Analysis of the contractile effect of 5-hydroxytryptamine on the isolated posterior communicating artery of the cat.

5-Hydroxytryptamine (5-HT) induced dose-dependent increases in tension on the isolated posterior communicating artery (PCA) of the cat were significantly antagonized by lysergic acid diethylamide (LSD, 6 X 10(-9). In the presence of the phentolamine (10(-6) M) the contraction induced by the two lowest doses of 5-HT was significantly reduced. Pretreatment of the animals with reserpine (3 mg kg-1, i.p., total dose) did not modify the dose-response curve to 5-HT except for the lowest dose. Removal of both superior cervical sympathetic ganglia 15 days before the experiment brought about a significant increase in the vasoconstriction induced by 5-HT at all the doses compared with the control. Cocaine (10(-6) M) induced a significant shift to the left of the dose-response curve to 5-HT but the maximum response was the same as in the control. The augmented response to 5-HT after denervation was partially antagonized by LSD (6 X 10(-9) M) but not by phentolamine (10(-6) M). These results show that the vasoconstriction elicited by 5-HT in the PCA of the cat is mainly due to direct stimulation of tryptaminergic receptors. The participation of an indirect adrenergic component in the contractile effects of 5-HT seems to be negligible.     

Noradrenergic component in the vasoconstriction induced by 5-hydroxytryptamine in goat cerebral arteries

5-Hydroxytryptamine (5-HT) elicited dose-dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10^?8 M) and methysergide (10^?7 M). In the presence of phentolamine (10^?6 M), the dose-response curve to 5-HT was shifted to the right, the pA₂ value for this antagonism was 6·52. Pretreatment of goats with reserpine (0·02 mg kg^?1 day^?1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5-HT higher than 10^?7 M. The remaining contraction produced by 5-HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5-HT induced tritium release from goat pial arteries preloaded with (?)-[³H]noradrenaline, 2 × 10^?7 M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5-HT there are two components. The first appears with low concentrations (up to 10^?7 M) in which 5-HT acts directly on 5-HT receptors. The second occurs at high doses (>10^?7 M) in which 5-HT also acts indirectly on α-adrenoceptors by release of noradrenaline from noradrenergic nerve endings.     

Noradrenergic component in the vasoconstriction induced by 5-hydroxytryptamine in goat cerebral arteries

5-Hydroxytryptamine (5-HT) elicited dose-dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10(-8) M) and methysergide (10(-7) M). In the presence of phentolamine (10(-6) M), the dose-response curve to 5-HT was shifted to the right, the pA2 value for this antagonism was 6.52. Pretreatment of goats with reserpine (0.02 mg kg-1 day-1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5-HT higher than 10(-7) M. The remaining contraction produced by 5-HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5-HT induced tritium release from goat pial arteries preloaded with (-)-[3H]noradrenaline, 2 X 10(-7) M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5-HT there are two components. The first appears with low concentrations (up to 10(-7) M) in which 5-HT acts directly on 5-HT receptors. The second occurs at high doses (greater than 10(-7) M) in which 5-HT also acts indirectly on alpha-adrenoceptors by release of noradrenaline from noradrenergic nerve endings.     

The action of 5-hydroxytryptamine and some of its antagonists on the umbilical vessels of the human placenta

The vasoconstrictor action of 5-hydroxytryptamine (5-HT) in the human placental preparation is about 10 times stronger than that of adrenaline and is antagonized by anti-adrenaline compounds like phentolamine. Both 5-HT and adrenaline are antagonized by yohimbine and chlorpromazine. Specific and strong anti-5-HT action is demonstrated for lysergic acid diethylamide (LSD) and tryptamine. Both LSD and tryptamine in larger doses have a vasoconstrictor action. Mescaline has no certain modifying effect on the action of 5-HT, but itself causes vasoconstriction in large doses. The antihistamine drug phenbenzamine in histamine blocking doses abolishes the action of 5-HT in half the preparations tested. The ganglionic blocking agent trimetaphan in large doses antagonizes the action of 5-HT added subsequently, and also, to a lesser degree, the effect of adrenaline. Hexamethonium and tetraethylammonium bromides are ineffective in this preparation. No certain modifying action of reserpine on subsequently added 5-HT could be demonstrated, and the same was true for heparin even in very high concentrations.     

Depolarizing responses recorded from nodose ganglion cells of the rabbit evoked by 5-hydroxytryptamine and other substances

Membrane potential changes induced by 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and 1,1-dimethyl-4-phenyl piperazinium (DMPP) were recorded from nodose ganglia (NG) by the sucrose-gap method. An amount of 0.002–0.5 μmol of the depolarizing agent was injected into the superfusion stream to the ganglion. Responses to 5-HT were also evoked from superior cervical (SCG) and dorsal root ganglia (DRG). 5-Hydroxytryptamine elicited depolarizations of graded amplitude. Maximal responses were 4.5 ± 0.4 mV in nodose ganglia compared to 2.2. ± 0.2 mV in superior cervical and 0.6 ± 0.1 mV in dorsal root ganglia (means ± SEM). In nodose ganglia, GABA induced smaller maximal depolarizations than did 5-HT, similar to those evoked by DMPP; dopamine was a weak depolarizing agent while substance P was apparently inactive.The dose-response curve for 5-HT in nodose ganglia was parallel to that for 5-HT in superior cervical ganglia and significantly to the left (ED₅₀ values 0.029 and 0.098 μmol). Curves for 5-HT and GABA in nodose ganglia were superimposable. The high sensitivity of nodose ganglia cells to 5-HT is briefly discussed. Analogues of 5-HT lacking a hydroxyl group at position 5 on the nucleus were relatively inactive as depolarizing agents.Picrotoxin (10^?6 ? 10^?5 M) reduced or suppressed responses in nodose ganglia to GABA, whereas responses to 5-HT and DMPP were not much affected or, in the case of 5-HT, sometimes somewhat reduced. Quipazine (10^?6 M) was a selective antagonist of 5-HT responses in nodose ganglia; those to GABA and DMPP were not significantly altered. Neither trazodone nor LSD displayed antagonist properties at 5-HT receptors in nodose ganglia.     

A pre-junctional action of 5-hydroxytryptamine and methysergide on noradrenergic nerves in dog isolated saphenous vein

Electrical stimulation (2 Hz for 2 min) of dog isolated saphenous vein strips pre-incubated with tritiated noradrenaline increased the overflow of tritium of which about 80% was noradrenaline. 5-Hydroxytryptamine (5-HT; 1·0 × 10^?9-1·0 × 10^?7 mol litre^?1) and methysergide (3·0 × 10^?8-3·0 × 10^?8 mol litre^?1) inhibited the induced overflow of total tritium by a maximum of 78 ± 4% and 47 ± 7% respectively (mean ± s.e. mean, n = 6 for each). Methysergide was about 30 times less potent than 5-HT and the maximum inhibition obtained was less than with 5-HT. Both compounds inhibited electrically-induced contractions and overflow of tritiated noradrenaline. Their inhibitory actions on tritium overflow were little affected by phentolamine (1·0 × 10^?8 mol litre^?1) or cyproheptadine (1·0 × 10^?8 mol litre^?1), nor was the inhibitory effect of methysergide on electrically induced contractions antagonized by atropine, mepyramine, cimetidine or propranolol. The findings suggest that the prejunctional inhibitory effect of methysergide may be mediated via stimulation of a 5-HT receptor which, unlike the D-receptor, is not blocked by cyproheptadine. The possibility that the pre-junctional 5-HT receptor in the dog saphenous vein is the same as the post-junctional receptor in this preparation is discussed.     

Changes in electrocortical activity induced by the perfusion of 5-hydroxytryptamine into the nucleus of the solitary tract

Various concentrations of 5-hydroxytryptamine, d-lysergic acid diethylamide (LSD) or 2-bromolysergic acid diethylamide (bromo-LSD), were perfused at 120 μl/min bilaterally into the region of the nuclei of the solitary tract and the adjacent reticular formation. 5-Hydroxytryptamine (10^?5?2.5 × 10^?4m) induced or increased the amount of electrocortical synchronisation. Concommitantly the responsiveness of the animal to auditory stimulation, or electrical stimulation of the mesencephalic reticular formation, decreased. Concentrations of 5-hydroxytryptamine in excess of 5 × 10^?4 m elicited a secondary alerting effect towards the end of the 12 min perfusion period. In contrast, LSD (5 × 10^?5?10^?3m) induced alerting or produced varying degrees of electrocortical desynchronisation when perfused into a sleeping animal. Prior perfusion of 10^?4m LSD, which produced an increase in sensory responsiveness but only transient electrocortical desynchronisation, blocked the sedative effects of a subsequent perfusion of 5-hydroxytryptamine. In these experiments LSD and 5-hydroxytryptamine appeared to act additively in that alerting and electrocortical desynchronisation was usually the eventual consequence of the sequential perfusion of these substances. Bromo-LSD (up to 6 × 10^?3m) was without effect on the electrocorticogram, sensory responsiveness or the sedative effects of a 5-hydroxytryptamine perfusion.     

Response of Rabbit Ear and Femoral Arteries to 5-Hydroxytryptamine During Cooling

The effects of cooling on the response of cutaneous and non-cutaneous arteries to 5-hydroxytryptamine (5-HT) were analysed. Segments 2-mm long from rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries were prepared for isometric tension recording in an organ bath at 37 and 24°C (cooling). 5-HT (10^?9-3 times 10^?4 M) induced concentration-dependent contraction of the arteries. The sensitivity and maximal contraction of ear arteries and only the maximal contraction of femoral arteries to this amine were reduced at 24°C. Endothelium removal or pretreatment with the nitric oxide synthase inhibitor N^G-nitro-l -arginine methyl ester (l -NAME, 10^?5 m ) did not affect the response at 37°C but reversed the decreased sensitivity at 24°C in ear arteries, and neither procedure modified the reactivity at 24 or 37°C in femoral arteries to 5-HT. At both temperatures, the response of ear arteries to 5-HT was shifted to the right by phentolamine (10^?6M) more than by the 5-HT antagonist, ketanserin (3 times 10^?7M), and that of femoral arteries was shifted to the right by ketanserin or the 5-HT₁/5-HT₂ antagonist methysergide (3 times 10^?7 M) more than by phentolamine, in arteries with and without endothelium. These data concur with the proposition that the contraction to 5-HT is mediated mainly by α-adrenergic receptors in ear arteries and mainly by 5-HT-ergic receptors in femoral arteries, and suggest that cooling reduces the sensitivity of cutaneous, but not of deep arteries to 5-HT, probably by endothelium-nitric oxide-dependent mechanisms.     

The Prejunctional Inhibitory Effect of α-Methylnoradrenaline in the Rat Vas Deferens is Not Mediated via α2-Adrenoceptors

In field-stimulated rat vas deferens, clonidine (10^?9–10^?7 m ) and α-methylnoradrenaline (10^?7–3 times 10^?5 m ) concentration-dependently inhibited twitch response to electrical field stimulation. The inhibitory effects of clonidine and α-methylnoradrenaline were similarly reduced by phenoxybenzamine (10^?6 m ). However, idazoxan (3 times 10^?7 m ) antagonized clonidine but not α-methylnoradrenaline-induced responses. The inhibitory effect of α-methylnoradrenaline was also not antagonized by phentolamine (3 times 10^?7 m ), SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methylthienol[4,3,2 ef][3]benzazepine) 3 times 10^?6 m ) or yohimbine 3 times 10^?7 m ). These antagonists however, attenuated the twitch-inhibiting effect of clonidine. The -logK_B values were 8·02 ± 0·05, 6·91 ± 0·10, and 7·58 ± 0·07 for phentolamine, SK&F 104856 and yohimbine respectively. In-vivo treatment of rats with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (6 mg kg^?1), to inactivate prejunctional α₂-adrenoceptors, attenuated clonidine, but not α-methylnoradrenaline-induced responses. It was concluded that adrenoceptors are not involved in the prejunctional inhibitory effects of α-methylnoradrenaline in the rat vas deferens.     

5-Hydroxytryptamine agonistic action of methysergide and the absence of supersensitivity to 5-HT agonists in spinal flexor reflexes in rats

The intravenous administration of L-5-hydroxytryptophan (5-HTP), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), p-chloroamphetamine (PCA), LSD and methysergide to acute spinal rats, transected at C1, stimulated the flexor reflexes induced by electrical stimulation applied to the skin of the toe. The enhancement produced by 5-HTP, 5-MeODMT and PCA, was not antagonized by the prior administration of a dose of LSD or methysergide, although the enhancement produced by 5-MeODMT, LSD and methysergide, but not that produced by 5-HTP and PCA, was antagonized by cyproheptadine. In rats treated with 5,6-dihydroxytryptamine (intracisternal administration, 2 weeks previously) supersensitivity was observed to the effects of 5-HTP, a precursor of 5-HT, while subsensitivity was observed for the effects of PCA, a releaser of 5-HT. However, no supersensitivity was observed for the effects of 5-MeODMT, LSD and methysergide. These results suggest that methysergide may have an agonistic action on the 5-HT receptors in spinal cord and that supersensitivity to 5-HTP in rats treated with 5,6-dihydroxytryptamine was due to the lack of uptake of 5-HT into terminals of descending 5-HT fibres or to the change in 5-HT receptors which were not sensitive to 5-MeODMT, LSD, methysergide or cyproheptadine.     

Release of [3H]noradrenaline induced by 5-hydroxy-tryptamine from cat pial arteries

Pial arteries of cats were used to analyse the effects of 5-hydroxytryptamine (5-HT) on the release of [³H]noradrenaline. To achieve this the vessels were preincubated with [³H]noradrenaline and the effect of different concentrations of 5-HT (10^?6, 10^?5, 10^?4 M) on the release of tritium was studied. 5-HT elicited release of radioactivity in a dose-dependent manner. Removal of both superior cervical sympathetic ganglia 15 days before the experiment or pretreatment of the animals with reserpine (3 mg kg^?1, total dose) produced a significant decrease in the outflow of tritium induced by 5-HT. In these arteries, the amount of radioactivity retained at the end of the experiment was much diminished. Cocaine (10^?6 M) caused a significant decrease in the tritium efflux induced by 5-HT (10^?5 M). These results show that 5-HT has an indirect adrenergic effect in the pial arteries of the cat only at high doses of 5-HT, and confirm that sympathetic innervation of these vessels mainly comes from the superior cervical ganglia.     

Actions of D-lysergic acid diethylamide (LSD) and its derivatives on 5-hydroxytryptamine receptors in the isolated uterine smooth muscle of the rat

Several metabolites of D-lysergic acid diethylamide (LSD) such as D-lysergic acid ethyl, 2′-hydroxyethylamide (LEO), D-lysergic acid ethyl,vinylamide (LEV), D-lysergic acid ethylamide (LAE) and D-norlysergic acid diethylamide (norLSD) are formed by liver tissue and by Streptomyces. These metabolites and synthetic N⁶-alkyl substituted derivatives such as N⁶-ethyl-, N⁶-propyl, N⁶-allyl and N⁶-hexyl-D-norLDS (ethyl-, propyl-, allyl- and hexyl-norLSD, respectively) were studied for their anti-d-hydroxytryptamine (anti-5-HT) and oxytoxic activities on isolated rat uteri. The LSD derivatives had less anti-5-HT activity than LSD. Except for hexyl-norLSD, N⁶-alkyl substituted derivatives of LSD had higher oxytocic activities than LSD, LEO or LAE. Minimum effective concentrations as well as ED₅₀ values for oxytocic activities of ethyl-norLSD, propyl-norLSD and allyl-norLSD were lower than that of LSD whereas those of the metabolites (LEO, LAE and norLSD) were higher than that of LSD. The oxytocic activity of allyl-norLSD was effectively antagonized by LSD and cyproheptadine, suggesting that this activity was due to its 5-HT-like action. These results suggest that N⁶-alkyl substituted derivatives (ethyl-, propyl-, allyl-norLSD) have higher, but the metabolites of LSD have lower affinity for 5-HT receptors than LSD, and that N⁶-substituted derivatives except for hexyl-norLSD have higher intrinsic activity than LSD.     

Actions of dopamine and apomorphine on the vasoconstrictor responses of perfused mesenteric arteries of mouse,rat and rabbit

Dopamine (10^?7-10^?6 m) and apomorphine (5 × 10^?7 ? 5 × 10^?6 m) inhibited the vasoconstrictor responses of the perfused mesenteric artery preparations of rat, rabbit and mouse to adrenergic nerve stimulation but did not affect responses to added noradrenaline. The inhibitory effects of both dopamine and apomorphine were prevented by haloperidol (3 × 10^?7 m) but not by yohimbine (3 × 10^?8 m) in rat and rabbit mesenteric artery preparations. In contrast, yohimbine (3 × 10^?8 m), but not haloperidol, antagonized the inhibitory effect of dopamine and apomorphine in mouse mesenteric artery preparations. In higher concentrations, dopamine (10^?6 ? 10^?4 m) produced a direct vascoconstrictor effect, which involved post-junctional α-adrenoceptors in all three species. However, in preparations contracted with 10^?7 m 5-hydroxytryptamine and in the presence of phentolamine (3 × 10^?7 m) and propranolol (10^?6 m), dopamine (10^?6 ? 10^?4 m) produced a direct relaxant effect in rabbit mesenteric artery preparations but not in those of rat and mouse. It is suggested that inhibition of neurogenic vasoconstrictor responses, by dopamine and apomorphine, may be mediated through a specific prejunctional inhibitory dopamine receptor in the mesenteric artery of rat and rabbit whereas in the mouse they involve activation of α-adrenoceptors.     

Ouabain-induced potentiation on the contractions of the guinea-pig vas deferens

This contractile responses of the guinea-pig vas deferens to norepinephrine, isoproterenol, tyramine, ACh, carbachol, histamine and 5-HT were non-specifically potentiated by ouabain (10^?6?10^?5 g/ml); potentiations of tyramine and 5-HT were particularly marked. Ouabain enhanced the responses to norepinephrine, 5-HT and angiotensin on the denervated preparation.The response of the tissue to 5-HT consisted of a fast and a slow component. The latter was augmented by methysergide. The marked potentiation of the slow phase by ouabain was prevented by pretreatment with reserpine, cocaine or phentolamine. Denervation abolished the slow phase abolished but increased the fast phase. The latter was inhibited by phenoxybenzamine, but not by phentolamine. Therefore, the slow and fast phases may be due to actions of 5-HT at pre- and post-synaptic sites, respectively.From these results, it is concluded that ouabain potentiation is due to increased catecholamine release and to excitation of the post-synaptic membrane.     

Investigation of possible interactions between substance P and transmitter mechanisms in the substantia nigra and corpus striatum of the rat

The effect of substance P (SP) on the uptake and release of radiolabelled dopamine (³H-DA), 5-hydroxytryptamine (³H-5-HT) and γ-aminobutyric acid (³H-GABA) was studied in slices of rat substantia nigra and corpus striatum. SP, 10^?9 to 10^?5m , failed to modify the uptakes of these compounds during incubations (10–90 min) with slices of either brain region. SP, 10^?6m , had no apparent effect on the spontaneous output of any of these compounds in either substantia nigra or corpus striatum. In the corpus striatum, SP seemed to potentiate the potassium-stimulated outflow of ³H-DA and ³H-5-HT, but not ³H-GABA, while the releases from substantia nigra were unaffected. Morphine (10^?3m ), but not met-enkephalin (5 × 10^?6m ), weakly antagonized K⁺-evoked release of ³H-DA in the corpus striatum. These results are discussed with reference to the possible interaction of SP with transmitter mechanisms at presynaptic sites in the central nervous system.     

Characterization and radioautography of [3H] LSD binding by rat brain slices in vitro: The effect of 5-hydroxytryptamine

Binding of D-[³H] lysergic acid diethylamide (LSD) to rat coronal brain slices and its blockade by 5-hydroxytryptamine (5-HT) had characteristics similar to those of brain homogenates in respect of K_D, kinetics and reversibility of binding. Radioautography was done on slices that had been incubated in 6 nM [³H] LSD and on adjacent slices incubated in the same concentration of tritiated LSD plus 10^?5 M of 5-HT. Choroid plexus showed densest labeling of [³H] LSD. In neuropil, dense labeling occurred within parts of the hippocampal formation except for fields CA2 and CA3 which were sparsely labeled. All layers of the cortex except the posterior cingulate gyrus were labeled by LSD. 5-HT blocked labeling of choroid plexus, hippocampal formation, septum, pons, medulla and parts of cortex but only reduced labeling of most other structures. LSD binding sites may relate to some of its pharmacological effects.     

Analysis of the adrenergic receptors of pacemaker and myocardial cells

Chronotropic and inotropic dose-response curves for epinephrine and phenylephrine were determined in rabbit atria spontaneously beating and electrically-driven. The curves were obtained in the absence and in the presence of propranolol, 10⁻⁷ M, or phentolamine, 2 × 10⁻⁶ M. Propranolol antagonized the chronotropic effects of epinephrine and phenylephrine, and the inotropic effects of epinephrine. This antagonist reduced the inotropic responses to high doses of phenylephrine, but left unaltered the effects of low doses. Phentolamine antagonized the inotropic effects of low doses of phenylephrine which were unaffected by propranolol. The inotropic curve for epinephrine was shifted 2.5-fold to the right by phentolamine. In contrast, phentolamine did not modify the chronotropic responses to these amines.     

DU 24565, a quipazine derivative,a potent selective serotonin uptake inhibitor

DU 24565, 6-nitro,2-(1-piperazinyl)quinoline, is a potent and selective inhibitor of the synaptosomal uptake of serotonin (5-HT). At concentrations at least 10³-fold higher it affects the uptake of norepinephrine (NA) and dopamine (DA). The IC₅₀ values are: 5-HT: 4 × 10^?8 M; NA: 6 × 10^?5 M and DA: 4 × 10^?5 M. Uptake of 5-HT by rat blood platelets is also strongly inhibited (K_i ～ 5 × 10^?8 M); the inhibition is probably noncompetitive. In vivo, DU 24565 is active at low oral doses: the 5-HT depletion in rat brain caused by p-chloroamphetamine is antagonized by DU 24565 (oral ED₅₀ 0.7 mg/kg). The decrease in the 5-HT content caused by 4,α-dimethyl-m-tyramine (H 77/77) is antagonized by DU 24565 at 1 mg/kg orally, without any effect on the depletion of catecholamines. 5-HT turnover, measured by the probenecid method, is reduced by the same dose of DU 24565. Other tests confirmed the activity and selectivity of DU 24565: it potentiated the behavioural effects of the 5-HT precursor 5-hydroxytryptophan (5-HTP) in mice (ED₅₀ 1.5 mg/kg orally); it potentiated the temperature increases caused by 5-HTP in the rabbit; it had low activity or no effect at all in NA potentiation tests. This new compound is more potent and selective than the known 5-HT uptake inhibitors. It is a potential antidepressant and can be useful as a pharmacological tool to study the role of 5-HT in the central nervous system.     

Analysis of the heart rate effects of 5-hydroxytryptamine in the cat; mediation of tachycardia by 5-HT1-like receptors

Summary The effects of 5-hydroxytryptamine (5-HT) on heart rate in anaesthetized cats were analysed both in intact animals and after spinal section plus vagotomy.The intact cat responded to 5-HT (3, 10 and 30 g·kg^–1, i.v.) with a brief, but intense, bradycardia and a longerlasting hypotension. Administration of MDL 72222, a selective antagonist of M-type 5-HT receptors, blocked bradycardia elicited by 5-HT without affecting that caused by stimulation of the vagus nerve.In spinal cats the same doses of 5-HT increased heart rate and blood pressure. These effects remained essentially unchanged after bilateral adrenalectomy, guanethidine, propranolol and burimamide, suggesting that 5-HT acted directly on the myocardium and blood vessels. The tachycardic responses to 5-HT in spinal cats were little affected by 0.5 mg·kg^–1 doses of MDL 72222 or of the 5-HT₂ receptor antagonists, ketanserin, ritanserin or cyproheptadine. In contrast, the non-selective 5-HT receptor antagonist, methysergide, which binds to both 5-HT₁ and 5-HT₂ recognition sites in rat brain membranes, potently antagonized the 5-HT-induced tachycardia in doses of 0.05 to 0.5 mg·kg^–1. However pizotifen and mianserin, two other 5-HT₂ antagonists which show poor affinity for 5-HT₁ recognition sites, were also effective against the tachycardic response to 5-HT in doses of 0.5–4.5 mg·kg^–1. The pressor responses to 5-HT in the spinal cat were markedly inhibited by all six 5-HT₂ antagonists at a dose of 0.5 mg·kg^–1.5-Carboxamido-tryptamine, which has a high and selective affinity for 5-HT₁ recognition sites, elicited marked tachycardia in doses of 0.1–10 g/kg^–1 in spinal cats treated with saline. These responses were not affected in animals treated with 4.5 mg·kg^–1 of ketanserin, which was able to shift the dose-response curve for 5-HT to the right. On the other hand, methysergide (0.5 mg·kg^–1) displaced the dose-response curves for both 5-carboxamidotryptamine and 5-HT to a similar extent.Unlike on the dog saphenous vein, methysergide showed no agonist effects on heart rate in the spinal cat.On the basis of the above results, we conclude that: (i) the reflexogenic bradycardic response elicited by 5-HT overshadows its direct tachycardic response on heart rate in the intact cat; (ii) M-type 5-HT receptors mediate the bradycardic response; (iii) the pressor response to 5-HT in the spinal cat involves 5-HT₂ receptors; (iv) tachycardia by 5-HT in the spinal cat is mediated mainly by 5-HT₁-like receptors, but an additional, though less important, non-5-HT₁ mechanism may also be involved; (v) the cardiac 5-HT₁ receptors are similar, but perhaps not identical, to those delineated in the dog saphenous vein or rat brain membrane preparations; and (vi) the tachycardic responses to 5-HT and, in particular the more selective, 5-carboxamidotryptamine may be conveniently utilized to characterize new chemical compounds designed for potential 5-HT₁ receptor antagonist activity.     

Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT

The effect of midalcipran, an equipotent inhibitor of the uptake of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), on the inhibition of release of 5-HT induced by lysergic acid diethylamide (LSD), was investigated by studying the overflow of transmitter from slices of hypothalamus from the rat prelabelled with [3H]5-HT. The (Z)-enantiomer of midalcipran, at 0.1 microM, displaced to the right the concentration-effect curve of inhibition of release of [3H]5-HT elicited by electrical stimulation induced by LSD. In contrast, the (E)-enantiomer, which does not inhibit the uptake of monoamines, was devoid of any antagonizing effect. The inhibitory effect of 0.1 microM LSD was not modified in the presence of maprotiline, bupropion or mianserin at 1 microM. The results of this study show that the interaction between the 5-HT autoreceptor and the inhibitors of the uptake of 5-HT is related exclusively to their potency at inhibiting the uptake of 5-HT. The effect of the monoamine oxidase inhibitor, pargyline (1-10 microM), was also studied on the field-stimulated release of [3H]5-HT. The inhibitory effect of this drug was antagonized by methiothepin at 0.1 and 1 microM, by phentolamine 1 microM and 10 microM and by the inhibitor of the uptake of 5-HT, citalopram at 0.1 and 1 microM. The action of pargyline appeared to be mediated through the activation of the serotonergic autoreceptor and of the presynaptic alpha-adrenoceptor located on serotonergic nerve terminals. The results obtained with pargyline are consistent with the hypothesis of an interaction between the 5-HT autoreceptor and the uptake site for 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)