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Results for “Serotonin 5-HT1 Receptor Agonists”

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At least 19 recordsLinked to original sources

PubMed1992

Serotonin agonists increase transferrin levels via activation of 5-HT1C receptors in choroid plexus epithelium.

Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.

Amino Acid Isomerases↗

PubMed1992

[Sumatriptan and its use in treatment of migraine and cluster headaches].

The methods used presently for abortion of the attacks of migraine and cluster headache are not fully satisfactory which causes that the search for new therapies is continuing. Although the mechanism of migraine attacks remains unexplained, it is thought that an important role in it is played by serotonin receptors, vasodilation in certain regions and opening of arteriovenous communications in the head. Sumatriptan is an agonist of 5-HT1 -like receptors and exerts a selective vasoconstricting effect on the arteries of the head, particularly in the rami of the carotid artery. In 1988 the first reports appeared on the effectiveness of the drug in migraine attacks. In the following years extensive, multicentre and international studies of the drug were carried out on over 600 healthy volunteers and nearly 6000 patients with migraine. The studies demonstrated that Sumatriptan was effective in abortion of migraine attacks. After oral administration of 100 mg or subcutaneous injection of 6 mg in nearly 70% of cases the attack regressed or was greatly alleviated, similarly as other symptoms accompanying the headache such as photophobia, nausea, vomiting. Studies were undertaken also on the effectiveness of Sumatriptan in emergency treatment of cluster headache, and good results were again achieved. The tolerance of the drug is good, although in some cases side effects develop, usually transient and mild, among them tingling, feeling of pressure, heat or heaviness of the head or chest, taste change and burning sensation at the site of injection. Sumatriptan, similarly as all novel drugs, requires caution in its use, particularly in patients with coronary heart disease and hypertension, and also in old patients. As yet, the use of the drug in paediatric migraine or in pregnancy is not recommended.

Cluster Headache↗

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

[The role of serotonin in the pathophysiology of migraine].

Of the many factors that have been implicated in the pathophysiology of migraine, none seems to have a better claim than serotonin (5-hydroxytryptamine, 5-HT). The evidence for this is: 5-HT concentrations in blood increase during the prodromal (aura) phase and subsequently, decrease to subnormal levels in the headache phase; migraine attacks may be triggered, in susceptible, subjects, by reserpine which depletes body serotonin; migraine attacks may be triggered, in susceptible subjects, by reserpine which depletes body serotonin; migraine attacks may be relieved by intravenous injection of 5-HT; medications known to affect 5-HT concentrations have been shown to be efficacious in both aborting (agonists of 5-HT1 receptors) and preventing (antagonists of 5-HT2 receptors) migraine attacks. Since most of 5-HT in blood is stored in the platelets, attention of many investigators focused on the platelet function abnormalities. The positive findings provoked some of them to hypothesise that migraine is a primarily platelet disorder. Advances in the understanding of the role of 5-HT in migraine and the pharmacology of this amine have now resulted in the development of a highly selective 5-HT1 -like receptor agonist which selectively constricts cranial blood vessels and inhibits neurogenically-mediated plasma protein extravasation in the dura mater.

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↗

PubMed1992

[Sumatriptan--future development, alternative features and potential new indications].

Sumatriptan is a highly selective 5 HT1 receptor subtype agonist. The efficacy and safety profiles of sumatriptan given by tablet or subcutaneous injection have been extensively investigated in the acute treatment of migraine attacks, where it has proved effective and well tolerated. A substantial proportion of patients with an acute attack of migraine suffer from once or more gastrointestinal symptom, including nausea, vomiting and occasionally diarrhoea. The presence of these symptoms may make the oral administration of acute treatments unsatisfactory. Subcutaneous administration is an alternative, but fear or dislike of injections or an inability to self inject makes subcutaneous treatment unacceptable to some patients. Alternative routes of administration are being investigated to overcome these difficulties including intranasal sprays and rectal suppositories. For those patients who experience difficulties swallowing whole tablets, an effervescent tablet is under development. Recent data have demonstrated that sumatriptan offers effective relief of cluster headache attacks, a condition where suffers experience repeated severe headache attacks, of short duration, during a cluster period. Further new indications are being investigated including the treatment of menstrual migraine, paediatric migraine and other headaches.

Administration, Oral↗

PubMed1992

Serotonin-norepinephrine interactions: a voltammetric study on the effect of serotonin receptor stimulation followed in the N. raphe dorsalis and the Locus coeruleus of the rat.

In vivo voltammetry with carbon fibre electrodes was used to study the effect of the serotoninergic (5-HT) neuronal system on the noradrenergic (NE) system in the Locus coeruleus of the rat. The voltammetric DOPAC signal in the Locus coeruleus, used as a measure of NE neuronal activity, was increased after systemic application of the 5-HT1B agonist CGS-12066B, the 5-HT2 antagonist ritanserin, and, to a lesser extent, by ipsapirone, a 5-HT1A agonist. The findings suggest that the NE neuronal system of the Locus coeruleus is stimulated by 5-HT1A and 5-HT1B receptor activation and inhibited by 5-HT2 receptors. Likewise the 5-HT releaser and uptake inhibitor fenfluramine increased the DOPAC level in the Locus coeruleus. In contrast to the 5-HT1 agonists, which reduced 5-hydroxyindoleacetic acid (5-HIAA) in the Nucleus raphe dorsalis, ritanserin increased the 5-HIAA signal in this nucleus. This finding could help to explain the action of ritanserin as sleep-modulating substance.

3,4-Dihydroxyphenylacetic Acid↗

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

Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake?

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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

Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics.

The general purpose of the present study was to analyze the possible interactions between the GABA-benzodiazepine and the serotonergic (5-HT) systems in the anxiolytic action of diazepam and the 5-HT1A agonists, ipsapirone, indorenate, and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effect of the benzodiazepine receptor antagonist, flumazenil (10.0 mg/kg), on the anxiolytic action of ipsapirone (5.0 mg/kg), indorenate (5.0 mg/kg), and 8-OH-DPAT (0.125 mg/kg) was examined on the avoidance exploratory behavior paradigm in mice. The effect of the 5-HT1 blockers, methiotepin (0.31 mg/kg), pindolol (3.1 mg/kg), and alprenolol (5.0 mg/kg), on the anxiolytic action of diazepam (0.5 mg/kg) was also studied. In the last part of this work, the putative potentiation between diazepam (0.25 mg/kg) and each of the serotonergic anxiolytics was investigated. The antianxiety effect of diazepam, ipsapirone, indorenate, and 8-OH-DPAT was prevented by flumazenil. The serotonergic/beta-blocker, alprenolol, partially antagonized the diazepam effect. Finally, a potentiation of suboptimal doses of diazepam and ipsapirone, but not with indorenate or 8-OH-DPAT, was observed. The findings suggest an interaction between both systems on the anxiolytic action of diazepam and the 5-HT1A agonists.

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

PubMed1992

Role of alpha-adrenoceptors in the effects of buspirone and 5-carboxamidotryptamine in rabbit isolated thoracic aorta.

1. The role of alpha-adrenoceptors in the vascular effects of buspirone (BUS) and 5-carboxamidotryptamine (5-CT) was investigated in rabbit thoracic aorta. 2. Buspirone produced a concentration-dependent contraction. The non-selective 5-HT1 and 5-HT2-receptor antagonist methysergide and the 5-HT2 receptor antagonist ketanserin did not alter the contractile effect of buspirone. However, the competitive antagonist of alpha 1-adrenoceptors, prazosin, shifted the concentration-response curve of buspirone to the right without changing the maximal response. 3. Benextramine tetrahydrochloride monohydrate (BHC), a noncompetitive antagonist of alpha 1-adrenoceptors, inhibited the contraction induced by buspirone in a noncompetitive manner. After pretreatment with two different concentrations of BHC, the estimated apparent dissociation constants of buspirone were found to be identical. 4. In addition, buspirone antagonized the concentration-response curve of phenylephrine again showing a similar dissociation constant, suggesting a partial agonistic action of buspirone at the level of alpha 1-adrenoceptors. 5. The concentration-response curve of 5-HT showed two components in the thoracic aorta obtained from reserpine treated and untreated animals as verified by different pD2 values. The second component was observed with relatively higher concentrations of 5-CT and could be blocked by prazosin or BHC. Neither of these compounds altered the first component. After Pretreatment with BHC, the first component of 5-CT was competitively antagonized by methysergide and ketanserin, having pA2 values of 8.81 and 9.1 respectively. 6. These results suggest that the contraction induced by buspirone is mainly mediated by alpha 1-adrenoceptors, while the higher concentrations of 5-CT caused contraction via alpha 1-adrenoceptor stimulation in addition to its 5-HT2 agonistic effect.

Adrenergic alpha-Antagonists↗

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↗

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

Pharmacological analysis of the cardiac effects of 5-HT and some 5-HT receptor agonists in the pithed rat.

A pharmacological analysis of the effects of 5-HT on heart rate has been performed in the pithed rat. 5-HT induced a dose-dependent increase in heart rate whereas 5-HT1 receptor agonists--8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT), 5-methoxy 3-(1,2,3,6-tetrahydro-4-piridinyl) 1H indole (RU 24969) and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP)--failed to increase heart rate. The increase in heart rate induced by the selective 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI) was not significant. The dose-response curve to 5-HT for its tachycardic effects was shifted two-fold to the right by ketanserin and LY 53857 and nine-fold to the right by methiothepin. The effects of high doses of 5-HT (higher than 100 micrograms/kg iv) were antagonized by methiothepin, (-)propranolol, 2-(2-[4(O-methoxyphenyl)-piperazine-1-yl]-ethyl)4,4-dimethyl-1,3 (2H-4H) isoquinoline-dione (AR-C 239) and by pretreatment with reserpine. The 5-HT1 receptor antagonists, pindolol and spiroxatrine, the 5-HT3 receptor antagonist MDL 72222 and the alpha 2-adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5-HT. It is concluded that in the pithed rat, the tachycardia induced by 5-HT remained unexplained (implication of 5-HT2 receptors probably different from the classical vascular 5-HT2 receptor, or implication of 5-HT1C receptors?). Moreover, at high doses (higher than 100 micrograms/kg iv), 5-HT may increase heart rate by releasing catecholamines.

Animals↗