Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to examine the role of serotonin (5HT) in the discriminative stimulus effects of kappa opioids. Pigeons were trained to discriminate 5.6 mg/kg of the kappa opioid, U50,488, from water. During substitution tests, both U50,488 and another kappa opioid, spiradoline, produced > 80% responding on the U50,488-appropriate key. In contrast, the non-opioid compound, phencyclidine and several serotonergic compounds failed to substitute for the U50,488 discriminative stimulus across a wide range of doses. During combination tests, the selective 5HT1A agonist, 8-OH-DPAT (0.001-3.2 mg/kg), dose-dependently attenuated the discriminative stimulus effects of 5.6 mg/kg U50,488 and 3.2 mg/kg spiradoline. This effect was reversed by the 5HT1A antagonist, NAN-190 (0.01-1 mg/kg), in a dose-dependent manner. Buspirone (0.01-10 mg/kg), a 5HT1A partial agonist, also attenuated the discriminative stimulus effects of the training dose of U50,488 but ipsapirone, another 5HT1A partial agonist, did not. Ketanserin, a 5HT2 antagonist, and MDL72222, a 5HT3 antagonist, attenuated the effects of U50,488, whereas the 5HT1B,1C agonist, mCPP, and the 5HT2 agonist, DOI, did not. Depletion of 5HT with p-CPA also attenuated U50,488's discriminative stimulus effects. Taken together, the results suggest that serotonin release is an important component in the discriminative stimulus effects produced by kappa opioids; however, the effects of DOI and mCPP alone suggest that activation of post-synaptic 5HT receptors is not sufficient to produce the full spectrum of kappa opioid discriminative stimulus effects.
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PMID:Serotonin involvement in the discriminative stimulus effects of kappa opioids in pigeons. 787 Sep 36

Tertatolol is a beta-blocker with unique renal vasodilatatory effects, mainly at the level of the microcirculation. Since many vasodilatory agents inhibit human mesangial cell (HMC) proliferation, the effects of tertatolol on the incorporation of 3H-thymidine in HMC were studied. Tertatolol plus mitogens (either fetal calf serum, platelet-derived growth factor (PDGF) or bovine thrombin) were incubated with HMC for 28 h, and 3H-thymidine was added during the last 4 h. Trichloroacetic acid-precipitable counts per well were divided by the mean number of cells in representative wells from the same experiment. The effect of tertatolol on angiotensin II (10(-6) mmol/l)-induced HMC contraction was also assessed by measuring the planar surface area of individual cells. In serum-free media, tertatolol did not significantly alter the incorporation of 3H-thymidine after 28 h of incubation in HMC. When tertatolol was added in the presence of 1% serum, 3H-thymidine incorporation was significantly reduced, compared to 1% serum alone. Tertatolol also inhibited 3H incorporation when PDGF and thrombin were used as the stimulus. The increase in cell number normally seen after 7 days in serum was also reduced by tertatolol. Tertatolol inhibited the reduction in planar surface area of HMC induced by angiotensin II. The inhibitory effect of tertatolol on HMC proliferation was also potentiated by ritanserin and MDL 72222, 5HT2 and 5HT3 antagonists, respectively. Conversely, the 5HT1A agonist 8-OH-DPAT did not modify the 3H-thymidine incorporation in HMC in the presence of tertatolol. In conclusion, tertatolol inhibits HMC proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tertatolol: a beta-blocker with unique effects on human glomerular cell function. 790 16

In rabbits fed with hypercholesterolemic diet the normal coronary vasodilator response to serotonin is replaced by vasoconstriction sensitive to 5HT2 receptor blockade. These experiments were designed to determine the receptor subtype involved in the contractile response of large isolated coronary arteries (without endothelium) taken from control and atherosclerotic rabbits. In both tissues the agonists' rank potency was 5-carboxamidotryptamine > serotonin (5HT) > sumatriptan > 8-OHDPAT: (+/-)-8-Hydroxydipropylaminotetralin HBr > 2-methylserotonin. In arteries from young rabbits, 5HT and sumatriptan induced contractions which were not influenced by ketanserin up to 3 x 10(-8) M. However, the 5HT2 antagonist at the concentration of 10(-6) M induced a significant rightward shift of the concentration-response curves. The contractions to the two serotoninergic agonists were competitively inhibited by methiothepin. NAN 190, a 5HT1A antagonist, LY 53857, a 5HT1C and 5HT2 antagonist, cyanopindolol, a 5HT1A and 5HT1B antagonist and ICS 205-930, a 5HT3 and 5HT4 antagonist (up to 10(-6) M) did not inhibit the contractile response to 5HT. Rauwolscine (10(-6) M) significantly shifted the concentration-response curves to the two agonists. Very similar results were obtained in coronary arteries from atherosclerotic rabbits. These data demonstrate that in rabbit epicardial coronary artery smooth muscle, the receptor involved in the serotoninergic response is a 5HT1-like subtype, possibly a 5HT1D. In this preparation, under our experimental conditions, there was no evidence for the presence of 5HT2 receptors. The induction of atherosclerosis did not induce significant changes in the serotoninergic response in these large coronary arteries, illustrating the marked heterogeneity between microvasculature and large arteries in the rabbit heart.
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PMID:Serotoninergic receptor subtype in coronary artery smooth muscle from young and atherosclerotic rabbit. 830 47

The roles of 5-hydroxytryptaminergic (5HT) neurons and receptor subtypes in mediating the effects of stress on the activity of periventricular hypophysial dopaminergic (PHDA) neurons and the secretion of alpha-melanocyte-stimulating hormone (alpha MSH) were examined in female rats. Periventricular hypophysial dopaminergic neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid in the intermediate lobe of the pituitary. Brief exposure to diethylether followed by 30 min of supine restraint decreased intermediate lobe 3,4-dihydroxyphenylacetic acid concentrations and increased plasma concentrations of alpha MSH. These stress-induced effects were not observed in animals in which 5HT neurons had been previously destroyed by 5,7-dihydroxytryptamine or inhibited by the administration of the 5HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin. Pretreatment of rats with the 5HT2 receptor antagonist MDL-11,939 blocked the inhibitory effects of stress on intermediate lobe 3,4-dihydroxyphenylacetic acid concentrations and the corresponding increase in plasma alpha MSH concentrations, whereas the 5HT3 receptor antagonist ondansetron was without effect. These results reveal that 5HT neurons, acting via 5HT2 receptors, mediate the inhibitory effects of stress on periventricular hypophysial dopaminergic neurons and the consequent increase in secretion of alpha MSH.
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PMID:5HT2 receptors mediate the effects of stress on the activity of periventricular hypophysial dopaminergic neurons and the secretion of alpha-melanocyte-stimulating hormone. 838 38

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT1-5HT2 antagonist administered intravenously (200 micrograms/kg) or intracerebroventricularly (20 micrograms/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Spiroxatrine, a selective 5HT1A antagonist, intravenously (100 micrograms/kg) or intracerebroventricularly (10 micrograms/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT2 antagonist ritanserin given intravenously (200 micrograms/kg) or intracerebroventricularly (20 micrograms/kg). Granisetron, a 5HT3 antagonist, injected intravenously (150 micrograms/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 micrograms/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT1A and 5HT2 receptors at the level of the central nervous system and 5HT3 receptors located peripherally.
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PMID:Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep. 850 3

It seems that psychopharmacology may be well on its way toward the goal of developing new anxiolytic drug(s) that are fast acting and free from the unwanted effects associated with the traditional benzodiazepines. Several specific candidates exist, based upon rational targeting of neurotransmitter receptors shown to be linked to the neurobiology of anxiety. Thus, partial agonists at the benzodiazepine receptor, such as alpidem, abecarnil, and bretazenil, have highly promising preclinical profiles, and some useful preliminary results in clinical testing of anxiety disorder subjects. Neurosteroids are another interesting set of pharmacologic agents that target the benzodiazepine receptor, have a preclinical anxiolytic profile, and now need to be tested in clinical populations. Targeting of various serotonin (5HT) receptor subtypes is a very active area of current research for novel anxiolytic agents. 5HT3 antagonists may have an anxiolytic profile, but clinical results are still preliminary and need more validation. Of considerable interest is the idea of developing new drugs that act at 5HT1A, 5HT2A, or 5HT2C receptors. It has even been proposed that simultaneous targeting of both 5HT2A and 5HT1A receptors could result in robust anxiolytic agents that will have more immediate onset of action than currently available 5HT1A receptor acting drugs. Neuropeptide receptor agonists and antagonists with anxiolytic properties may represent one of the most striking new classes of potential anxiolytic drugs, but this is an emerging field that still requires considerably more systematic clinical testing. Nevertheless, preclinical studies as well as early clinical studies suggest that at least three neuropeptide receptors are provocative targets for novel anxiolytic agents: namely antagonists for CCK-B receptors, antagonists for CRF receptors, and agonists for neuropeptide Y receptors. Rational development of new pharmacologic agents based upon targeting receptors for those neurotransmitters that regulate the neurobiology of anxiety promises to bring forth a number of exciting therapeutic agents for the treatment of anxiety disorders in the future.
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PMID:Future directions in anxiolytic pharmacotherapy. 874 88

This experiment was conducted to determine whether drugs acting on brain serotonin modulate the effects of the mu opioid, morphine, as measured by the squirrel monkey shock titration procedure and, if so, whether serotonergic modulation is mediated via specific 5HT receptor subtypes. Under this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses on a lever during the 15-s shock period terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The intensity below which monkeys maintained shock 50% of the time (median shock level or MSL) and rate of responding (RR) in the presence of shock were determined under control conditions and after administration of morphine alone and in combination with various serotonergic compounds. Morphine increased median shock level and decreased rate of responding in a dose-dependent manner. These effects of morphine was attenuated by the 5HT1A receptor agonists, 8-OH-DPAT [(+)-8-hydroxy-2(di-n-propylamino tetralin HBr] and ipsapirone. The effects of morphine were not altered by the 5HT1A receptor antagonist, NAN-190 [1-(2-methoxyphenyl-4-[4-(2-phthalimido) butyl] piperazine HBr], and 5HT2 receptor antagonist, ketanserin, the 5HT3 receptor antagonist, MDL 72222 [3-tropanyl-3,5-dichlorobenzoate], the alpha 2 adrenergic antagonist, yohimbine, or the alpha2 adrenergic agonist, clonidine. These results suggest that 5HT1A receptors may be involved in the effects of morphine in the shock titration procedure, whereas 5HT2, 5HT3 and alpha 2 adrenergic receptors do not appear to play a role in morphine's effects in this procedure.
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PMID:The role of serotonergic receptors in the effects of mu opioids in squirrel monkeys responding under a titration procedure. 885 15

The 5HT1B agonist RU24969 (2.5-5.0 mg/kg) and anpirtoline (2.0 mg/kg) induced a striking increase in striatal Fos-like immunoreactivity in rats. In the rostral and dorsal regions of the striatum staining was dense and relatively homogeneous. In the ventral region of the striatum at more caudal levels, however, both drugs induced staining in patches which were in register with the opiate receptor rich striosomes. The effects of RU24969 could not be antagonized by the selective 5HT1A antagonist p-MPPI and little or no striatal Fos expression could be observed after injections of the selective 5HT1A agonist 8-OHDPAT or the selective 5HT3 antagonist MDL-72222.
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PMID:Serotonin-1B agonists induce compartmentally organized striatal Fos expression in rats. 960 97

Depression, a chronic disease and a leading cause of disability worldwide, will generate increasing needs in terms of public health in the coming years. Many antidepressants are now available. However, these molecules present real limitations and disadvantages. Thus there are great expectations on the part of the clinicians for more efficient drugs that are better tolerated. How can we satisfy such hopes and innovate in this domain today? One original and most promising strategy for developing new antidepressants that are more efficient and better tolerated involves antagonizing both alpha 2-noradrenergic and 5HT2 and 5HT3 serotonergic receptors, without blocking 5HT1A serotonergic receptors. The technology now available in pharmacological research allows the development of such molecules.
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PMID:[Pharmacological management of failure of treatment with antidepressants]. 992 1

Depression, a chronic disease and a leading cause of disability worldwide, will generate increasing needs in terms of public health in the coming years. Many antidepressants are now available. However, these molecules present real limitations and disadvantages. Thus there are great expectations on the part of the clinicians for more efficient drugs that are better tolerated. How can we satisfy such hopes and innovate in this domain today? One original and most promising strategy for developing new antidepressants that are more efficient and better tolerated involves antagonizing both alpha 2-noradrenergic and 5HT2 and 5HT3 serotonergic receptors, without blocking 5HT1A serotonergic receptors. The technology now available in pharmacological research allows the development of such molecules.
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PMID:[Pharmacological approach to failures of antidepressant treatment]. 994 41


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