Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin is a monoamine and is widely distributed in the human organism. Serotonin is synthesized from the amino acid tryptophane and is broken down via mono-amino-oxydase enzymes to 5-hydroxy-indol-acetic acid and by acetylizing and methylizing to melantonin. In 1986, a consensus concerning the classification of the serotonergic receptors was established. Three main classes were determined, viz: 5-HT1, 5-HT2 and 5-HT3. 5-HT1 receptors were further subdivided into A, B, C and D-receptors and, of these, the 5-HT1A-receptor is involved in the centrally mediated blood pressure control via reduction in the pre- and postganglionic sympathetic activity. The 5-HT2 receptors are primarily involved in control of peripheral blood pressure where agonizing results in vascular contraction of the large arteries and veins and thrombocyte aggregation. The 5-HT1 receptors are also involved peripherally in connection with release of relaxing factors derived from endothelium. In vitro and in animal experiments, it has been demonstrated that serotonin is capable of inducing arrhythmia and myocardial dysfunction via 5-HT3 receptors. Several preparations with effects on both the central and peripheral serotonergic receptors are already marketed for treatment of hypertension and other conditions.
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PMID:[Serotonin and cardiovascular control]. 221 14

Administration of serotonin (5-hydroxytryptamine, 5-HT) to pyramidal cells of the CA1 region of the hippocampus results in a hyperpolarizing response which is followed by a rebound depolarization and a decrease in the calcium-activated afterhyperpolarization (AHP). While the hyperpolarizing response has been previously shown to be mediated by receptors of the 5-HT1A subtype, the identity of the receptor(s) involved in the depolarizing response and decrease of the AHP have not been identified. In the present study the effectiveness of a series of 5-HT receptor antagonists in blocking the membrane depolarization and reduction of the AHP was assessed. While a variety of 5-HT1 and 5-HT2 antagonists were found to be ineffective, the substituted benzamide BRL 24924 was found to be a potent and selective antagonist of the 5-HT-induced depolarization and decrease in the AHP in this region. This effect however appeared unrelated to the ability of this compound to block 5-HT3 receptors, as ICS 205-930 and MDL 72222 were markedly less efficacious in blocking these effects of 5-HT. Upon blockade of 5-HT1A receptors, 5-HT elicits a depolarization which is accompanied by a marked increase in excitability. These effects were also dose-dependently antagonized by BRL 24924. The present results thus suggest the presence in the CA1 region of the hippocampus of a novel 5-HT receptor at which BRL 24924 functions as a selective antagonist and which is capable of mediating slow excitatory responses in central neurons.
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PMID:Pharmacological and functional analysis of a novel serotonin receptor in the rat hippocampus. 222 19

The side effects and unwanted or unnecessary ancillary pharmacological properties of benzodiazepine anxiolytic drugs resulted in a continuing search for new agents with improved profiles of activity. Buspirone was the first novel drug to emerge from this search in almost thirty years. Investigations into its mechanism of action revealed a key role for serotonin in the pharmacotherapy of anxiety. A variety of serotonergic agents are now in preclinical and clinical development as anxiolytics, including 5-HT1A partial agonists, 5-HT2 antagonists, and 5-HT3 antagonists. In addition to the new drugs which will be developed as a consequence of these investigations, their clinical efficacy will prompt the development of new animal models of psychopathology, leading us ever closer to a full understanding of the neurobiological substrates of anxiety. In addition, deployment of these new agents in the armamentaria of the clinician and the basic scientist will lead to new insights into the treatment of other disorders and the biochemical mechanisms by which the effects of these drugs are obtained.
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PMID:Serotonin agents in anxiety. 225 34

alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT; 2) and 2-methyl-5-hydroxytryptamine (2-Me-5-HT; 3) are considered to be 5-HT2-selective and 5-HT3-selective agents, respectively. These agents were synthesized and examined at serotonin (5-HT) binding sites because there is relatively little documentation as to their selectivity and because they have not been previously examined at the newly discovered 5-HT1D and 5-HT1E sites. As previously reported, 2-Me-5-HT possesses a low affinity (Ki greater than 500 nM) for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2 sites; this agent also displays a low affinity for 5-HT1D (Ki = 1220 nM) and 5-HT1E (Ki greater than 10,000 nM) sites. However, alpha-Me-5-HT displays little selectivity for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D sites (Ki = 42, 85, 150, and 150 nM, respectively) and a very low affinity for 5-HT1E (Ki greater than 10,000 nM) sites. Depending upon the radioligand used to label the sites, alpha-Me-5-HT displays either a low affinity (Ki = 880 nM with [3H]ketanserin) or a high affinity (Ki = 3 nM with [3H]DOB) for 5-HT2 sites. These results suggest that alpha-Me-5-HT is not as selective as previously considered and that caution should be used when employing this agent in pharmacological studies because it may act as mixed 5-HT1/5-HT2 agonist.
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PMID:5-HT1 and 5-HT2 binding profiles of the serotonergic agents alpha-methylserotonin and 2-methylserotonin. 229 41

Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.
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PMID:Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. 231 90

Serotonin (5-hydroxytryptamine; 5-HT) and its analogs activate adenylate cyclase in membrane particles from neuroblastoma NCB.20 cells. Low concentrations of GTP (EC50 = 60 nM) were required for activation by serotonin. Guanosine 5'-O-(2-thiodiphosphate) inhibited serotonin-activated cyclase in these cells. The nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (EC50 = 3 nM) and guanylyl-imidodiphosphate (EC50 = 100 nM) substituted for GTP in potentiating serotonin activation. Pretreatment of the cells with cholera toxin potentiated enzyme activation by serotonin, whereas pertussis toxin was found to have little effect, indicating the involvement of the alpha subunit of a stimulatory GTP-binding protein in enzyme activation. Homologous desensitization of the serotonin-stimulated adenylate cyclase was demonstrated in membranes prepared from intact cells pretreated with serotonin. Cell membrane particles that were desensitized to serotonin were still responsive to beta-adrenergic agonists and to prostaglandin E1. Evidence is presented indicating that serotonin stimulation of adenylate cyclase is mediated by receptors that are distinct from other positively coupled receptors (beta-adrenergic, histamine, and prostacyclin). Equilibrium binding analysis with [3H]serotonin, [3H]lysergic acid diethylamide, and [3H]dihydroergotamine suggested that the site density was below the level of detection of binding of these radioligands. The pharmacological characteristics of the serotonin-activated cyclases were analyzed in order to compare these serotonin receptors with the family of different receptor subtypes. Correlation analysis between the potencies of different agonists and antagonists at the cyclase in these cells and their reported relative potencies for different serotonin receptor subtypes showed no correlation with the 5-HT1A, 5HT1B, 5HT1D, 5-HT2, and 5-HT3 receptors. On the other hand, the analysis showed that the NCB.20 serotonin receptors are similar but not identical to the rat and pig brain 5-HT1C receptors and to the serotonin receptors coupled to adenylate cyclase in the trematodes Schistosoma mansoni and Fasciola hepatica. The results point to a novel serotonin receptor which has a low density in these cells.
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PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46

The actions of 5-hydroxytryptamine (5-HT) on the electrically induced twitch responses of mouse vas deferens were studied. 5-HT at the concentration range of 10(-8) to 10(-4) M produced a "bell-shaped" concentration-response curve on the field-stimulated twitch contractions; the enhancement of the contractions was maximum at 10(-5) M and progressively reduced at the concentrations of more than 10(-5) M. In the presence of ketanserin, whereas the stimulatory response to low concentrations of 5-HT (less than or equal to 10(-6) M) was not changed, that to high concentrations was reversed. The stimulation by 5-HT (less than or equal to 10(-5) M) was principally antagonized by MDL 72222. In the presence of both MDL 72222 and ketanserin, 5-HT inhibited the twitch contractions in a dose-dependent manner. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and BP-554 (1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenyl piperazine), selective 5-HT1A agonists, only inhibited the twitch contractions. Downward slope of the contraction-response curve of 5-HT (greater than or equal to 10(-5) 5 M) was shifted to right in the presence of 8-OH-DPAT. 5-HT and 8-OH-DPAT had no effect on the tension of unstimulated organs. Contractions elicited by ATP were potentiated by 5-HT, which was antagonized by ketanserin. 8-OH-DAPT did not affect ATP-elicited contractions. These results suggest the presence of presynaptic 5-HT1, maybe 5-HT1A and 5-HT3 receptors mediating inhibition and potentiation, respectively, of neurotransmitter release and of postsynaptic responsible for enhancing neurogenic contractions in mouse vas deferens.
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PMID:5-Hydroxytryptamine modulation of electrically induced twitch responses of mouse vas deferens: involvement of multiple 5-hydroxytryptamine receptors. 239 4

The subdivision of serotonin (5-HT) receptors into three classes, designated 5-HT1, 5-HT2, and 5-HT3, has been based on radioligand binding studies and experiments in isolated tissues. As a result of radioligand binding studies, two types of 5-HT recognition sites have been postulated. One site specifically labeled by [3H]5-HT was termed 5-HT1, and the other one labeled by [3H]spiperone or [3H]ketanserin was designated 5-HT2. The pharmacological properties of the latter sites are obviously identical to those of the majority of the classical "D" receptors, whereas a smaller proportion of "D" receptors resemble the 5-HT1 type. Hence, according to the current definition, 5-HT1 and 5-HT2 receptors mediate effects previously ascribed to "D" receptors. Three subtypes of 5-HT1 binding sites, designated 5-HT1A, 5-HT1B, and 5-HT1C, can now be distinguished by improved binding assay with rather selective radioligands. The identity of a given 5-HT binding site with a 5-HT receptor was suggested by correlating the agonists' and antagonists' affinities for the binding site with their potencies to produce certain effects. This was further confirmed by the development of rather selective agonists and antagonists. A third class of 5-HT receptors, the "M" receptors, which are now designated 5-HT3 in order to distinguish them from muscarinic cholinoceptors, were identified in functional in vitro experiments. They are present on terminals of sympathetic and parasympathetic nerves and on afferent nerve fibers. All three receptor classes are involved in cardiovascular regulation.
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PMID:Classification of serotonin receptors. 244 65

Intracellular recordings were made from fetal mouse spinal cord neurons in primary culture. One type of neuron, with large somata (40-50 microns diameter) and thick neurites exhibited endogenous bursting or beating pacemaker electrical activity. Noradrenaline depolarized this type of neuron by decreasing an M-like conductance. Micropressure application of serotonin (10(-5) M in the delivery pipette) onto the surface of pacemaker neurons evoked a depolarization of the membrane potential in a dose-dependent manner with an increased input resistance. No such response was observed with other types of spinal cord neurons in culture. The response to serotonin was partially voltage-dependent. The serotonin-induced depolarization reversed at holding potential close to -100 mV. However, the input resistance variation evoked by serotonin increased exponentially when membrane potential was depolarized. The reversal potential was modified by increasing extracellular K+ concentration and it was unaltered by increasing the intracellular Cl- concentration. The decrease in K+ conductance induced by serotonin was not suppressed by the application of tetraethylammonium (50 mM) or 4-aminopyridine (10 mM). Furthermore, application of Ba2+ (6 mM) or Cd2+ (0.1 mM) had no effect on this response, suggesting that the depolarization evoked by serotonin application was not calcium-dependent. The serotonin evoked increase in input resistance was mediated by activation of a 5-HT1A-like receptor site. Spiperone, a 5-HT1A antagonist reversibly blocked the response. Methiothepin, a 5-HT1-5-HT2 antagonist (10(-3) M); cocaine, a 5-HT3 antagonist (10(-3) M); ketanserin, a 5-HT2 antagonist (10(-3) M); and prazosin, an alpha 1 antagonist (10(-3) M) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory effect of serotonin on pacemaker neurons in spinal cord cell culture. 247 69

The effects of drugs that bind selectively to different serotonin (5-HT) receptor subtypes were assessed in pigeons. Keypecking was maintained by a multiple fixed-ratio schedule of reinforcement in which responding also was punished during one component. The greatest increases in punished responding were produced by the buspirone analogs BMY 7378 and ipsapirone, which act at the 5-HT1A receptor. RU 24969, with high affinity for both 5-HT1A and 5-HT1B receptors, and 1-(2-methoxyphenyl)piperazine, a 5-HT1 compound, increased punished responding to a lesser extent, as did the 5-HT2 antagonists ketanserin and ritanserin. The 5-HT3 antagonists GR 38032F, ICS 205930 and MDL 72222 showed little systematic effect, and the mixed 5-HT1B/5-HT1C compound 1-(3-chlorophenyl)piperazine produced only decreases in punished responding. Levels of neurotransmitter metabolites in cerebrospinal fluid were assessed across a wide dose range of representative drugs used in the behavioral studies. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were decreased significantly by BMY 7378 and ipsapirone, were not changed by ritanserin and were increased at one dose by MDL 72222. The results are consistent with suggestions that decreased 5-HT neurotransmission is involved in the effects of novel nonbenzodiazepine anxiolytics such as buspirone. Behavioral and neurochemical data also indicate that the effects of these drugs on other neurotransmitter systems do not play a significant role in their anxiolytic actions.
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PMID:Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes. 247 47


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