNA hypertensive rats (percentage of phenylephrine contraction in sham = 7 +/- 4, and in LNNA = 61 +/- 7%). 5-HT(2B) receptor protein was present in aortic homogenates from sham and LNNA rats, but the density of 5-HT(2B) receptor protein in LNNA homogenates was 300% that in sham. Importantly, the 5-HT(2B) receptor antagonist LY272015 reduced blood pressure of the LNNA hypertensive but not the sham normotensive rats. Thus, these data suggest that the up-regulated 5-HT(2B) receptor in the LNNA hypertensive rats is physiologically activated to maintain elevated blood pressure.
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PMID:5-Hydroxytryptamine(2B) receptor function is enhanced in the N(omega)-nitro-L-arginine hypertensive rat. 1223 49

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.
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PMID:Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. 1224 4

These studies investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B), or 5-HT(2C) receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT(2A) receptor antagonist M100907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT(2C) receptor antagonist SB242084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT(2B) antagonist SB215505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100907 and SB242084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100907 (0.5-2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242084 (0.5-1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242084. These results indicate distinct, and in some cases opposite, effects of a 5-HT(2A) compared with a 5-HT(2C) receptor antagonist on various cocaine-mediated behavioral effects.
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PMID:Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. 1237 94

In the present study, we have used in situ hybridization to examine the distribution of serotonin (5-HT) receptors in rat dorsal root ganglion (DRG) neurons. Within DRG neurons, mRNAs for 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT3B and 5-HT4 receptors were readily detected in small (<25 microm), medium (25-45 microm) and large (>45 microm) diameter neurons. In contrast mRNAs for 5-HT1A, 5-HT1E, 5-HT2C, 5-HT5A, 5-HT5B, 5-HT6 and 5-HT7 receptors were undetectable in these neurons. The present study provides an insight into the molecular profile of 5-HT receptor subtypes in neurons responsible for modulating sensory information.
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PMID:Serotonin receptor mRNA expression in rat dorsal root ganglion neurons. 1253 38

5-HT(2) family serotonin receptors, principal sites of action of serotonin in the brain, represent major molecular targets for drugs used in treating a variety of diseases including schizophrenia, depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions and obesity. The 5-HT(2) family of receptors has three members: 5-HT(2A), 5-HT(2B) and 5-HT(2C). Therefore, it is likely that subtype-selective compounds will be needed to avoid serious side effects and to enhance therapeutic indices. Unfortunately, recent insights into the structure and function of 5-HT(2A) receptors have revealed that structurally-diverse agonists and antagonists have distinct modes of interacting with 5-HT(2A) receptors, complicating efforts at structure-based drug-design. These distinct binding modes would not have been predicted based on conventional structure-activity relationships or static docking models. Fortunately, these complicated binding modes can be predicted and simulated using molecular dynamics, allowing for the possibility of structure-based drug design. Thus, provided appropriately sophisticated drug design strategies are employed, it is likely that uniquely valuable medications will result which could have great potential for treating a variety of mental and physical illnesses.
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PMID:Insights into the structure and function of 5-HT(2) family serotonin receptors reveal novel strategies for therapeutic target development. 1254 Feb 78

1 The human 5-HT(2C) receptor, when expressed heterologously in various mammalian cell lines (HEK293, SH-EP and NIH-3T3) at various receptor densities (6 to 45 pmol mg(-1) protein), mediates robust agonist-induced GTPgamma(35)S binding from coupling to G(i) subtypes of G proteins, in addition to G(q/11). Such a phenotype, however, was not seen with the human 5-HT(2A) and 5-HT(2B) receptors, indicating their common pathway with 5-HT(2C) limited to G(q/11), not including G(i). 2 Because intracellular regions are largely responsible for signalling pathways, we prepared the chimeras of the 5-HT(2A) and 5-HT(2B) receptors where the second and third intracellular loops, and the C-terminal region were replaced with the 5-HT(2C) counterparts. 3 The chimeras showed robust agonist-induced GTPgamma(35)S binding. Relative intrinsic efficacies of agonists from the GTPgamma(35)S binding were nearly identical to the reported values for their parent receptors as measured with Ca(2+) or [(3)H]-inositol phosphate accumulation. Also the chimeras displayed the same ligand-binding properties as the parent receptors. 4 We conclude that the phenotype of agonist-induced GTPgamma(35)S binding is unique to 5-HT(2C) among the 5-HT(2) receptor family, and is transferable to 5-HT(2A) and 5-HT(2B), upon swapping intracellular sequences, without altering their receptor pharmacology.
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PMID:A unique phenotype of 5-HT2C, agonist-induced GTPgamma35S binding, transferable to 5-HT2A and 5-HT2B, upon swapping intracellular regions. 1256 67

The behavioural effects of 5-HT(2) receptor agonists, 5-HT(2A) and 5-HT(2C) receptor antagonists were investigated in the mouse four plates test (FPT), light/dark paradigm (L/D) and the elevated plus maze (EPM), in order to elucidate the role of the 5-HT(2) receptor subtypes in these models and to address the inconclusive results previously reported using rat psychopharmacological models. All compounds were administered intraperitoneally 30 min before each test. DOI, a preferential 5-HT(2A) agonist (0.5-8 mg/kg) and BW 723C86, a 5-HT(2B) agonist (8 and 16 mg/kg) provoked an anxiolytic-like response in the FPT. In the EPM, an anxiolytic-like effect was observed for DOI (0.5, 1 and 2 mg/kg), BW 723C86 (0.5, 4, 8 and 16 mg/kg), RO 60-0175 a 5-HT(2C) agonist (4 mg/kg) and the non-selective 5-HT(2) receptor agonist mCPP (0.25 mg/kg.). Ketanserin, a 5-HT(2A/2C) non-selective receptor antagonist (0.015 and 0.03 mg/kg), induced an anxiogenic-like effect in the L/D paradigm. The 5-HT(2C) antagonists (RS 10-2221, SDZ SER082 and SB 206553) were without effect in all three tests. These behavioural results are indicative of an anxiolytic-like action of 5-HT(2) receptor agonists, an anxiogenic-like effect of 5-HT(2A) receptor antagonism, whereas the blockade of 5-HT(2C) receptors are without effect in the mouse models studied.
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PMID:Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety. 1264 93


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