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At least 19 recordsLinked to original sources

PubMed1992

Fluoxetine: a review of receptor and functional effects and their clinical implications.

Downregulation of serotonin 5-HT1 receptors is the most frequently reported central nervous system neural effect of subchronic exposure to fluoxetine in rodents. However, downregulation of these receptors has not been universally demonstrated. Effects of subchronic exposure on 5-HT2 receptors are mixed. Fluoxetine exposure appears to have no effect on cholinergic muscarinic receptors. Effects on beta-adrenergic receptors are controversial, as only one laboratory has reported downregulation. The majority of studies have failed to show an effect on beta-adrenergic-receptor-stimulated cAMP generation. Electrophysiologic studies support the concept that fluoxetine facilitates net serotonergic transmission through downregulation of presynaptic inhibitory autoreceptors. Data suggest that its subchronic specificity and selectivity distinguish fluoxetine from members of other classes of available antidepressants, making it a distinct therapeutic option.

Animals↗

PubMed1992

From serotonin receptor classification to the antimigraine drug sumatriptan.

After the synthetic serotonin 5-hydroxytryptamine (5-HT) became available in the early 1950s, attempts were soon under way to study the nature of 5-HT receptors. Using the guinea-pig isolated ileum, Gaddum and Picarelli (1957) suggested that 5-HT-induced contractions were mediated by a morphine-sensitive "M" receptor located on the parasympathetic ganglion and a dibenzyline-sensitive "D" receptor located on the smooth muscle. Though this classification ws used during the next three decades, it was realized that some effects of serotonin, for example vasoconstriction within the carotid vascular bed, were not mediated by either "M" or "D" receptors. When radioligand binding studies led to the identification of 5-HT1 and 5-HT2 "receptors" in the rat brain membranes, it became increasingly apparent that the two receptor classifications were not identical. Thus, a new framework for serotonin receptor nomenclature and classification was proposed: 5-HT1-like (5-HT1), 5-HT2 (formerly "D") and 5-HT3 (formerly "M") receptors. At the present time, several subtypes of 5-HT1 receptors as well as a 5-HT4 receptor are also recognized. As the serotonin receptor classification was emerging to indicate that carotid vasoconstriction by serotonin is mediated by a subtype of 5-HT1 receptors, on the migraine front it was being suggested that the disease is associated with vasodilation within the cranial extracerebral circulation and deranged serotonin metabolism and that certain antimigraine drugs caused a selective carotid vasoconstriction, probably via serotonin receptors. Therefore, Humphrey and colleagues conceived that synthesis of serotonin derivatives may lead to a compound that would elicit highly selective carotid vasoconstriction and abort migraine attacks. Indeed, via the synthesis of 5-carboxamidotryptamine and AH25086, sumatriptan was designed. The drug acts as an agonist at the vasoconstrictor 5-HT1 receptor subtype and has proved highly effective in the therapy of migraine attacks.

Animals↗

PubMed1992

Blockade of electrical field stimulation-induced nonadrenergic noncholinergic (NANC) excitatory response of the guinea pig ileum.

Determination of guinea pig ileal response to electrical field stimulation (EFS) before and after complete adrenergic and cholinergic blockade showed that the nonadrenergic noncholinergic excitatory (NANC-e) response contributed 40% to the total contractile response. NANC-e responses were reproducible to consecutive identical EFS. Tetrodotoxin significantly blocked the NANC-e response. The NANC-e responses obtained before and after treatment of the tissues with receptor antagonists of histamine (pyrilamine), substance P ([D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP) and serotonin (5-HT1 & 5-HT2) indicated that the response could be blocked by substance P and serotonin antagonists. Only the serotonin antagonist cyproheptadine produced a dose-dependent blockade. Both substance P and serotonin are suggested to play an important role in the NANC-e neurotransmission.

Animals↗

PubMed1992

Mechanism of halothane attenuation of isometric tension induced by serotonin in isolated canine coronary artery rings.

We explored the mechanism of halothane's interaction with the serotoninergic contractile response of isolated canine coronary artery rings. The serotoninergic contractile response of both intact and denuded rings was measured with and without halothane. In some experiments, rings were pretreated with methiothepin, a 5-HT1 and 5-HT2 antagonist, or ketanserin, a 5-HT2 antagonist. The contractile responses to 5-carboxamidotryptamine (5-CT) and alpha-methylserotonin, a 5-HT1 and a 5-HT2 receptor agonist, respectively, were measured with and without halothane. Finally, the response to prostaglandin F2-alpha, another spasm mediator, was also measured with and without halothane. Halothane attenuated the coronary artery response to serotonin (5-hydroxytryptamine, 5-HT), and specific 5-HT1 and 5-HT2 agonists, and prostaglandin F2 alpha (PGF2 alpha). Its inhibitory effect on the serotoninergic response was abolished in vessels pretreated with either 5-HT1 or 5-HT2 blockers. These data suggest that halothane is not a direct smooth muscle depressant, that it is not a specific 5-HT1- or 5-HT2-subtype antagonist in canine coronary arteries, and that it might interfere with intracellular pathways activated by agonist-receptor interactions.

Animals↗

PubMed1992

5-HT4 receptor activation induces relaxation and associated cAMP generation in rat esophagus.

Changes in mechanical events and intracellular levels of cAMP induced by the activation of the 5-HT4 receptor were investigated in the rat esophagus tunica muscularis mucosae preparation. Serotonin (5-HT) and 5 methoxytryptamine (5-MOT; 5-HT4 agonist) caused concentration-related relaxation responses, while 5-carboxamidotryptamine (5-CT; 5-HT1 agonist), 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI; 5-HT2 agonist) and 2-methyl-serotonin (2-methyl-5-HT; 5-HT3 agonist) were less active. The prokinetic agents, cisapride and renzapride also induced concentration-dependent relaxation of rat esophagus which was intermediate to 5-HT and 5-MOT in potency. The relaxation was not due to activity at receptors other than the 5-HT4 since methysergide (5-HT1 and 5-HT2 antagonist) and granisetron (5-HT3 antagonist) did not block the relaxant response to 5-HT while ICS 205930 (5-HT4 antagonist) antagonized this response (pA2 = 6.45). Serotonin also caused concentration-related increases in tunica muscularis mucosae cAMP with the rank order of efficacy of 5-HT agonists in raising tissue cAMP levels reflecting their relaxant activities (5HT greater than or equal to 5-MOT greater than 5-CT greater than DOI = 2-methyl-5-HT = control). Enhancement of cAMP concentrations was also observed following renzapride treatment. This cAMP relaxation response was specific for 5-HT4 receptor activation as demonstrated by the lack of ICS 205930 inhibition of rat esophagus relaxation caused by isoproterenol, 16,16-dimethyl-prostaglandin E2 and forskolin.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Methoxytryptamine↗

PubMedDate not supplied

[Changes in the properties of the 5-HT1 receptors in the brains of rats, the progeny of parents consuming morphine for a long time].

Studies were performed in two-month rats whose parents had been given morphine for a long period before mating. Considerable changes were found in the properties of rat brain 5-HT1 receptors, which manifested as increased number of ligand binding sites (Bmax) and higher KD, which indicates a lower receptor affinity for ligand. Single morphine administration to the animals caused normalization of the properties of the receptors.

Animals↗

PubMed1992

Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat.

Most antidepressants produce changes in monoamine receptors in brain after chronic administration in animals. The most commonly described alterations are a decreased density and function of beta-adrenergic receptors and have been postulated to be the mechanisms by which antidepressants exert their therapeutic effect. Milnacipran (previous name midalcipran) is a new, clinically-effective antidepressant, which inhibits the uptake of both serotonin and noradrenaline but has no affinity for any pre- or postsynaptic receptor studied. When given either orally at 7.5 mg/kg twice daily for 3 days, at 30 mg/kg once daily for 3 weeks, by osmotic mini-pump at 30 mg/kg/day for 27 days, or in drinking water at approximately 15 mg/kg/day for 6 weeks and after a washout period of 24 hr, milnacipran produced no down-regulation of beta-adrenoceptors. In addition, there were no alterations of alpha 1- or alpha 2-adrenoceptors, 5-HT1, 5-HT2 receptors or benzodiazepine binding sites. Moreover, uptake and accumulation of serotonin and noradrenaline were unmodified. In addition, the potency for milnacipran to inhibit monoamine uptake in vitro in the cortex was not altered in treated rats, compared to control animals. Thus, in spite of its action on both the uptake of serotonin and noradrenaline, milnacipran appears to be without long-term action on beta-adrenoceptors or the other receptors studied, suggesting that, at least for this antidepressant, these modifications are not essential for clinical activity.

Animals↗

PubMed1992

Effects of serotonin and cAMP on calcium currents in different neurones of Helix pomatia.

Effects of application of serotonin (5-HT) and intracellular administration of cyclic adenosine monophosphate (cAMP) on voltage-gated calcium current (ICa) were studied in isolated, intracellularly perfused Helix pomatia neurones. Two types of the effects of 5-HT (1-10 microM) were observed in different neurones: reversible inhibition (by about 20%) or reversible potentiation (up to 50%) of the current amplitude. Some cells did not respond to 5-HT application. In cells with the potentiating effect of 5-HT, ICa could also be increased by intracellular introduction of cAMP (100 microM), but not the guanosine analogue, cGMP (50-100 microM). These effects were not additive and could be potentiated by theophylline (5 mM) and 3-isobutyl-1-methylxanthine (IBMX, 100-500 microM); they could be mimicked by forskolin (10-50 microM) and abolished by tolbutamide (1-5 mM) or protein kinase inhibitor (500 micrograms/ml), indicating that cAMP-dependent phosphorylation mediates the potentiating action of 5-HT on ICa. In neurones showing inhibitory effect of 5-HT, neither cAMP nor forskolin increased ICa. Methiothepin (10-50 microM), a 5-HT1,2 receptor antagonist, irreversibly inhibited the potentiating effect of 5-HT, while antagonists of 5-HT2 receptors cyproheptadine (10-50 microM) or ketanserine (10-60 microM) and of 5-HT3 receptors ISC 205-930 (10-50 microM) or cocaine (5-25 microM) had no effect on ICa and its enhancement by 5-HT. It is suggested that in certain snail neurones the possibility of cAMP-dependent up-regulation of ICa correlates with the presence of 5-HT1-like receptors in the neuronal membrane.

Animals↗

PubMed1992

Neurochemical effects of 5-HT1 receptor ligands in pigeons.

Pigeon cerebrospinal fluid was assayed for 5-HT (5-hydroxytryptamine) and catecholamine metabolites after systemic drug injection. The 5-HT1-like receptor agonists 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), and 1-(3-chlorphenyl)piperazine (mCPP) decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) without altering other metabolites. 5-HIAA decreases occurred at doses of 8-OH-DPAT and RU 24969 that have anti-conflict effects in pigeons, whereas TFMPP and mCPP decreased 5-HIAA only at behaviorally disruptive doses. The novel compound 1-(2-methoxyphenyl)-1-(4-(2-phthalimido)butyl)piperazine (NAN-190), a putative 5-HT1A receptor antagonist, did not affect 5-HIAA, but attenuated the decreases produced by the agonists. NAN-190 and the alpha 1-adrenoceptor antagonist prazosin increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol and had additive effects when co-administered. The rank order of potency in inhibiting [3H]8-OH-DPAT binding in pigeon cerebrum was 8-OH-DPAT = RU 24969 > NAN-190 >> mCPP > TFMPP. The results support suggestions that decreased 5-HT neurotransmission underlies the anxiolytic-like effects of 5-HT1A receptor agonists in pigeons.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

An investigation of the 5-HT1D receptor binding affinity of 5-hydroxytryptamine, 5-carboxyamidotryptamine and sumatriptan in the central nervous system of seven species.

The ability of three 5-HT1 receptor agonists, 5-HT (5-hydroxytryptamine), 5-CT (5-carboxyamidotryptamine) and sumatriptan to inhibit the binding of [3H]5-HT, in the presence of cyanopindolol and mesulergine, from cerebral cortical and/or caudate membranes in seven species (dog, guinea-pig, rabbit, pig, human, hamster and calf) has been investigated. Under the experimental conditions used, 5-CT and sumatriptan consistently yielded displacement curves best fit to a two-site model whereas 5-HT always gave a monophasic displacement curve. The pIC50 values obtained with 5-HT displacement gave a mean of 8.1 +/- 0.1 (mean +/- S.E.M.). In contrast the biphasic displacement curves for 5-CT and sumatriptan yielded high and low affinity pIC50 values of 8.3 +/- 0.1, 5.5 +/- 0.1 and 7.6 +/- 0.1, 5.0 +/- 0.1, respectively. These data indicate that under these experimental conditions the high affinity component labelled by [3H]5-HT is the same receptor subtype, previously denoted the 5-HT1D receptor, in all seven species.

Animals↗

PubMed1992

Prior chronic exposure to cocaine inhibits the serotonergic stimulation of ACTH and secretion of corticosterone.

The effect of long-term pretreatment with cocaine on serotonergic regulation of ACTH (adrenocorticotropic hormone; corticotropin) and secretion of corticosterone in rats was investigated. The following observations were made: (1) Pretreatment with cocaine had no significant effect on basal levels of ACTH and corticosterone in plasma. However, cocaine caused a reduction in the ability of the 5-HT (5-hydroxytryptamine, serotonin) releaser p-chloroamphetamine (PCA) to increase corticosterone in plasma, 42 hr after the last injection of cocaine. (2) Exposure to cocaine for 7 days was sufficient to produce a maximal inhibition of the PCA-induced increase in ACTH in plasma. (3) The inhibitory effect of cocaine on PCA-induced release of ACTH was more marked than on corticosterone. (4) Conversely, the dose-dependent stimulatory effect of two 5-HT1 agonists, RU 24969 (5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole) and m-CPP (m-chlorophenylpiperazine), on ACTH and corticosterone was not reduced by 7 days of exposure to cocaine. Taken together, these findings indicate that pretreatment with cocaine reduced the function of serotonergic nerve-terminals but not postsynaptic receptors, that stimulate ACTH and secretion of corticosterone.

Adrenocorticotropic Hormone↗

PubMed1992

Pharmacological profile of the 5-hydroxytryptamine receptor that mediates relaxation of rat oesophageal smooth muscle.

1. The pharmacological profile of the inhibitory 5-hydroxytryptamine (5-HT) receptor in rat oesophageal smooth muscle has been characterized by means of a series of agonists active at 5-HT1-, 5-HT2-, 5-HT3- and 5-HT4-receptor sites, and a broad range of antagonists. The possible involvement of cyclic nucleotides in the 5-HT response was also examined. 2. Under conditions of tone induced by muscarinic receptor activation, the upper two-thirds (proximal segment) of the oesophageal smooth muscle tunic was more sensitive to the inhibitory effects of 5-HT receptor agonists when compared with the distal region. 3. The inhibitory response to 5-HT was blocked by MDL 72222 (5-HT3 antagonist) and ICS 205-930 (5-HT3/5-HT4 antagonist) but not by antagonists active at 5-HT1- or 5-HT2-receptors. 4. The phosphodiesterase inhibitor, 3-isobutyl-methyl-xanthine (IBMX) enhanced oesophageal smooth muscle inhibitory response to 5-HT, isoprenaline and forskolin, but not that elicited by the potassium channel opener, BRL 34915. 5. 5-HT increased tissue cyclic AMP content over basal levels in proximal and distal segments of oesophageal smooth muscle. However, 5-HT had no significant effect on basal cyclic GMP levels in both segments. 6. We conclude that the inhibitory 5-HT receptor in rat oesophageal smooth muscle may represent a high affinity subtype which is sensitive to 5-HT3/5-HT4 antagonists and is coupled to the cyclic AMP pathway.

Animals↗

PubMed1992

Agonist activity of sumatriptan and metergoline at the human 5-HT1D beta receptor: further evidence for a role of the 5-HT1D receptor in the action of sumatriptan.

We have recently cloned a novel human 5-HT1D receptor subtype termed 5-HT1D beta. CHO K1 cells expressing the human serotonin 5-HT1D beta receptor were assayed to determine the second messenger system of this receptor. Cyclic AMP radioimmunoassays revealed that the 5-HT1D beta receptor is negatively coupled to adenylate cyclase in this cell system. A maximum of 50% inhibition of forskolin stimulated cAMP production was obtained with 5-HT1 receptor agonists which was blocked by the non-selective 5-HT receptor antagonist methiothepin (pKB = 100 nM). The novel anti-migraine drug sumatriptan, a putative 5-HT1D selective compound, acted as an agonist at the 5-HT1D beta receptor. Most notably metergoline, a putative 5-HT1 receptor antagonist, did not block the effects of 5-HT and was found to be acting as a full agonist at the 5-HT1D beta receptor. The ability of metergoline to act as an agonist at the 5-HT1D beta receptor may explain why it does not inhibit 5-HT and sumatriptan induced contraction of dog saphenous vein and other large conducting arteries. These results suggest that the 5-HT1D beta receptor may be the site of action of sumatriptan in preventing migraine, and that metergoline's actions on the dog saphenous vein are not contradictory to that hypothesis, as previously reported.

Cells, Cultured↗

PubMedDate not supplied

Scheduling of monoaminergic neurotransmitter receptor expression in the primate neocortex during postnatal development.

Quantitative in vitro autoradiography was used to study the postnatal development of monoaminergic receptors (D1 and D2 dopaminergic, 5-HT1 and 5-HT2 serotonergic, and alpha 1, alpha 2, and beta noradrenergic sites) in the prefrontal, primary motor, somatosensory, and visual cortex of rhesus monkeys at birth and 1, 2, 4, 8, 12, 36, and 60 months of age. The density of all receptors studied increased rapidly within the first 2 postnatal months to levels as high as two times that recorded in the adults. After the fourth month, receptor density began a decline that subsided around the time of puberty. This course of developmental change was similar in all cortical layers and in all regions examined. However, the magnitude of the transient overproduction and eventual reduction in receptor density varied across the cortical layers and cytoarchitectonic areas in a manner specific to the individual receptor sites. Overall, cortical maturation was associated with the increased tendency of monoaminergic receptors to concentrate preferentially in the superficial cortical layers. The common developmental course of monoaminergic receptors in diverse cytoarchitectonic areas reveals an impressive coordination in the expression and regulation of these functionally relevant proteins in the cerebral cortex during infancy and adolescence.

Aging↗

PubMed1992

Terminal autoreceptor control of 5-hydroxytryptamine release as measured by in vivo microdialysis in the conscious guinea-pig.

In vivo microdialysis in the frontal cortex of the freely moving guinea-pig was used to measure extracellular 5-hydroxytryptamine (5-HT) and study terminal autoreceptor control of its release. The indoleamine levels were determined by HPLC with electrochemical detection. Release of extracellular 5-HT and, to a lesser extent, 5-hydroxyindoleacetic acid was sensitive to tetrodotoxin, confirming the neuronal origin of measured neurotransmitter levels. Both systemic and local administration of the 5-HT1 agonist 5-carboxamidotryptamine caused inhibition of extracellular 5-HT levels, confirming the regulatory role of the terminal, and possibly also the somatodendritic, 5-HT autoreceptor on neuronal 5-HT release. Levels of extracellular 5-hydroxyindoleacetic acid were not affected by 5-carboxamidotryptamine following either central or peripheral administration.

Animals↗

PubMed1992

Inhibition of [3H] gamma-aminobutyric acid release from guinea-pig hippocampal synaptosomes by serotonergic agents.

We studied the effects of (m-trifluoromethyl-phenyl)piperazine (TFMPP) and quipazine on the K(+)-evoked [3H]GABA release from guinea-pig hippocampal synaptosomes loaded with [3H]GABA.TFMPP and quipazine inhibited the K(+)-evoked release of [3H]GABA dose-dependently (IC50 = 153 and 123 microM, respectively). Serotonergic antagonists such as methiothepin (0.1, 0.3 and 1 microM), ketanserin (0.1, 0.3 and 1 microM), dihydroergotamine (0.1 microM), metergoline (0.1 and 0.3 microM), methysergide (0.3 microM), propranolol (1 microM) and yohimbine (1 microM) did not significantly alter the inhibitory effect of TFMPP on [3H]GABA release suggesting that neither 5-HT1 nor 5-HT2 receptors are involved in this process. By contrast, the effect of TFMPP was diminished by selective 5-HT3 receptor antagonist: MDL 72222 (0.3 microM), tropisetron (0.3 and 1 microM), ondansetron (0.3 microM) and metoclopramide (1 microM). Tropisetron (1 microM) and ondansetron (0.3 microM) also inhibited significantly the quipazine effect whereas methiothepin (1 microM), dihydroergotamine (0.1 microM), yohimbine (1 microM) and ketanserin (1 microM) were ineffective on the quipazine inhibition of [3H]GABA release. Our results show a serotonergic modulatory effect on the K(+)-evoked [3H]GABA release from guinea-pig hippocampal synaptosomes by receptors which are neither 5-HT1, 5-HT2 or 5-HT4. They appear to be pharmacologically related to the 5-HT3 type but different from the 5-HT3 ionic channel receptors.

Animals↗

PubMed1992

Studies on the mechanism of 5-HT1 receptor-induced smooth muscle contraction in dog saphenous vein.

1. We have investigated the mechanism of smooth muscle contraction evoked by activation of 5-HT1-like receptors in dog isolated saphenous vein. 2. In the presence of the 5-HT2 receptor antagonist, ritanserin (0.1 microM), concentration-effect curves (10 nM-300 microM) for 5-hydroxytryptamine (5-HT)-induced smooth muscle contraction were biphasic. This could be attributed to a direct action on 5-HT1-like receptors at low concentrations of 5-HT (10 nM-10 microM) and an indirect (through the release of noradrenaline from sympathetic neurones) activation of postjunctional alpha-adrenoceptors at higher 5-HT concentrations. In contrast, concentration-effect curves (100 nM-100 microM) for sumatriptan-induced contractions were not biphasic, and were due solely to activation of 5-HT1-like receptors. 3. Smooth muscle contractions evoked either by low concentrations of 5-HT or by sumatriptan were abolished by removal of extracellular calcium and were markedly inhibited, but not abolished, by the calcium channel blocker, verapamil (1-30 microM). In contrast, contractions evoked by high concentrations of 5-HT were markedly less sensitive to removal of extracellular calcium or to verapamil. 4. 5-HT and sumatriptan also inhibited (to a maximum of about 50%) prostaglandin E2 (PGE2, 5 microM)-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. This effect was mimicked by the alpha 2-adrenoceptor agonist, azepexole (B-HT933) but not by the alpha 1-adrenoceptor agonist, methoxamine.5. In contrast to mediation of smooth muscle contraction, the 5-HT1-like receptor-mediated inhibition of PGE2-stimulated cyclic AMP formation evoked by 5-HT or sumatriptan was not attenuated by removal of extracellular calcium or by verapamil (1 microM).6. A directly-acting inhibitor of adenylyl cyclase, 2',3'-dideoxyadenosine (1 mM) inhibited PGE2-stimulated cyclic AMP formation but did not produce smooth muscle contraction.7. These results suggest that contractile responses of dog isolated saphenous vein arising through activation of 5-HT1-like receptors are associated with both an influx of extracellular calcium ions (to a large extent via voltage-dependent channels) and an inhibition of adenylyl cyclase. However, although these two responses are coupled to the same receptor, they appear to be independent.

Adenylyl Cyclase Inhibitors↗

PubMed1992

The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase.

1. The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2. The voltage-activated K+ current of the neurones was partially blocked by 8-bromo adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205,930, the classical 5-HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5-HT4 receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K+ current. 4. The current was insensitive to the 5-HT1 and 5-HT3 receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24,969, carboxamidotryptamine, 2-CH3-5-HT) as well as to 5-HT1, 5-HT2 and 5-HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38,032]). Moreover, these antagonists did not affect the actions of the tested 5-HT4 receptor agonists. 5. The present results show that part of the voltage-activated K+ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT4 receptor subtype.The putative implication of 5-HT4 receptors in neuronal plasticity, via a blockade of K+ channels, is discussed.

Animals↗