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PubMed1978

Paradoxical decrease of brain 5-HT turnover by metergoline, a central 5-HT receptor blocker.

Since metergoline (1-methyl-8-beta-carbobenzyloxy-aminomethyl-10-alpha-ergoline) is a potent 5-HT antagonist in peripheral organs, its possible blocking effects on 5-HT receptors in the rat brain were investigated. In vitro, metergoline inhibited both the specific high affinity binding of 3-H-5-HT onto synaptosomal membranes (IC 50 = 18 nM) and the stimulating effect of 10 micron 5-HT on the adenylate cyclase activity in colliculi homogenates from newborn rats (IC 50 = 12 micron. In vivo, the administration of metergoline (10 mg/kg i.p., 60 min before death) resulted in a significant decrease in the 3-H-5-HT binding capacity of synaptosomal membranes from the forebrain of adult rats. Taken together, these data clearly indicated that metergoline is a potent blocker of some serotoninergic receptors in the rat brain. Surprisingly, the changes in 5-HT turnover occurring in the brainstem and in the forebrain 1 h after metergoline (2-10 mg/kg) treatment were similar to those normally induced by a central 5-HT agonist: both the rate of 5-HT utilisation and that of 5-HT synthesis were significantly decreased. These changes were in contrast to the acceleration of 5-HT turnover induced by the administration of another potent central 5-HT antagonist, methiothepin. These results are discussed in relation to the possible existence of several types of serotoninergic receptors in the rat brain. It is possible that the positive feedback regulation of 5-HT turnover is triggered by the blockade of serotoninergic receptors sensitive to methiothepin, but not to metergoline.

Adenylyl Cyclases↗
PubMed1997

Nature of 5-HT1-like receptors mediating depressor responses in vagosympathectomized rats; close resemblance to the cloned 5-ht7 receptor.

It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated by '5-HT1-like' receptors since this effect is mimicked by 5-carboxamidotryptamine (5-CT), is not modified by cyproheptadine, ketanserin or MDL 72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NC-IUPHAR subcommittee on the classification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 microg x kg(-1)), 5-HT (1-30 microg x kg(-1)) and 5-methoxytryptamine (5-MeO-T; 1-30 microg x kg(-1)) produced dose-dependent hypotensive responses with a rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine with sumatriptan (30-1000 microg x kg(-1)) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 microg x kg(-1)) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT; the rank order of apparent pA2 values against 5-HT and 5-CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) > or = mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenaline-induced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor and the lack of blockade by GR127935, our results indicate that the 5-HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5-ht7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guinea-pig ileum as well as feline tachycardia).

5-Methoxytryptamine↗
PubMed1998

Native 5-HT1B receptors expressed in OK cells display dual coupling to elevation of intracellular calcium concentrations and inhibition of adenylate cyclase.

The opossum kidney (OK) cell line has been shown previously to express endogenous 5-HT1B receptors which negatively couple to adenylate cyclase. Since other Gi-linked receptors have been shown to inhibit adenylate cyclase and to elevate intracellular calcium concentrations ([Ca2+]i), studies were initiated to determine whether native opossum 5-HT1B receptors could also display dual coupling to these signal transduction mechanisms. Saturation studies using [125I](-)-iodocyanopindolol ([125I]CYP) to radiolabel the 5-HT1B receptor in OK cell membranes (in the presence of 3 microM (-)-isoproterenol to mask beta-adrenergic receptors) yielded an equilibrium dissociation constant (pKd) of 10.04 and binding site density (Bmax) of 55 fmol/mg protein. Exposure of intact OK cells to 5-HT, CP 93,129, a selective rodent 5-HT1B receptor agonist, and (+/-)-cyanopindolol, a mixed 5-HT1A/1B receptor agonist/antagonist, produced concentration-dependent inhibitions of forskolin (3 MM)-stimulated cAMP accumulation (FSCA; Emax=90-95%) and elevations of [Ca2+]i (Emax approximately 200 nM increase above basal levels). Agonist potencies (pEC50) ranged from 9.7 to 8.1 and were comparable between the two second messenger assays, although slightly higher agonist potencies (approximately three-fold) were observed in the cAMP assay. GR 127,935, a selective 5-HT1B/1D receptor antagonist, behaved as a strong partial agonist in both the cAMP and calcium assays, with an intrinsic activity of 0.7 relative to 5-HT. Methiothepin, a nonselective 5-HT receptor antagonist, competitively antagonized the inhibitory cAMP response elicited by CP 93,129, yielding an apparent pKb value of 7.3. Methiothepin (10 microM) completely antagonized the stimulatory calcium response evoked by a saturating concentration of CP 93,129 (100 nM). Pertussis toxin pretreatment blocked the CP 93,129-induced inhibition of FSCA and elevation of [Ca2+]i in OK cells, indicating the involvement of Gi/o proteins in transducing these second messenger responses. The agonist properties of (+/-)-cyanopindolol and GR 127,935 observed in both second messenger assays suggests that a large degree of receptor reserve may be present, even though 5-HT1B receptor expression is low in OK cells. The OK cell line continues to serve as a model system to investigate 5-HT1B receptor-mediated signaling events.

Adenylate Cyclase Toxin↗
PubMed2003

Mechanisms involved in the loss of excitatory post-stimulus responses by inflammation.

AIM: Electrical stimulation of colonic muscles elicits a response during the stimulation period, and a transient excitation after the stimulus. Post-stimulus or "rebound" excitation has been linked to pathways involving inhibitory neurotransmitters, prostaglandins and substance P but the mechanism is incompletely understood. Because rabbit colitis is characterized by a loss of inhibitory neurotransmission we hypothesized it might affect the rebound response. Therefore we characterized rebound responses in non-inflamed and inflamed tissue by comparing the effect of antagonists/blockers of putative (nitric oxide [NO], ATP, substance P, prostaglandins) and new (serotonin) neurotransmitters. METHODS: Strips from rabbits with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) were subjected to electrical field stimulation. Because rebound responses are more prominent under nonadrenergic noncholinergic (NANC) conditions, the effect of specific antagonists (N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin, SR140333, methiothepin) on the rebound response was compared under normal and NANC conditions. RESULTS: NANC-conditions increased rebound responses in non-inflamed strips, but this effect was reduced or abolished in inflamed strips. Rebound responses were reduced by pretreatment with the NO-synthase inhibitor, L-NAME, under NANC conditions in non-inflamed strips but not affected in inflamed tissue. In contrast, the P(2) purine receptor antagonist, suramin, did not affect rebound responses in inflamed and non-inflamed strips. The effect of the cyclo-oxygenase inhibitor (COX), indomethacin, on rebound responses was reversed from excitatory to inhibitory by inflammation. Under NANC conditions rebound contractions were also reduced by the neurokinin-1 (NK(1)) antagonist, SR140333, both in normal and inflamed strips. The most pronounced reduction in rebound responses in inflamed and non-inflamed strips under normal conditions was observed with the 5-hydroxytryptamin (1,2) (5-HT(1,2)) antagonist, methiothepin. CONCLUSION: Rebound responses are mainly non-cholinergic and involve NO, substance P, serotonin and inhibitory prostaglandins. In inflamed tissue the nitrergic pathway is absent, excitatory prostaglandins prevail and the cholinergic and tachykinergic components are relatively more important. However there remains an important serotonergic contribution. Our data suggest that inflammation damages different neural pathways to a different extent and is most selective for nitrergic pathways.

Adenosine Triphosphate↗
PubMed1995

Downregulation of muscarinic- and 5-HT1B-mediated modulation of [3H]acetylcholine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts of septal origin.

Adult Long-Evans female rats sustained electrolytic fimbria-fornix lesions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [3H]choline accumulation and the electrically evoked [3H]acetylcholine ([3H]ACh) release were assessed in hippocampal slices. The release of [3H]ACh was measured in presence of atropine (muscarinic antagonist, 1 microM), physostigmine (acetylcholinesterase inhibitor, 0.1 microM), oxotremorine (muscarinic agonist, 0.01 microM-10 microM), mecamylamine (nicotinic antagonist, 10 microM), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 microM), 8-OH-DPAT (5-HT1A agonist, 1 microM), 2-methyl-serotonin (5-HT3 agonist, 1 microM) and CP 93129 (5-HT1B agonist, 0.1 microM-100 microM), or without any drug application as a control. In lesion-only rats, the specific accumulation of [3H]choline was reduced to 46% of normal and the release of [3H]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [3H]ACh release and was significantly more effective in grafted (-70%) than in sham-operated (-56%) or lesion-only (-54%) rats. When physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [3H]ACh release in all groups, but this increase was significantly larger in sham-operated rats (+209%) than in the other groups (lesioned: +80%; grafted: +117%). Oxotremorine dose-dependently decreased the [3H]ACh release, but in lesion-only rats, this effect was significantly lower than in sham-operated rats. Whatever group was considered, 8-OH-DPAT, methiothepin and 2-methyl-serotonin failed to induce any significant effect on [3H]ACh release. In contrast, CP 93129 dose-dependently decreased [3H]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that cholinergic terminals in the intact hippocampus possess inhibitory muscarinic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted cholinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats show a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downregulations might contribute to (or reflect) an increased cholinergic function that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1980

Pharmacological characterization of serotonin receptors in the facial motor nucleus: a microiontophoretic study.

The effects of 'peripheral' serotonin (5-HT) antagonists on the facilitation of facial motoneuron excitation by 5-HT were investigated in the present study. Microiontophoretic application (5--10 aA) or intravenous administration of methysergide (0.5--1.0 mg/kg), cyproheptadine (0.5--1.0 mg/kg), cinanserin (0.5--1.0 mg/kg), or metergoline (50--100 micrograms/kg) antagonized the facilitating effect of 5-HT but not that of norepinephrine (NE) on facial motoneurons. Blockade developed within 1--2 min of the intravenous administration of methysergide, cyproheptadine and cinanserin and continued up to 30 min. The antagonism produced by intravenous metergoline took 8--15 min to develop and lasted for at least 6 h. Chronic administration of metergoline resulted in supersensitivity to 5-HT and NE in the facial nucleus. The putative 5-HT antagonists chlorpromazine, propranolol, and methiothepin failed to block the facilitating effect of 5-HT; however, methiothepin did block NE. The results are discussed in relation to a two-component model of the 5-HT mediated motor syndrome consisting of : (1) patterned excitatory inputs to motor nuclei; (2) 5-HT facilitation of these excitatory inputs. The 'peripheral' 5-HT antagonists appear to directly block the latter component.

Animals↗
PubMed1983

Regional differences in the response of serotonergic neurons in rat CNS to drugs.

In vivo rates of 5-hydroxytryptophan accumulation (following administration of the decarboxylase inhibitor R04/4602/1) and levels of 5-HT in the nucleus raphe dorsalis (DR), nucleus centralis superior (NCS), nucleus septalis lateralis (LS), nucleus suprachiasmaticus (SCN), nucleus hypothalamicus anterior (AH), and nucleus amygdaloideus centralis (AG) were determined following administration of fluoxetine, 5-methoxy-N,N-dimethyltryptamine, methiothepin, L-tryptophan and reserpine. Fluoxetine and 5-methoxy-N,N-dimethyltryptamine inhibited 5-hydroxytryptophan synthesis in all nuclei, although inhibition of synthesis in the DR was resistant to fluoxetine. Methiothepin inhibited 5-HT synthesis in the DR, NCS, LS and AG, but not in the SCN or AH. L-Tryptophan greatly increased 5HT synthesis in all areas, but this increase was not uniform, being fourfold greater in the NCS than in the LS. Reserpine, while greatly depleting 5HT did not increase 5-hydroxytryptophan synthesis in any nucleus. In no region could changes in brain tryptophan account for the observed drug effects on serotonin metabolism. We conclude that not all CNS serotonergic structures respond to the same drug in a uniform manner.

5-Hydroxytryptophan↗
PubMed1988

Identification of 5-HT3 binding sites in rat spinal cord synaptosomal membranes.

The 5-HT3 receptor antagonists, ICS 205-930 and MDL 72222, displace 47-55% of the specific [3H]serotonin (100 nM) binding to synaptosomal membranes derived from the dorsal, but not ventral, spinal cord of rats with IC50s less than 1.0 nM. Methiothepin (10 microM) increased displacement to 86-94% without shifting these IC50s. Scatchard plots of [3H]5-HT binding in the presence of methiothepin (10 microM) reveal a single population of sites (KD = 11.5 nM, Bmax = 282 fmol mg-1 protein). These results indicate the presence of 5-HT3 binding sites in dorsal spinal cord.

Binding Sites↗
PubMed1989

The 5-HT1-like receptor mediating reduction of porcine carotid arteriovenous shunting by RU 24969 is not related to either the 5-HT1A or the 5-HT1B subtype.

Using the radioactive microsphere technique in anaesthetized pigs, we studied the systemic and carotid haemodynamic effects of intracarotid infusions (0.3, 1, 3 and 10 micrograms/kg.min) of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969), a drug with high affinity for 5-HT1A and 5-HT1B recognition sites. Unlike in the rat, RU 24969 did not elicit hypotension in the pig. Instead, the two highest doses of the drug caused a slight increase in blood pressure. RU 24969 reduced common carotid artery blood flow by decreasing the non-nutrient, arteriovenous anastomotic blood flow; the nutrient, arteriolar blood flow was mildly increased. The decrease in common carotid and arteriovenous anastomotic blood flow was only slightly attenuated in animals pretreated with the 5-HT2 receptor antagonist, ketanserin (0.5 mg/kg i.a.), but was markedly reduced in animals pretreated with the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (1.0 mg/kg i.a.). However, these responses were not modified after pretreatment with the putative 5-HT1A and 5-HT1B receptor antagonist, (+/-)-pindolol (4.0 mg/kg i.v.). The slight increase in arteriolar blood flow was attenuated in the animals pretreated with either ketanserin, methiothepin or (+/-)-pindolol. It is concluded that the RU 24969-induced reduction in common carotid and arteriovenous anastomotic blood flow is mediated mainly by 5-HT1-like receptors, which do not seem to correspond to either the 5-HT1A or 5-HT1B receptor subtypes.

Animals↗
PubMed1990

Constriction of porcine arteriovenous anastomoses by indorenate is unrelated to 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptor subtypes.

The study concerns the effects of indorenate, a tryptamine derivative with antihypertensive properties as well as high affinity for the 5-HT1A binding site, on carotid haemodynamics in anaesthetized pigs. Intracarotid infusions of indorenate (0.3, 1.0, 3.0 and 10.0 micrograms.kg-1.min-1 for 10 min each) caused dose-related decreases in total common carotid artery blood flow due almost exclusively to a reduction in arteriovenous anastomotic flow. These effects of indorenate were not appreciably modified after treatment with the 5-HT2 receptor antagonist ketanserin (0.5 mg.kg-1 i.a.), but were markedly reduced after treatment with methiothepin (1.0 mg.kg-1 i.a.), which antagonizes not only 5-HT2 receptors, but also the putative 5-HT1A, 5-HT1B 5-HT1C and 5-HT1D subtypes of 5-HT1-like receptors. Nonetheless, metergoline (1 mg.kg-1 i.a.), a drug with higher affinity than methiothepin for the above 5-HT1 receptor subtypes, failed to significantly modify the responses to indorenate. It is therefore concluded that, like 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), indorenate reduces both total common carotid and cephalic arteriovenous anastomotic blood flow in the pig by stimulating 5-HT1-like receptors; these receptors, however, do not seem to correspond to either 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites.

5-Methoxytryptamine↗
PubMed1995

Modulation of rat neocortical high-voltage spindle activity by 5-HT1/5-HT2 receptor subtype specific drugs.

To investigate the role of serotonin (5-hydroxytryptamine; 5-HT) receptors in the modulation of rat thalamocortical oscillations, we studied the effects of 5-HT1/5-HT2 receptor subtype specific drugs on neocortical high-voltage spindle activity in adult male rats. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.03, 0.1, 0.3 and 1.0 mg/kg s.c.), had no effect on neocortical high-voltage spindle activity. Furthermore, a mixed 5-HT1/5-HT2 receptor antagonist, methysergide (1.0, 5.0 and 15.0 mg/kg i.p.), had no effect, whereas a non-specific mixed 5-HT1/5-HT2 receptor antagonist, methiothepin (0.2, 1.0 and 5.0 mg/kg i.p.), significantly increased neocortical high-voltage spindles. Of the 5-HT2 receptor antagonists, ritanserin (0.1, 1.0 and 5.0 mg/kg s.c.) had no effect, whereas ketanserin (1.0, 5.0 and 20.0 mg/kg s.c.) increased neocortical high-voltage spindles, but only at the highest dose used. A 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.5, 1.0 and 2.0 mg/kg s.c.), at the two highest doses significantly decreased neocortical high-voltage spindle activity, and this effect was blocked by the 5-HT2 receptor antagonists, ketanserin (1.0, 5.0 and 20.0 mg/kg s.c.) and ritanserin (1.0 and 5.0 mg/kg s.c.), as well as by methiothepin (0.2, 1.0 and 5.0 mg/kg i.p.) and methysergide (1.0, 5.0 and 15.0 mg/kg i.p.). Furthermore, unilateral intrathalamic infusions, but not intrahippocampal control infusions, of DOI (10 and 50 micrograms/1.0 microliters/rat) decreased neocortical high-voltage spindle activity and systemic administration of ketanserin (20.0 mg/kg s.c.) completely blocked this effect. The present results suggest that (1) the serotonergic system modulates rat thalamocortical oscillations as measured by neocortical high-voltage spindle activity, (2) activation of 5-HT2 receptors, possibly located in the thalamus, with a specific 5-HT2 receptor agonist, DOI, causes a reduction in rat neocortical high-voltage spindle activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

The activity of 5-HT1D receptor ligands at cloned human 5-HT1D alpha and 5-HT1D beta receptors.

The present study has examined the functional activity of the 5-HT1D receptor agonist, sumatriptan, and antagonists, GR127935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyl ic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide), GR55562 (3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide), metergoline and methiothepin in HeLa cells, stably transfected with either 5-HT1D alpha or 5-HT1D beta receptor subtypes. Sumatriptan, GR127935 and metergoline (each 0.01-1 microM) behaved as agonists, producing a concentration-dependent inhibition of forskolin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production at both 5-HT1D alpha and 5-HT1D beta receptor subtypes (mean pIC50 values of 8.4 and 8.3 for sumatriptan, 7.9 and 8.0 for GR127935, and 7.9 and 8.3 for metergoline, respectively). In contrast, GR55562 and methiothepin behaved as competitive 5-HT1D receptor antagonists and were devoid of any agonist activity. GR55562 (10 microM) caused a rightward displacement of the GR127935 and metergoline concentration-response curves. The agonist activity of GR127935 and metergoline, observed in the present study, contrasts with their recognised 5-HT1D receptor antagonist profiles in animal isolated tissue and behavioural models. Unlike GR127935, GR55562 behaved as a silent antagonist at the cloned human 5-HT1D alpha and 5-HT1D beta receptors in the study.

Cyclic AMP↗
PubMed1996

Effects of acute and repeated administration of citalopram on extracellular levels of serotonin in rat brain.

The effects of acute (2 days) and repeated (21 days) administration (50 mg/kg in the diet) of the selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitor, citalopram, on extracellular levels of 5-HT and their modulation by terminal autoreceptors in the hypothalamus of freely moving rats were compared in vivo by microdialysis. When studied without washout, extracellular levels of 5-HT were increased by both acute and repeated citalopram administration. In rats treated repeatedly, extracellular 5-HT levels were 43% (but not significantly) greater than in those treated acutely. Extracellular levels of 5-HT in control and citalopram-treated rats were similar when measured after 24 h washout. The enhancing effect of non-selective serotonergic autoreceptor antagonists, methiothepin (100 microM) or 1-(1-naphthyl)piperazine (NP) (10 microM), administered through the microdialysis probe, after 24 h washout, was similar in both control and chronically treated groups. These results suggest that repeated administration of citalopram followed by a washout of 24 h does not lead to desensitization of the terminal autoreceptor as measured in vivo in contrast to the effects we have shown previously in vitro. In rats treated chronically with citalopram without washout, methiothepin had a greater maximal effect on 5-HT outflow in comparison to rats receiving acute citalopram treatment. This finding suggests that a 5-HT autoreceptor antagonist or a combination of such a drug with a 5-HT uptake inhibitor would produce a greater increase of extracellular levels of 5-HT in hyposerotonergic states such as depression.

Animals↗
PubMed1996

Role of alpha1-adrenoceptors in the reduction of external carotid blood flow induced by buspirone and ipsapirone in the dog.

The effects of the 5-HT1A receptor agonist with anxiolytic properties, buspirone and ipsapirone, in the external carotid bed of anaesthetized dogs were analyzed. Since these agonists produce several vascular effects via activation of both 5-HT receptors and alpha1-adrenoceptors, their effects were compared with those elicited by the 5-HT agonist, quipazine, and the alpha1-adrenoceptor agonist, methoxamine. 1-Min intracarotid (i.c.) infusions of buspirone (300 microgram/min), ipsapirone (40 microgram/min), quipazine (300 microgram/min) and methoxamine (15 microgram/min) produced consistent decreases in external carotid blood flow (ECBF); since these changes in blood flow were not accompanied by modifications in systemic blood pressure, the agonists produced parallel increases in external carotid resistance. After interruption of the sympathetic tone by bilateral cervical vagosympathectomy, the vasoconstrictor responses to all the agonists remained unaffected. The intravenous (i.v.) administration of the nonselective 5-HT1-like receptor antagonist, methiothepin (1-100 microgram/kg), potently and dose-dependently antagonized buspirone-, ipsapirone- and quipazine-induced vasoconstriction; methiothepin similarly antagonized the vasoconstrictor responses to methoxamine. Interestingly, the alpha1-adrenoceptor antagonist, prazosin (1-100 microgram/kg, i.v.), also antagonized the vasoconstrictor responses to buspirone, ipsapirone and methoxamine in a dose-dependent manner. Finally, buspirone (300 microgram/min, i.c.) and ipsapirone (40 microgram/min, i.c.) did not modify the responses to noradrenaline (10 microgram/min, i.c.) or tyramine (100 microgram/min, i.c.). It is concluded that canine external carotid vasoconstriction induced by buspirone and ipsapirone is mainly mediated by activation of alpha1-adrenoceptors located in vascular smooth muscle. These data further highlight the ability of the above anxiolytics to produce significant vascular effects under in vivo conditions.

Adrenergic alpha-Agonists↗
PubMed1982

The serotonin autoreceptor: antagonism by quipazine.

The purpose of this study was to attempt to reproduce previous findings regarding the antagonist specificity of the 5HT autoreceptor and to find additional antagonists of this receptor. Crude synaptosomal preparations of the rat hypothalamus were loaded with [3H]5HT, placed on glass microfiber filters and superfused with modified Krebs--Henseleit buffer at 37 degrees C. The release of [3H]5HT was stimulated by raising the buffer K+ concentration and was Ca2+-dependent. In the presence of 100 nM fluoxetine (a selective 5HT uptake inhibitor), exogenous 5HT inhibited the K+-induced release of [3H]5HT but did not affected basal [3H]5HT release. The K+-induced [3H]5HT release was maximally inhibited by 30 nM 5HT to a level of 66.4 +/- 4.0% of control. The concentration of 5HT required to inhibit half-maximally K+-induced [3H]5HT release was approx. 7 nM. Methiothepin and quipazine were found to block the inhibition of K+-induced [3H]5HT release by exogenous 5HT (30 nM). The IC50S for blockade of the effects of 5HT were approx. 3.8 and 670 nM for methiothepin and quipazine, respectively. Several other putative 5HT antagonists, the dopamine receptor antagonist, spiperone and the alpha receptor antagonist, phentolamine, were without effect. Thus, the 5HT autoreceptor appears to have a unique specificity for certain 5HT antagonists. In addition, blockade of 5HT autoreceptors may be one mechanism by which quipazine produces behavioral effects characteristic of a 5HT receptor agonist.

Animals↗
PubMed1986

Effects of serotonergic agonists and antagonists on the locomotor activity of neonatal rats.

The locomotor activity of neonatal rats was measured after treatment with serotonin agonists or antagonists. Treatment with the serotonin agonists 5-hydroxytryptophan or quipazine resulted in the elimination of the peak in activity which normally results from increases in activity from days 10 to 15 of life followed by decreases from days 15 to 20 of life. The drug-induced decreases in activity occurred at doses that did not alter locomotor activity after day 17, when most of the peak in activity had passed. The dose of 5 mg/kg of the serotonergic antagonist methysergide eliminated the peak in activity without changing locomotor activity after the peak had passed. The antagonists methiothepin and cinanserin only produced decreases in locomotor activity which did not appear to be related to the peak in activity. The serotonergic agonist data are compatible with the hypothesis that the development of the serotonin system contributed to the inhibition of locomotor activity. The methiothepin and cinanserin data neither confirm nor dispute the hypothesis, as their effects may have been either nonserotonergic or on serotonin receptors that were different than those acted on by the agonists.

5-Hydroxytryptophan↗
PubMed1992

Age-dependent changes in serotonergic modulation of yawning in the rat.

Serotonin (5-HT) effects on physostigmine (PHY)-induced yawning were studied in LY Sprague-Dawley rats by injecting Lu 10 171 (citalopram), a specific 5-HT uptake blocker, and two antagonists--methiothepine and ritanserin--which differ slightly in the selectivity of their actions on different 5-HT receptor subtypes. Infant and young rats show significant increases in PHY-induced yawning when preinjected with citalopram (5-10 mg/kg). Two-month-old animals show this effect only with 10 mg/kg. With adult animals (3-5 months old), the effect is the opposite: Yawning decreases. The facilitory effect in infant and young rats was counteracted by methiothepine but not by ritanserin, suggesting that it is mediated through 5-HT1A or 5-HT1B receptor subtypes. The inhibitory effect of citalopram in adult rats was unmodified by the two antagonists used, leaving open the possibility that it is mediated by 5-HT3 receptors.

Aging↗
PubMed1995

The effect of paroxetine on 5-HT efflux in the rat dorsal raphe nucleus is potentiated by both 5-HT1A and 5-HT1B/D receptor antagonists.

Serotonin (5-HT) efflux in slices of rat dorsal raphe nucleus (DRN) was evoked by pseudo one pulse electrical stimulation (20 pulses at 100 Hz, 190 ms train duration) and measured, along with 5-HT uptake, by fast cyclic voltammetry (FCV). The selective serotonin re-uptake inhibitor (SSRI) paroxetine (10(-7) M) increased 5-HT efflux to 147 +/- 6% of pre-drug values at maximum (mean +/- SEM, n = 5) and the half-life of uptake to 443 +/- 38%. The non-selective 5-HT1 antagonist methiothepin (2 x 10(-7) M) increased 5-HT efflux to 147 +/- 9% at maximum but had no effect on uptake half-life. In contrast, (+)-WAY 100135 (10(-6) M) and GR 127935 (5 x 10(-8) M), selective antagonists at 5-HT1A and 5-HT1B/D receptors, respectively, affected neither 5-HT efflux nor uptake. When given in combination with paroxetine, the antagonists significantly increased the effect of paroxetine on efflux: methiothepin to 228 +/- 24% (P < 0.001), (+)-WAY 100135 to 212 +/- 31% (P < 0.05) and GR 127935 to 203 +/- 23% (P < 0.01). These data suggest that, under these experimental conditions, DRN 5-HT autoreceptors are tonically activated in the presence of the uptake blocker and that the antagonists act by blocking this counteracting autoinhibitory tone. The data also strongly indicate that 5-HT efflux in the rat DRN is under the control not only of 5-HT1A but also of 5-HT1B/D receptors.

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