Evidence for excitatory 5-HT2-receptors on rat brainstem neurones.

1. The technique of microiontophoresis was used to investigate the identity of the receptor mediating the excitatory effects of 5-hydroxytryptamine (5-HT) upon neurones in the midline of the medullary brainstem of the rat in vivo. 2. The 5-HT1-like receptor agonists 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) failed to excite the majority of neurones excited by 5-HT. The mobilities of 5-CT and 8-OH-DPAT when tested in vitro were found not to differ significantly from that of 5-HT, suggesting that the lack of effect of these agonists was not due to a lower rate of release from the microelectrodes. 3. The excitatory responses to 5-HT were attenuated by the 5-HT 2-receptor antagonists ketanserin and methysergide when applied microiontophoretically or administered intravenously (0.3 and 1 mg kg-1 respectively). Excitatory responses to glutamate and noradrenaline were not reduced. 4. The 5-HT3-receptor antagonist MDL 72222 failed to attenuate selectively the excitatory response to 5-HT when applied either by microiontophoresis or administered intravenously (1 mg kg-1). 5. Microiontophoretic application of the alpha 1-adrenoceptor antagonist prazosin did not attenuate excitatory responses to either 5-HT or noradrenaline. Intravenously administered prazosin (0.8 mg kg-1) also failed to attenuate excitatory responses to 5-HT, but did block excitatory responses to noradrenaline. 6. These results suggest that 5-HT2-receptors, but not 5-HT1-like receptors, 5-HT3-receptors or alpha 1-adrenoceptors, are involved in the excitatory response of midline medullary neurones to 5-HT.     

The actions of the novel anti-aggressive drug eltoprazine on central neurones in the anaesthetised rat

5-Hydroxytryptamine (5-HT) and the novel anti-aggressive drug eltoprazine (1-(2,3-dihydro-1,4-benzodioxin-5-yl) piperazine hydrochloride) were applied by microiontophoresis to spinal motorneurones and also to neurones in the brainstem which gave two distinctly different responses to 5-HT. In vitro microiontophoretic release studies showed that the electrophoretic mobility of eltoprazine and 5-HT were similar and that similar amounts of each drug would be applied by similar iontophoretic currents. Cells in the brainstem have been shown previously to be excited by 5-HT, acting at a 5-HT2 receptor. Eltoprazine only occasionally and weakly mimicked the excitatory effect of 5-HT on these cells. Although a potent antagonism of the 5-HT excitation by eltoprazine was observed, this was a non-selective effect, as responses to glutamate and D,L-homocysteic acid were also reduced. Cells in the lateral brainstem are depressed by 5-HT, acting on a receptor which has previously been shown to be of the 5-HT1-like group. At this receptor, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) and 5-carboxamidotryptamine, are potent agonists. Eltoprazine was a more potent depressant agonist than 5-HT on these brainstem neurones. The antagonist metergoline did not antagonise responses to either 5-HT or eltoprazine. It is suggested however that both drugs act at the same receptor to depress these cells because desensitizing the receptor by repeated, frequent applications of 5-HT abolished responses to 5-HT and eltoprazine, without altering responses to GABA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 5-HT and 5-HT1A receptor agonists and antagonists on dorsal vagal preganglionic neurones in anaesthetized rats: an ionophoretic study.

1. Effects of ionophoretic administration of 5-hydroxytryptamine (5-HT) and selective 5-HT1A receptor agonists and antagonists on identified dorsal vagal preganglionic and dorsal raphe neurones were studied in pentobarbitone sodium or chloral hydrate-anaesthetized rats, respectively. 2. Extracellular recordings were made from 176 preganglionic neurones in the dorsal vagal nucleus (DVN). Application of 5-HT at low currents (< or = 10 nA) increased the activity of these neurones. However, at increased currents (10-60 nA), it had a predominantly depressant effect. Application of selective 5-HT1A receptor antagonists, (+/-)-pindolol or WAY-100635, attenuated the excitatory responses evoked by 5-HT. 3. Ionophoresis of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5-30 nA) increased the firing rate of 19 and decreased that of 67 of the 104 vagal neurones tested. Other 5-HT1A receptor agonists, flesinoxan and N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT) also had predominantly depressant effects. 4. (+/-)-Pindolol attenuated excitations but not inhibitions evoked by 8-OH-DPAT. Surprisingly, WAY-100635 and 8-OH-DPAT produced the same effect on these neurones and when applied together, WAY-100635 failed to attenuate the 8-OH-DPAT responses. 5. Dorsal raphe neurones were identified by their low, regular firing rate and their subsequent histological localization. 8-OH-DPAT reversibly reduced the activity in all 7 neurones tested and this was antagonized by WAY-100635 in all 3 neurones tested. 6. In conclusion, 5-HT applied to vagal preganglionic neurones evokes excitatory and inhibitory responses. The excitatory, but not the inhibitory responses may be mediated, at least in part, by activation of 5-HT1A receptors.     

Comparison of the positive chronotropic response to 5-hydroxytryptamine with beta-adrenoceptor agonists on the guinea pig atria in vitro

The positive chronotropic response to 5-hydroxytryptamine (5-HT) in the isolated guinea pig atria was analyzed. The response to 5-HT was compared with the effects of 5-carboxamidotryptamine (5-CT), 8-dihydroxydiphenylaminotetralin (8-OH-DPAT), isoprenaline, prenalterol, dobutamine, salbutamol, and norepinephrine (NE). In comparison to isoprenaline 5-HT, prenalterol, dobutamine, salbutamol, and NE acted as partial agonists, whereas 5-CT and 8-OH-DPAT did not produce a response. The response to 5-HT was unaffected by 1 microM methysergide, metergoline, ketanserin, MDL 72222, ICS 205-930, phentolamine, or 0.1 mM hexamethonium. However, the beta-adrenoceptor antagonists, pindolol and atenolol, antagonized the response to 5-HT in a noncompetitive manner. The response to 5-HT was unaffected by reserpinization or beta-adrenoceptor desensitization. Thus, the positive chronotropic response to 5-HT in this preparation is a direct effect but is not mediated by 5-HT1-like, 5-HT2, or 5-HT3 receptors.     

5-Hydroxytryptamine-induced vasodilatation in the isolated perfused rat kidney: are endothelial 5-HT1A receptors involved?

Left kidneys obtained from male Wistar rats were perfused with Tyrode solution; the perfusion pressure was measured continuously and taken as an index of vascular resistance in the kidneys. 5-Hydroxytryptamine (5-HT; 3-50 nmol) caused dose-dependent dilator responses in kidneys preconstricted with noradrenaline (0.6 microM) and pretreated with ritanserin (10 nM) and ICS 205930 (10 nM). The 5-HT1 agonist 5-carboxamidotryptamine (5-CT; 16-64 nmol) also caused renal dilatations under similar conditions. The dilator responses to both 5-HT and 5-CT were antagonized by the non-selective 5-HT receptor antagonist metergoline (0.2 microM) and by the selective 5-HT1A receptor antagonist BMY 7378 (0.4 microM). The guanylate cyclase inhibitor methylene blue (30 microM) and the nitric oxide (NO) synthase inhibitor nitro-L-arginine (L-NNA; 100 microM) significantly attenuated the dilator responses to 5-HT and 5-CT. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5-16 nmol) also caused dose-dependent dilator responses in preconstricted rat kidneys. These responses were antagonized by metergoline and BMY 7378 and significantly attenuated by the NO inhibitors hemoglobin (10 microM) and L-NNA. The renal dilator responses noted with the beta-adrenoceptor blocker tertatolol (1-32 nmol) were also antagonized by metergoline and BMY 7378 and significantly reduced by L-NNA and hemoglobin. Both 8-OH-DPAT and tertatolol (1-30 microM) significantly reduced the vasoconstrictor responses to angiotensin II (20 pmol). Our data indicate that 5-HT receptors located on the vascular endothelium of the renal circulation are involved in the dilator actions of 5-HT, 5-CT, 8-OH-DPAT and tertatolol, and suggest that these receptors resemble the 5-HT1A subtype.     

Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5. Taken together, the above results suggest that the inhibitory action of 5-HT on the electrically-induced pressor responses is primarily mediated by an action on inhibitory prejunctional 5-HT1-like receptors leading to a decrease in the sympathetic nerve discharge. Interestingly, 5-HT-induced excitatory mechanisms could be made manifest once the inhibitory action of 5-HT had been antagonized.     

Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis

1. We have previously found that the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) decreases hippocampal 5-hydroxytryptamine (5-HT) release in the anaesthetized rat, as measured by brain microdialysis. The present study attempted to characterize the receptor involved in this response using a range of monoamine receptor antagonists. 2. The classical 5-HT receptor antagonists, metergoline (5 mg kg-1 s.c.), methysergide (10 mg kg-1 s.c.) and methiothepin (10 mg kg-1 s.c.) each reduced dialysate levels of 5-HT which complicated their use as antagonists in these experiments. Nevertheless, pretreatment with metergoline but not methiothepin and methysergide partially reduced the 5-HT response to a maximally effective dose of 8-OH-DPAT (0.25 mg kg-1 s.c.). 3. The mixed 5-HT 1/beta-adrenoceptor antagonist pindolol (8 mg kg-1 s.c.) was without effect on spontaneous 5-HT output but attenuated the effect of both maximally (0.25 mg kg-1 s.c.) and submaximally (0.05 mg kg-1 s.c.) effective dose of 8-OH-DPAT. In comparison, propranolol (10 mg kg-1 s.c.) did not affect 5-HT output when injected alone and did not alter the response to 8-OH-DPAT (0.25 mg kg-1 s.c.). 4. The 5-HT2 receptor antagonist ritanserin (0.2 mg kg-1 s.c.) and the 5-HT3 receptor antagonist BRL 43694 (0.5 mg kg-1 s.c.) neither altered 5-HT output alone nor significantly changed the response to 8-OH-DPAT (0.25 mg kg-1 s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of cortical neurones to stimulation of the nucleus raphé medianus: a pharmacological analysis of the role of indoleamines

Single shock stimulation of the nucleus raphé medianus evoked complex responses from the large majority of neurones tested. These responses consisted of a short-latency (mean 21 msec) inhibition of firing followed by a longer latency (mean 160 msec) increase in firing rate. Occasionally, cells were encountered which exhibited pure inhibitory or pure excitatory responses. Prior treatment with the tryptophan hydroxylase inhibitor rho-chlorophenylalanine reduced the excitatory effects of raphé stimulation but greatly increased the inhibitory effects. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT), on the other hand, reduced both inhibitory and excitatory effects of raphé stimulation. Methysergide was found to be an effective antagonist of excitatory responses to iontophoretically applied 5-hydroxytryptamine (5-HT) but less effective against depressant responses to either 5-HT or tryptamine. In contrast metergoline consistently antagonized 5-HT and tryptamine-induced depressions but not 5-HT elicited excitations. When tested against stimulation evoked responses of cortical neurones methysergide antagonized the excitatory effects of raphé stimulation but had much less effect on the inhibitory responses, while the reverse held true for metergoline. The present results may be compatible with a mediation of the excitatory effects of stimulation by 5-HT and the inhibitory effects by tryptamine.     

Effects of 5-hydroxytryptamine agonists and antagonists on the responses of rat spinal motoneurones to raphe obscurus stimulation.

1. The excitability of lumbar spinal motoneurones was studied in halothane-anaesthetized rats by recording with microelectrodes the amplitude of the population spike evoked antidromically by stimulation of the cut ventral roots. 2. Electrical stimulation of the nucleus raphe obscurus for 1 min at 20 Hz increased the population spike amplitude and, as shown by intracellular recording, depolarized motoneurones. This response could be mimicked by microinjection of DL-homocysteic acid into raphe obscurus but the response was not present in animals pretreated with the 5-hydroxytryptamine (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). 3. Microiontophoretically applied 5-HT had very similar effects on the extracellularly recorded population spike to those caused by stimulation of the raphe obscurus. These responses to 5-HT were larger in 5,7-DHT-pretreated animals. 4. The effects of 5-HT were potently mimicked by iontophoretically applied 5-carboxamidotryptamine but 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was without effect. 5. Antagonists were applied by microiontophoresis and also by intravenous injection. Ketanserin, the selective 5-HT2 antagonist, did not antagonize the effects of 5-HT. Neither did the 5-HT3-receptor antagonist MDL 72222 or the selective 5-HT1 binding ligand cyanopindolol. 6. The non-selective 5-HT1/5-HT2-receptor antagonist methysergide was an effective antagonist of both the effects of 5-HT and the response to raphe obscurus stimulation. Methysergide did not reduce the excitatory effects of noradrenaline. 7. It is concluded that 5-HT application and stimulation of raphe obscurus increase the excitability of motoneurones by an action on a 5-HT1-like receptor which appears to be different from the 5-HT1A-and the 5-HT1B-binding sites characterized by others.     

5-HT1-like receptor agonists enhance wakefulness.

The effects of four 5-HT1-like receptor agonists (8-OH-DPAT, RU 24969, BEA 1654 and 5-carboxamidotryptamine) and some putative 5-HT1-like receptor antagonists on vigilance were examined in an attempt to clarify the role of 5-HT1-like receptors in the sleep-waking pattern of rats. Both 8-OH-DPAT (0.5-2.0 mg/kg, s.c.) and RU 24969 (0.5-2.0 mg/kg, s.c.) increased wakefulness and the latencies of slow wave and rapid eye movement (REM) sleep. The slow wave and REM sleep were correspondingly decreased or completely abolished. The two other 5-HT1-like receptor agonists had either a slight (BEA 1654, 1.0-5.0 mg/kg, s.c.) or no (5-carboxamidotryptamine, 0.5-2.0 mg/kg, s.c.) effect on sleep pattern. The arousal effect of 8-OH-DPAT was further potentiated in rats pretreated with reserpine (2.5 mg/kg, i.p.; 18 hr before 8-OH-DPAT). The non-selective 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (2.0 mg/kg, i.p.) and the beta-adrenoceptor antagonist propranolol (16.0 mg/kg, s.c.), which is a putative antagonist at 5-HT1A and 5-HT1B receptor subtypes, significantly potentiated the arousal effect of RU 24969. The putative 5-HT1A and 5-HT1B receptor antagonist, cyanopinolol (4.0 mg/kg, s.c.), mixed 5-HT1A receptor agonist/antagonist MDL 72832 (1.0 mg/kg, s.c.) and the alpha 1-adrenoceptor antagonist prazosin (2.0 mg/kg) did not affect the vigilance, altered by RU 24969. These results suggest that the arousal effect of 5-HT1-like receptor agonists is probably not mediated by any of the subtypes of 5-HT1-like receptors or by an activation of a noradrenergic system.     

Quipazine reduces food intake in the rat by activation of 5-HT2-receptors.

1. To determine which subtype(s) of 5-hydroxytryptamine (5-HT) receptor are involved in the anorectic action of quipazine, the ability of selective antagonists at 5-HT2- and 5-HT3-receptors, and an antagonist at 5-HT1-like receptors, to block this response were investigated in non-deprived rats, trained to eat a palatable diet. 2. Quipazine (0.5-8 mg kg-1, i.p.) produced a dose-related reduction in the intake of palatable diet. 3. The anorectic effect of 4 mg kg-1 quipazine was antagonized by the nonselective 5-HT-receptor antagonist methysergide (5 mg kg-1, i.p.) and by the selective 5-HT2-receptor antagonists ketanserin (1 mg kg-1 and 2.5 mg kg-1, i.p.) and ritanserin (0.5 mg kg-1 and 1 mg kg-1, i.p.). The selective 5-HT3-receptor antagonist GR38032F (1 mg kg-1, i.p.) and (-)-pindolol (4 mg kg-1, i.p.), which blocks some of the effects mediated at 5-HT1-like receptors, did not block the reduction in food intake produced by this dose of quipazine. 4. None of the 5-HT-receptor antagonists had any effect on food intake when they were administered alone, suggesting that endogenous 5-HT is not involved in the tonic control of food intake under the conditions of these experiments. 5. It is concluded that the anorectic action of quipazine is mediated, at least in part, by activation of 5-HT2-receptors.     

Molecular pharmacology of 5-HT1D recognition sites: Radioligand binding studies in human,pig and calf brain membranes

1) The binding characteristics of [3H]5-HT (5-hydroxytryptamine, serotonin) were investigated in membrane preparations of several regions from calf, pig and human brain in the presence of 100 nmol/l 8-OH-DPAT (8-hydroxy-2[di-n-dipropylamino]tetralin) and 100 nmol/l mesulergine in order to mask 5-HT1A and 5-HT1C sites. 2) [3H]5-HT bound rapidly, reversibly and stereo-selectively to a population of high affinity recognition sites in membranes from pig caudate, calf caudate and human cortex, caudate and substantia nigra. 3) Saturation experiments carried out with [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and 100 nmol/l mesulergine revealed that non-5-HT1A non-5-HT1C sites represented from 50 to more than 90% of the total 5-HT1 sites (determined with [3H]5-HT in the absence of 8-OH-DPAT and mesulergine), depending on the tissue source. 4) The pharmacological profile of these sites was characterized in competition experiments performed with a variety of ligands in membranes of calf, pig and human caudate membranes. Under these conditions, [3H]5-HT labelled a population of "5-HT1-like" sites which display nanomolar affinity for tryptamines (5-carboxamidotryptamine greater than 5-HT greater than or equal to 5-methoxytryptamine greater than tryptamine) and some ergolines (metergoline greater than methysergide). In contrast, these sites showed low affinity for drugs with high affinity and/or selectivity for 5-HT1A (8-OH-DPAT, buspirone), 5-HT1B (21-009, RU 24969), 5-HT1C (mesulergine, mianserin) and 5-HT2 sites (ketanserin, cinanserin).(ABSTRACT TRUNCATED AT 250 WORDS)     

Complex actions of serotonergic agonists on cold-stimulated TSH secretion in male rats

The effects of serotonergic activation on cold-stimulated thyrotropin (TSH) and prolactin secretion were studied in male rats. Peripheral injections of both 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and 1-(3-chlorophenyl)piperazine (m-CPP), a 5-HT1 agonist, decreased TSH levels. The action of 8-OH-DPAT was antagonized by (+/-)-pindolol, which is known to have 5-HT1 antagonist activity, but not by metergoline or ketanserin. The action of m-CPP was antagonized by ketanserin but not by metergoline. TSH levels were not affected by a 5-HT3 receptor agonist, 2-methyl-5-HT, or by a 5-HT3 antagonist, MDL 72222. Infusion of 8-OH-DPAT into the anterior third ventricle increased TSH levels; 5-HT tended to increase TSH levels, but the effect was not significant. Inversely, infusion of 5-HT, 8-OH-DPAT or m-CPP into the posterior third ventricle decreased TSH levels. The action of 5-HT was counteracted by metergoline, ketanserin and (+/-)-pindolol. Unexpectedly, m-CPP infusion into the anterior third ventricle also inhibited TSH secretion. The prolactin-elevating effects of 5-HT, 8-OH-DPAT and m-CPP were neither consistent nor site-specific. In conclusion, stimulation of both 5-HT1 and 5-HT2 receptors may inhibit TSH secretion, but the exact mechanism underlying the site-dependent action of 5-HT and 8-OH-DPAT on TSH secretion remains to be identified.     

Characterization of presynaptic 5-HT receptors on adrenergic nerves supplying the bovine ovarian follicle.

1. The effects of 5-hydroxytryptamine (5-HT) on contraction and release of [3H]-noradrenaline were investigated in vitro in bovine ovarian follicle strips. Using available selective agonists and antagonists, an effort was made to characterize the type of receptor mediating the inhibitory effect of 5-HT on neurogenic contraction and release of [3H]-noradrenaline by electrical field stimulation. 2. 5-Hydroxytryptamine inhibited the neurogenic contraction and release of [3H]-noradrenaline evoked by electrical field stimulation in a concentration-dependent manner. Like 5-HT, 5-carboxamidotryptamine (5-CT) and methysergide reduced the transmitter release as well as the neurogenic contraction, whereas 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) failed to inhibit both responses in concentrations up to 0.1 microM. 3. The 5-HT (1 microM)-induced inhibition of contractile responses was more evident during stimulation at low frequencies (4 and 8 Hz) than during high frequency electrical stimulation (16 and 32 Hz). 4. Methiothepin (1 microM) and methysergide (10 microM) significantly antagonized the inhibitory effect of 5-HT on the electrically evoked release of tritium, whereas cyanopindolol, MDL 72222 and ketanserin (all 0.1 microM) were without effect. In addition, ketanserin, MDL 72222, cimetidine, pyrilamine, atropine, propranolol and indomethacin were without effect on the 5-HT-induced inhibition of the neurogenic contraction. 5. It is suggested that 5-HT inhibits the electrically evoked transmitter release from adrenergic nerves in the bovine ovarian follicle wall via prejunctional 5-HT1-like receptors. This was based on the findings that 5-CT was a potent agonist, methiothepin an antagonist and the lack of effect of MDL 72222, cyanopindolol and ketanserin.     

Peripheral 5-carboxamidotryptamine (5-CT) elicits drinking by stimulating 5-HT1-like serotonergic receptors in rats.

Subcutaneous administration of the prototypical 5-HT1-like agonist, 5-carboxamidotryptamine (5-CT), increased 2-h water intake by nondeprived rats (ED50 = 0.04 mumol/kg). The 5-HT1 agonists 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT, 0.04-0.32 mumol/kg) and RU 24969 (0.16 mumol/kg) did not produce drinking. The dipsogenic effect of 5-CT (0.08 mumol/kg) was prevented by the 5-HT1/2 antagonist, methysergide (ID50 = 4 mumol/kg), but not by 16 mumol/kg of the 5-HT2 antagonist, ketanserin; the 5-HT21C antagonist, mianserin; or the 5-HT3 antagonist, MDL 72222, 5-CT also increased drinking and reduced food intake when food-deprived rats were given 2-h access to mash. Methysergide (16 mumol/kg) inhibited both actions of 5-CT but an equimolar dose of the 5-HT1/beta adrenergic antagonist, (-)-propranolol, blocked only the drinking. The 5-HT21C antagonist, ritanserin (16 mumol/kg), altered neither ingestive action of 5-CT although, by itself, ritanserin increased mash intake. The results suggest that activating a subtype of peripheral 5-HT1-like receptor stimulates drinking in rats. This receptor is unlike either the 5-HT1A or the 5-HT1C sites found in the brain. Furthermore, the dipsogenic and anorectic actions of 5-CT occur independently.     

Differential effects of centrally-active antihypertensives on 5-HT1A receptors in rat dorso-lateral septum, rat hippocampus and guinea-pig hippocampus.

1. The electrophysiological responses elicited by 5-hydroxytryptamine1A-(5-HT1A) receptor agonists in rat and guinea-pig CA1 pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2. In the presence of 1 microM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3. The hypotensive drug flesinoxan, a selective 5-HT1A receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HT1A-receptors, 5-methyl-urapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4. In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HT1A-receptor antagonist. 5. The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6. It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HT1A receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated.     

The influence of 5-hydroxytryptamine agonists and antagonists on identified sympathetic preganglionic neurones in the rat, in vivo.

1. 5-Hydroxytryptamine (5-HT) was applied by microiontophoresis in the vicinity of identified sympathetic preganglionic neurones in the upper thoracic spinal cord of the rat, in vivo. 2. Sympathetic preganglionic neurones responded in one of three ways to 5-HT: by (a) excitation (76%), (b) inhibition (4%) or (c) in a biphasic manner (5%). 3. The excitatory responses evoked by 5-HT were mimicked by 5-carboxamidotryptamine (5-CT) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). The inhibitory and biphasic responses evoked by 5-HT were mimicked by 2-methyl-5-hydroxytryptamine (2-Me-5-HT). The observed responses evoked by 5-HT and selective agonists may be different on the same cell. In several instances a single neurone excited by one agonist was inhibited by another agonist. 4. The 5-HT2-receptor antagonists, ketanserin and LY 53857, failed to abolish selectively the excitatory responses evoked by 5-HT and alpha-Me-5-HT, when applied by microiontophoresis. The antagonists non-selectively reduced the excitatory responses evoked by 5-HT, 5-CT, alpha-Me-5-HT, D,L-homocysteic acid (DLH) and noradrenaline (NA). A reduction in synaptically evoked activity was also observed. 5. The 5-HT3-receptor antagonist, ICS 205-930, failed to abolish the inhibitory responses evoked by 5-HT. 6. It was concluded that the excitatory responses evoked by 5-HT are mediated by a receptor that is neither 5-HT2 or 5-HT3, but shows similarities to the 5-HT1-like receptor profile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater.

1. We describe the effects of pretreatment with 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on neurogenically-mediated plasma protein extravasation ([125I]-albumin) in rat dura mater and in extracranial tissues (temporalis muscle fascia, conjunctiva, eyelid and lip) induced by electrical stimulation of the right trigeminal ganglion. 2. Leakage of [125I]-bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, 5 ms, 5 Hz for 5 min) was significantly reduced by the intravenous administration of drugs active at 5-HT receptors with some selectivity for the 5-HT1 receptor subtypes: 5-carboxamidotryptamine (5-CT) (threshold dose, 1 ng kg-1); 5-benzyloxytryptamine (5-BT) (10, 30 or 100 micrograms kg-1); 8-hydroxydipropylaminotetralin (8-OH-DPAT) (300 micrograms kg-1); and as previously reported, sumatriptan (100 micrograms kg-1), dihydroergotamine (DHE) (50 micrograms kg-1); ergotamine tartrate (100 micrograms kg-1) and chronically administered methysergide (1 mg kg-1). 3. The putative 5-HT receptor antagonist, metergoline 100 micrograms kg-1, inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5-HT1 receptor subtype-mediated mechanism, although it was not effective against 5-CT (1 ng kg-1). Methiothepin (300 micrograms kg-1) did not affect the response to sumatriptan. When administered at high concentrations (1 mg kg-1) methiothepin and metergoline decreased plasma protein extravasation in rat dura mater.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.

1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

A 5-HT1-like receptor mediates a sympathetic ganglionic hyperpolarization

5-HT induced a hyperpolarization of the rat superior cervical ganglion in vitro which was resistant to both MDL 72222 (10 microM), a 5-HT3 antagonist, and ketanserin (1 microM), a 5-HT2 antagonist. The 5-HT1-selective ligands 5-carboxamidotryptamine and 8-OH-DPAT also hyperpolarized the ganglion. The 5-HT-induced hyperpolarization was potently antagonised by spiperone. These results suggest that 5-HT hyperpolarizes the rat superior cervical ganglion via a 5-HT1-like receptor which resembles the central 5-HT1A binding site.