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PubMed2005

Involvement of pre- and post-synaptic serotonergic receptors of dorsal raphe nucleus neural network in the control of the sweet-substance-induced analgesia in adult Rattus norvegicus (Rodentia, Muridae).

In order to investigate the effects of monoaminergic mechanisms of the dorsal raphe nucleus on the elaboration and control of sweet-substance-induced antinociception, male albino Wistar rats weighing 180-200 g received sucrose solution (250 g/L) for 14 days as their only source of liquid. After the chronic consumption of sucrose solution, each animal was pretreated with unilateral microinjection of methiothepin mesylate (5.0 microg/0.2 microL), or methysergide maleate (5.0 microg/0.2 microL) in the dorsal raphe nucleus. Each rat consumed an average of 15.6g sucrose/day. Their tail withdrawal latencies in the tail-flick test were measured immediately before and after this treatment. An analgesia index was calculated from the withdrawal latencies before and after the pharmacological treatment. The blockade of serotonergic receptor in the dorsal raphe nucleus with methysergide after the chronic intake of sucrose decreased the sweet-induced antinociception. However, microinjections of methiothepin in the dorsal raphe nucleus did not cause a similar effect on the tail-flick latencies after the chronic intake of sucrose solution, increasing the sweet-substance-induced analgesia. These results indicate the involvement of serotonin as a neurotransmitter in the sucrose-produced antinociception. Considering that the blockade of pre-synaptic serotonergic receptors of the neural networks of the dorsal raphe nucleus with methiothepin did not decrease the sweet-substance-induced antinociception, and the central blockade of post-synaptic serotonergic receptors decreased the sucrose-induced analgesia, the modulation of the release of serotonin in the neural substrate of the dorsal raphe nucleus seems to be crucial for the organization of this interesting antinociceptive process.

Analgesia↗
PubMed1997

Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine.

1. The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. 2. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA > or = MDMA > or = (+)-Fen > > (+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph > > pCA = MDMA > > (+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). 3. [3H]-5HT and/or [3H]-dopamine release induced by all these compounds was partially (31-80%), but significantly Ca(2+)-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by omega-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca(2+)-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. 4. Methiothepin inhibited the Ca(2+)-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca(2+)-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. 5. These results indicate that the release induced by these compounds is both 'carrier-mediated' and Ca(2+)-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca(2+)-dependent release is mediated by Ca(2+)-influx (mainly through P-type Ca(2+)-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes.

Amphetamine↗
PubMed1990

Endothelium-dependent vasorelaxations in response to aggregating platelets are impaired in reversed vein grafts.

The endothelium releases factor(s) that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses to aggregating platelets are altered in vein grafts. Segments of jugular veins were grafted in the reverse position into the carotid arteries in 16 rabbits. After 4 weeks the patent grafts (14 of 16) were removed, and the endothelium-dependent responses were examined in vitro. In control veins aggregating platelets, adenosine diphosphate, and serotonin caused endothelium-dependent relaxations. The platelet-induced relaxations were attenuated by apyrase (adenosine diphosphatase and adenosine triphosphatase) but not by methiothepin (serotonergic blocker). In vein grafts, endothelium-dependent relaxations in response to aggregating platelets were absent, and only contractions that could be attenuated by methiothepin were observed. In vein grafts, endothelium-dependent relaxations in response to adenosine diphosphate were reduced, and only endothelium-independent contractions were observed in response to serotonin. These contractions were attenuated by methiothepin. These results suggest that (1) the endothelium exerts an inhibitory effects mediated mainly by adenosine diphosphate in response to aggregating platelets in rabbit jugular veins and (2) endothelium-dependent relaxations in response to aggregating platelets are impaired in vein grafts because of reduced endothelium-independent contractions in response to serotonin. This impairment of endothelium-dependent responses in vein grafts may contribute to failure of the grafts.

Adenosine Diphosphate↗
PubMed1991

Pressor effects following microinjection of 5-HT1A receptor agonists into the raphe obscurus of the anaesthetized rat.

1. The effects of electrical stimulation and microinjections (90 nl) of the 5-HT1A receptor agonists, flesinoxan and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and glutamate into the raphe obscurus on blood pressure, heart rate and phrenic nerve activity (central inspiratory drive) were investigated in rats anaesthetized with alpha-chloralose. 2. Electrical stimulation of the raphe obscurus caused a rise in blood pressure which was associated with bradycardia, while glutamate (2.7 nmol) caused only a rise in blood pressure. 3. Flesinoxan (1.3 nmol) and 8-OH-DPAT (0.7 nmol) increased blood pressure by 9 +/- 1 and 14 +/- 2 mmHg, respectively and did not affect heart rate. For both agonists the effect on blood pressure was shown to be dose-dependent; again no effect on the heart rate was observed over the dose-ranges chosen. 4. Microinjections of the non-selective 5-HT1A receptor antagonists, (+/-)-pindolol (2.7 nmol) or methiothepin (5.2 nmol), into the raphe obscurus prevented the increase in blood pressure caused by microinjection of flesinoxan. However, (+/-)-pindolol caused a sustained rise in blood pressure of 15 +/- 1 mmHg while methiothepin caused a transient rise in blood pressure. Neither drugs affected heart rate. The ability of methiothepin to attenuate the pressor effect of flesinoxan was found to be partially reversed after 30 min. 5. It is suggested that activation of 5-HT1A receptors within the raphe obscurus can cause sympatho-excitation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery.

1. The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT1 agonist), sumatriptan (5-HT1D-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HT1A receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT1+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HT1D receptor antagonist) were also studied. 2. All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3. Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan. 4. The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 microM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5. The novel 5-HT1D receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6. The results suggest that the human pulmonary artery has a functional population of 5-HT1D-like receptors which are involved in the contractile response to 5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Limited contributions of serotonin to long-term hyperexcitability of Aplysia sensory neurons.

Serotonin (5-HT) has provided a useful tool to study plasticity of nociceptive sensory neurons in Aplysia. Because noxious stimulation causes release of 5-HT and long-term hyperexcitability (LTH) of sensory neuron somata and because 5-HT treatment can induce long-term synaptic facilitation of sensory neuron synapses, a plausible hypothesis is that 5-HT also induces LTH of the sensory neuron soma. Prolonged or repeated exposure of excised ganglia to 5-HT produced immediate hyperexcitability of sensory neurons that showed little desensitization, but the hyperexcitability decayed within minutes of washing out the 5-HT. Prolonged or repeated treatment of either excised ganglia or dissociated sensory neurons with various concentrations of 5-HT failed to induce significant LTH even when long-term synaptic facilitation was induced in the same preparations. Use of a high-divalent cation solution to reduce interneuron activity during 5-HT treatment failed to enable the induction of LTH in excised ganglia. Pairing 5-HT application with nerve shock failed to enhance LTH produced by nerve shock or to reveal covert LTH produced by 5-HT. The induction of LTH by nerve stimulation was enhanced rather than inhibited by treatment with methiothepin, a 5-HT antagonist reported to block various 5-HT receptors and 5-HT-induced adenylyl cyclase activation. This suggests that endogenous 5-HT may have inhibitory effects on the induction of LTH by noxious stimulation. Methiothepin blocked immediate hyperexcitability produced by exogenous 5-HT and also inhibited the expression of LTH induced by nerve stimulation when applied during testing 1 day afterward. At higher concentrations, methiothepin reduced basal excitability of sensory neurons by mechanisms that may be independent of its antagonism of 5-HT receptors. Several observations suggest that early release of 5-HT and consequent cAMP synthesis in sensory neurons is not important for the induction of LTH by noxious stimulation, whereas later release of 5-HT from persistently activated modulatory neurons, with consequent elevation of cAMP synthesis, may contribute to the maintenance of LTH.

Animals↗
PubMed1986

Aggregating human platelets cause direct contraction and endothelium-dependent relaxation of isolated canine coronary arteries. Role of serotonin, thromboxane A2, and adenine nucleotides.

Aggregating human platelets contract isolated rings of canine coronary artery without endothelium, but relax rings with intact endothelium. We performed experiments to identify the substances released from platelets responsible for these effects. The contraction in rings without endothelium was reduced by treating the platelets with thromboxane synthetase inhibitor, dazoxiben, or treating the vessels with the thromboxane-receptor antagonist, SQ 29548. The serotonergic antagonist, methiothepin, also reduced the platelet-induced contraction. The combination of methiothepin plus dazoxiben or SQ 29548 caused a further inhibition. The endothelium-dependent relaxation to platelets during contractions evoked by prostaglandin F2 alpha was nearly abolished by the ADP- and ATP-scavenger, apyrase. It was not inhibited by methiothepin, which antagonizes endothelium-dependent relaxations to serotonin. Thus, both serotonin and thromboxane A2 contribute to the direct activation of coronary smooth muscle by aggregating human platelets, whereas adenine nucleotides are the principal mediators of the endothelium-dependent relaxation.

Adenine Nucleotides↗
PubMed1976

The interaction of dopaminergic and serotonergic drugs on plasma prolactin in ovariectomized, estrogen-treated rats.

Pharmacologic agents that either block or stimulate dopaminergic or block serotonergic receptors were administered intraarterially alone or in combination to ovariectomized, estrogen-treated rats. Prolactin was estimated by radioimmunoassay of plasma collected by serial blood sampling from chronic aortic catheters. Apomorphine (10 mg/kg) depressed, whereas Pimozide (50 and 250 mug/kg) and Methiothepin (50, 500 and 5000 mug/kg) markedly increased prolactin levels. Apomorphine completely blocked the increases induced by the lowest does of Pimozide and Methiothepin, as well as the initial increases at the higher doses. However, at later time intervals after large doses of Pimozide and Methiothepin in apomorphine-pretreated rats there was a marked rebound of prolactin which was greater than the level induced by each drug alone. The serotonin antagonists SQ 10,631 and methysergide reduced the Pimozide-induced elevation in prolactin levels, suggesting that part of the increase in prolactin following dopaminergic blockage may result from the action of a tonically stimulatory serotonin system that is normally masked by the intense tonic inhibition by the dopaminergic system.

Animals↗
PubMed1999

Animal model of posthypoxic myoclonus: effects of serotonergic antagonists.

OBJECTIVE: To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus. BACKGROUND: Although serotonergic system dysfunction is implicated in posthypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated. METHODS: The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at -30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six doses across a range from the original dose studied to 10% of that dose. RESULTS: Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose-response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. CONCLUSIONS: 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance-Adams syndrome.

Acoustic Stimulation↗
PubMed1988

Effects of the 5-hydroxytryptamine receptor antagonist, BMY 7378, on 5-hydroxytryptamine neurotransmission: electrophysiological studies in the rat central nervous system.

In the present electrophysiological studies, the effects of the putative 5-hydroxytryptamine (5-HT) receptor antagonist, BMY 7378, on the response of dorsal raphe nucleus 5-HT neurons and of CA3 dorsal hippocampus pyramidal neurons to 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in chloral hydrate-anesthetized rats. The effectiveness of microiontophoretically applied 5-HT and 8-OH-DPAT in suppressing the firing activity of both neuronal populations was assessed before and during the microiontophoretic application of BMY 7378. BMY 7378 reduced the effectiveness of 8-OH-DPAT, but not that of 5-HT, in depressing 5-HT neuron firing rate, whereas that of both agonists was reduced by concurrent application of BMY 7378 in the hippocampus. To assess whether endogenous 5-HT also could be antagonized, the response of pyramidal neurons to electrical activation of the 5-HT pathway was determined before and after i.v. BMY 7378. Low doses enhanced the efficacy of the stimulation, whereas higher doses decreased it. The latter finding suggests that BMY 7378 antagonizes the effect of endogenous 5-HT. Three procedures were used to investigate the enhancing effect of BMY 7378 on 5-HT synaptic transmission: 1) administration of BMY 7378 after terminal 5-HT autoreceptor blockade by methiothepin: methiothepin abolished the enhancing effect of BMY 7378; 2) blockade of the effect of RU 24969, a terminal 5-HT autoreceptor agonist: pretreatment with methiothepin, but not with BMY 7378, blocked the effect of RU 24969 on 5-HT synaptic transmission; and 3) administration of BMY 7378 during a reduced level of activation of terminal 5-HT autoreceptors, obtained by lowering the stimulation frequency from 1 to 0.5 Hz: the enhancing effect of BMY 7378 was reduced when the stimulation was delivered at 0.5 Hz. It is concluded that BMY 7378 is an effective antagonist of 5-HT1A receptors in vivo and that the mechanism of its enhancing effect on 5-HT transmission at low doses, although still undetermined, is not due to a competitive interaction at the terminal 5-HT autoreceptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Interaction of the prejunctional inhibitory action of 5-hydroxytryptamine on noradrenergic transmission with neuronal amine uptake in rabbit isolated ear artery.

The interaction of the prejunctional inhibitory action of 5-hydroxytryptamine (5-HT) on noradrenergic transmission with the neuronal amine uptake mechanism has been studied in rabbit isolated ear artery preparations. Release of norepinephrine in response to stimulation of periarterial sympathetic nerves (30 pulses, 1 Hz) was deduced from the efflux of radioactivity which had been incorporated into the noradrenergic transmitter pool as [3H]norepinephrine. 5-HT (100 nM), applied alone, had no effect on the stimulation-induced efflux of radioactivity. However, in the presence of cocaine (1 microM), 5-HT reduced stimulation-induced efflux. The inhibitory effect of 5-HT, in the presence of cocaine, on stimulation-induced efflux was abolished by the nonselective 5-HT1/5-HT2 receptor antagonist, methiothepin (30 nM), but not by the selective 5-HT2 receptor antagonist, ketanserin (6 nM), or by the alpha adrenoceptor antagonist, phentolamine (30 nM). These findings indicate that the uptake of 5-HT into periarterial sympathetic nerves may limit its prejunctional "5-HT1-like" receptor-mediated inhibitory effect on noradrenergic transmission. In arteries which were incubated with 5-HT (1 microM) and the monoamine oxidase inhibitor, pargyline (10 microM), before loading the transmitter stores with [3H]norepinephrine, methiothepin (30 nM) enhanced stimulation-induced efflux markedly. The enhancing effect of methiothepin was not observed in arteries which were preincubated with cocaine (10 microM) together with 5-HT and pargyline. It is suggested that, following its uptake into periarterial sympathetic nerves, 5-HT may be coreleased with norepinephrine to activate prejunctional 5-HT1-like receptors and thereby mediate an autoinhibitory effect on transmitter release.

Animals↗
PubMed1986

Contractions of isolated canine coronary arteries resistant to S2-serotonergic blockade.

The purpose of this study was to compare the effect of two serotonergic receptor antagonists on the contractile responses mediated by 5-hydroxytryptamine (5-HT) in isolated canine coronary arteries. After removing the endothelium and blocking neuronal uptake with cocaine, the coronary artery contracted when exposed to nanomolar concentrations of 5-HT; at micromolar concentrations the amine caused relaxation. A relatively high concentration of the selective S2-serotonergic antagonist, ketanserin (10(-6) M), attenuated peak contractions caused by 5-HT by an average of only 52% and caused no significant change in sensitivity to the amine. In contrast, the antagonist behaved competitively in the canine femoral artery. Cyproheptadine (10(-6) M) also was a noncompetitive serotonergic antagonist in the coronary artery. The relatively nonselective S1- and S2-serotonergic receptor antagonist, methiothepin, competitively antagonized coronary contractions caused by 5-HT with an estimated pA2 of 8.0. The rightward shifts of coronary serotonergic contractions caused by methiothepin were not significantly different whether or not ketanserin (10(-6) M) was present in the assay to block S2-serotonergic receptors. Unlike ketanserin, methiothepin (10(-6) M) nearly abolished coronary artery contractions caused by aggregating platelets. These results indicate that serotonergic coronary contractions are resistant to S2-serotonergic blockade, and suggest that they are mediated at least in part by receptors which are different from the S2-serotonergic subtype.

Angiotensin II↗
PubMed1988

Comparison of serotonergic receptor subtypes on the smooth muscle and endothelium of the canine coronary artery.

To characterize the responses of the canine coronary artery to serotonin, rings with and without endothelium were suspended in organ chambers for isometric tension recording. Serotonin evoked an endothelium-dependent relaxation of prostaglandin F2 alpha-contracted rings which was inhibited by antagonists with affinity for 5-hydroxytryptamine (5-HT)1 and 5-HT2 receptors, methiothepin and metergoline, but was not mimicked or antagonized by the 5-HT1A-selective ligand, 8-hydroxy-2-di-n-propylamino tetralin. This relaxation is not mediated by 5-HT1B receptors as it was not antagonized by cyanopindolol; similarly, lack of inhibition by ketanserin and MDL 72222 rule out contributions of 5-HT2 receptors or 5-HT3 receptors. Rings without endothelium contracted to serotonin; this contraction was not blocked by cyanopindolol and was only weakly inhibited by ketanserin, but was antagonized in an apparently competitive fashion by methiothepin and was mimicked by 8-hydroxy-2-di-n-propylamino tetralin (although at higher concentrations than would be expected for its action at a 5-HT1A receptor). At high concentrations, serotonin evoked a relaxation of endothelium-denuded rings, which was blocked by very low concentrations of methiothepin but was unaffected by ketanserin or cyanopindolol. Thus, there appear to be three different serotonergic receptors in the coronary artery. Although available agents do not allow their precise classification as yet, none of them is of the 5-HT2 type.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Which type of 5-hydroxytryptamine receptor mediates relaxation of the longitudinal muscle of guinea pig proximal colon in vitro?

Concentration-dependent 5-hydroxytryptamine (5-HT) relaxations of guinea pig proximal colon were evoked in the presence of atropine (0.2 microM). 5-HT effect was neuronally mediated since it was blocked by tetrodotoxin (TTX) (0.5 microM). The type of 5-HT receptor mediating the relaxations was investigated using both 5-HT agonists and antagonists. Selective 5-HT3 antagonists tropisetron (10, 50, 500 nM) and ondansetron (1 microM) shifted the concentration-response curves for 5-HT to the right. Another 5-HT3 antagonist MDL 72222 (0.5 microM), 5-HT1/5-HT2 antagonists methiothepin (0.1 microM) and metergoline (0.1 microM), 5-HT(1A,B) antagonist propranolol (l microM) and 5-HT1B antagonist isamoltane (10 nM) were ineffective. Specific agonist of 5-HT3 receptors 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and agonist of 5-HT1 receptors 5-carboxamidotryptamine (5-CT) also relaxed the preparation, although the relaxation was not 5-HT relaxation. Neither was it neurogenic because it persisted in the presence of TTX (0.5 microM). The concentration-response curve for 2-methyl-5-HT was not affected by ondansetron (1 microM) or tropisetron (0.5 microM), but it was shifted to the right in the presence of 5-HT1/5-HT2 receptor antagonists methiothepin (0.1 microM) and metergoline (0.1 microM) and in the presence of 5-HT(1Da)/5-HT2A receptor antagonist ketanserin (1 microM). Methiothepin (0.1 microM) also inhibited the relaxations evoked in the presence of 5-CT. Specific agonist of 5-HT4 receptors 5-methoxytryptamine did not exert any effect on the preparation. It is suggested that there are two different mechanisms of relaxation in the guinea pig proximal colon. One is neurogenic and involves the activation of 5-HT3 receptors located on inhibitory neurons to the muscle; the other is myogenic and might be mediated via yet unclassified 5-HT receptors located on the muscle.

Animals↗
PubMed1990

Effects of short-term serotonin depletion on the efficacy of serotonin neurotransmission: electrophysiological studies in the rat central nervous system.

The effects of short-term serotonin (5-HT) depletion by p-chlorophenylalanine (PCPA) on the firing activity of dorsal raphe nucleus 5-HT neurons, on the responsiveness of dorsal hippocampus pyramidal neurons to microiontophoretically applied 5-HT and on the efficacy of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of CA3 dorsal hippocampus pyramidal neurons were assessed in chloral hydrate-anesthetized rats. PCPA (250 mg/kg/day i.p. for 2 days) reduced the 5-HT content of the dorsal hippocampus by 90%. However, the number of spontaneously active 5-HT neurons per microelectrode trajectory through the dorsal raphe or their average rate of firing was unaltered. The effect of afferent 5-HT pathway stimulation was reduced in only 40% of treated rats, whereas the sensitivity of CA3 pyramidal neurons to microiontophoretic 5-HT was not modified. The function of the terminal 5-HT autoreceptor was assessed using methiothepin, an autoreceptor antagonist. Methiothepin (1 mg/kg, i.v.) significantly enhanced the efficacy of the stimulation in PCPA-treated rats, although the degree of enhancement was much less than in controls. A greater reduction of the effectiveness of the stimulation was obtained by increasing the dose of PCPA (350 mg/kg/day i.p. for 2 days). This regimen reduced the 5-HT content of the dorsal hippocampus by 95%. In these rats, the sensitivity of the terminal 5-HT autoreceptor was assessed by increasing the frequency of the stimulation from 1 to 5 Hz. This procedure reduced to a similar extent the efficacy of the stimulation in treated and control rats, suggesting that the reduced effectiveness of methiothepin in enhancing 5-HT synaptic transmission in PCPA-treated rats is due to a lower degree of activation of the terminal 5-HT autoreceptor. The present results showing that the 350 mg/kg/day regimen of PCPA, but not the 250 mg/kg/day regimen, reduced the efficacy of the stimulation of the ascending 5-HT pathway suggest that a greater than 90% depletion is required to affect 5-HT neurotransmission significantly. The reduced level of activation of terminal 5-HT autoreceptors in rats treated with the lower dose of PCPA may facilitate the release of the remaining 5-HT per stimulation-triggered action potential, ensuring a virtually unaltered synaptic efficacy.

5,7-Dihydroxytryptamine↗
PubMed1992

5-Hydroxytryptamine-induced contractions of the human isolated saphenous vein: involvement of 5-HT2 and 5-HT1D-like receptors, and a comparison with grafted veins.

The receptors mediating the contractile effect of 5-hydroxytryptamine (5-HT) on the human isolated saphenous vein, obtained from 42 patients undergoing coronary bypass surgery, have been further characterized using a number of 5-HT-related drugs. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) approximately 5-HT greater than methysergide approximately sumatriptan approximately alpha-methyl-5-HT approximately 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuccinate (RU 24969) approximately 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) greater than 2-methyl-5-HT greater than 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Flesinoxan was inactive as an agonist. Ketanserin (1 mumol/l) hardly affected sumatriptan-induced contractions but it caused a rightward shift of the upper part of the concentration-response curve of 5-HT and 5-CT. The same concentration of ketanserin caused a parallel rightward shift of the concentration-response curves of alpha-methyl-5-HT and DOI with pKB values of 7.1 and 7.1, respectively. The responses to sumatriptan were antagonized by methiothepin (0.1 mumol/l), metergoline (0.1 and 1 mumol/l), rauwolscine (1 mumol/l) and cyanopindolol (1 mumol/l); the calculated pKB values were 7.3, 6.9, 7.3, 6.7 and 6.5, respectively. Contractions to 5-HT were antagonized by methysergide (1 mumol/l), methiothepin (0.1 mumol/l; pKB = 7.1), ICS 205-930 (1 mumol/l; pKB = 5.9) and flesinoxan (30 mumol/l; pKB = 5.3). Remarkably, the contractions elicited by 2-methyl-5-HT were not attenuated by ICS 205-930, but were antagonized by methiothepin (0.1 mumol/l) and, more markedly, by ketanserin (1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Bypass↗
PubMed1998

Labelling of recombinant human and native rat serotonin 5-HT1A receptors by a novel, selective radioligand, [3H]-S 15535: definition of its binding profile using agonists, antagonists and inverse agonists.

The novel benzodioxopiperazine, 5-HT1A receptor weak partial agonist, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine) bound with high affinity and selectivity to membranes of Chinese Hamster Ovary cells stably expressing the human (h) 5-HT1A receptor (Ki = 0.6 nM versus [3H]-8-hydroxy-dipropylamino-tetralin, [3H]-8-OH-DPAT): its affinity at h5-HT1A receptors was more than 70-fold higher than its affinity at > 50 other binding sites. S 15535 was tritiated to high specific activity (50 Ci/mmol) and its binding profile characterised. At 22 degrees C, [3H]-S 15535 associated and dissociated from h5-HT1A receptors with half-times of 2.9 and 5.0 min, respectively, yielding a Kd estimate of 3.6 nM. In saturation binding experiments, [3H]-S 15535 displayed a Bmax value for h5-HT1A receptors (1630 fmol/mg), higher than that obtained with the agonist [3H]-8-OH-DPAT (1023 pmol/mg). Guanylyl imidodiphosphate (GppNHp, 100 microM) reduced the binding of [3H]-S 15535 by only 25% compared with 79% for [3H]-8-OH-DPAT at h5-HT1A receptors. [3H]-S 15535 also showed high affinity, saturable binding to rat hippocampal membranes (Bmax = 820 fmol/mg versus 647 fmol/mg for [3H]-8-OH-DPAT). For both h5-HT1A and rat 5-HT1A receptors, the Ki values for competition binding of 15 serotonergic ligands with [3H]-S 15535 was highly correlated with that of [3H]-8-OH-DPAT. However, important differences were also observed. The agonist, 5-hydroxytryptamine (5-HT), displayed biphasic competition curves with [3H]-S 15535 but not with [3H]-8-OH-DPAT at h5-HT1A receptors. Similarly, the 'antagonists', spiperone, methiothepin and (+)butaclamol, showed biphasic competition isotherms versus [3H]-S 15535 but not [3H]-8-OH-DPAT. When [3H]-S 15535 competition binding experiments were carried out in the presence of GppNHp (100 microM) the 5-HT and 8-OH-DPAT competition curves shifted to the right, whereas the spiperone and methiothepin competition curves shifted to the left. In contrast, in the presence of GppNHp, the competition isotherms for N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-h exanecarboxamide (WAY 100,635) were not altered. Taken together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Vasodilator and vasoconstrictor responses induced by 5-hydroxytryptamine in the in situ blood autoperfused hindquarters of the anaesthetized rat.

In the present study we attempted to characterise the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT, serotonin) in in situ autoperfused rat hindquarters. Intra-arterial administration of the lowest doses of 5-HT used (0.12-12.5 ng/kg) induced vasodilator responses, whereas the highest doses (25-1000 ng/kg) produced vasoconstriction. The vasodilator effect was inhibited by methiothepin (a non-specific 5-HT(1,2,5,6,7) receptor antagonist) and by a 5-HT(1D/1B) receptor antagonist, i.e., 3-[4-(4-chlorophenyl)piperazin-1-yl]-1,1-diphenyl-2-propanolol (BRL 15572), but not by ritanserin (a selective 5-HT(2) receptor antagonist), 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole (SB 206553, a selective 5-HT(2B/2C) receptor antagonist) or mesulergine (a non-specific serotonergic antagonist that shows affinity to the 5-HT(7) receptor). This vasodilator effect was mimicked by administration of a selective 5-HT(1) receptor agonist - 5-carboxamidotryptamine (5-CT) - and by 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-1 H-indol-3-yl]ethanamine (L-694,247, a selective 5-HT(1D/1B) receptor agonist). Methiothepin, but not mesulergine, inhibited 5-CT-induced vasodilatation and the selective 5-HT(1D/1B) receptor antagonist (BRL 15572) inhibited the vasodilator action induced by L-694,247. The vasoconstrictor effect of 5-HT was significantly decreased by methiothepin, ritanserin and SB 206553, and was mimicked by alpha-methyl-5-HT (a selective 5-HT(2) receptor agonist) but not by administration of BW 723C86, a selective 5HT(2B) receptor agonist. Ritanserin, SB 206553 and spiperone (a non-specific 5-HT(1/2A) receptor antagonist) inhibited the alpha-methyl-5HT-induced vasoconstriction.Our data suggest that the vasodilator response induced by 5-HT in autoperfused rat hindquarters is mainly mediated by 5-HT(1D/1B) receptors, whereas the vasoconstrictor effect is mainly due to the activation of 5-HT(2A) receptors.

Analysis of Variance↗