The influence of 5-hydroxytryptamine agonists and antagonists on identified sympathetic preganglionic neurones in the rat, in vivo (original) (raw)
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Journal of Autonomic Pharmacology, 1989
The aim of the present work was to characterize the presynaptic 5-HT receptors that mediate either the facilitation of the responses to nerve stimulation in the nictitating membrane of the cat or the inhibition of the responses to nerve stimulation in the guinea-pig atria. ' 2 In the nictitating membrane of the cat, the shift to the left in the frequencyresponse curves produced by 5-HT (0.1 ,EM) was prevented by the 5-HT3 receptor antagonists, metoclopramide (1 ,EM) and MDL 72222 (0.01 p~). 6 The present results suggest that the facilitatory effects of 5-HT in the nictitating membrane of the cat are linked to the activation of 5-HT3 receptors whereas the inhibitory effects observed in the guinea-pig atria are mediated by 5-HT,-like receptors.
Brain Research, 1992
Whole-cell patch clamp recordings were made from neurons in the rat nucleus tractus solitarius (NTS) in transverse brainstem slices. 5-Hydroxytryptamine (5-HT. 100 p.M) and the selective 5-HT~ receptor agonist 2-methyl-5-HT (2-CH ~-5-HT, 100 p.M) depolarized 86% of NTS neurons at resting membrane potential (V m). This response was resistant to tetrodotoxin (TTX) and (~o-+ application. In addition, 2-CH3-5-HT (500 nM-10() p.M) increased the amplitude and frequency of both excitatory and inhibitory spontaneous synaptic potentials. This effect was also TTX-resistant. but was abolished by Co-'+. The effects of 2-CH3-5-HT on EPSPs and IPSPs evoked by electrical stimulation of the tractus solitarius (TS) were analyzed separately in the presence of bieuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. Concentrations of 2-CH.r5-HT between 500 nM and l p.M decreased the amplitude of evoked EPSPs and IPSPs with similar potency. The selective 5-HT 3 receptor antagonists ICS 205-930 (10 nM) and MDL 72222 (10/zM) reversibly blocked the effects of 2-CH.r5-HT at all doses examined, it is concluded that 5-HT.x receptors can mediate both pre-and postsynaptic responses in the NTS.
British Journal of Pharmacology, 1992
The actions of 5-hydroxytryptamine (5-HT) and some 5-HTA receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2 In the presence of tetrodotoxin (1 tiM) to block any indirect effects, bath application of 5-HT (0.3-30 AM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3 The 5-HTA receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT, receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50s were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 ptM and buspirone 110 nM. 5 At a concentration of 3 SAM, the putative 5-HTIA receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17. 6 The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 jiM) and the 5HT3 receptor antagonist, tropisetron (3 tiM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization. 7 It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.
Journal of Pharmacology and Experimental Therapeutics, 2005
The pharmacological properties of cyclohexanecarboxylic acid, {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2trifluoromethoxyphenyl)amide (Rec 27/0224), and cyclohexanecarboxylic acid, (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}amide (Rec 27/0074), were characterized using radioligand displacement and guanosine 5Ј-O-(3-[ 35 S]thiotriphosphate) ([ 35 S]GTP␥S) binding assays, as well as electrophysiological experiments, in rat hippocampal and dorsal raphe nucleus (DRN) slices. Both compounds showed a high affinity (K i , ϳ1 nM) and selectivity (Ͼ70-fold) at human 5-hydroxytryptamine (5-HT) 1A receptors versus other 5-HT receptors. In [ 35 S]GTP␥S binding assays on HeLa cells stably expressing human 5-HT 1A receptors, Rec 27/0224 and Rec 27/0074 inhibited basal [ 35 S]GTP␥S binding by 44.8 Ϯ 1.7% (pEC 50 ϭ 8.58) and 25 Ϯ 2.5% (pEC 50 ϭ 8.86), respectively. In intracellularly recorded CA1 pyramidal cells, 5-HT 1A (hetero)receptor-mediated hyperpolarization, elicited by 100 nM 5-carboxamidoytryptamine (5-CT), was partially antagonized by Rec 27/0224 (ϳ50%; IC 50 ϭ 18.0 nM) and Rec 27/0074 (74%; IC 50 ϭ 0.8 nM). In extracellularly recorded DRN serotonergic neurons, Rec 27/0224 and Rec 27/0074 fully antagonized the inhibition of firing caused by the activation of 5-HT 1A (auto)receptors by 30 nM 5-CT with an IC 50 of 34.9 nM and 16.5 nM, respectively. The antagonism had a slow time course, reaching a steady state within 60 min. Both compounds also antagonized the citalopram-elicited, endogenous 5-HT-mediated inhibition of cell firing. In conclusion, Rec 27/0224 and Rec 27/ 0074 exhibited inverse agonism in [ 35 S]GTP␥S binding assays and differential antagonistic properties on 5-HT 1A receptormediated responses in the hippocampus but not in the DRN. Whether this differential effect is causally related to inverse agonist activity is unclear. The qualitatively different nature of the antagonism in the hippocampus versus the DRN clearly distinguishes the compounds from neutral antagonists, such as N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide (WAY-100635).
British Journal of Pharmacology, 2003
1 Systemic administration of phenethylamine-derived, 5-hydroxytryptamine 2 (5-HT 2 ) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2 The 5-HT 2 receptor agonists DOI ((7)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((7)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10 -100 mg kg À1 i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by 480%.
Neuropharmacology, 1990
The effects of repeated treatment of rats with I-hydroxy-Z(di-n-propylamino)tetralin (g-OH-DPAT), 1 .O mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post-and presynaptic 5-HT,, receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the I-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to S-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT,, receptors in the cerebra1 cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with.[3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose. The strength of the 5-HT syndrome was almost abolished, when measured one day after the third injection, and still markedly decreased 1 but not 2 weeks after this injection. In contrast to these changes, no attenuation of the decrease in the turnover of 5-HT or the accumulation of 5-HTP was found in any of the regions examined. The kinetic parameters of the 5-HT,, receptors (&,, and &) were also unchanged in all the regions analyzed. These findings, which are contradictory to some previous observations, indicate that pre-and postsynaptic 5-HT,, receptor responses are mediated by different signal systems and that some of them, possibly G, proteins coupled to adenylate cyclase, may be quite sensitive to repeated stimulation.
Brain Research, 1991
It has been claimed that the aversive behaviour induced by electrical stimulation of the midbrain tectum (MT) has validity as an animal model of panic attack. A great deal of evidence obtained from behavioural studies suggests that 5-HT 2 mechanisms phasically inhibit the substrates of aversion in the MT. In order to test this hypothesis we employed the technique of microiontophoresis of drugs onto neurones of the MT to assess the identity of the receptors mediating the effects of 5-hydroxytryptamine (5-HT). The results obtained show that the majority of 5-HT responsive cells in MT are cells excited by 5-HT (72%). These cells were silent or showed very low spontaneous firing activity, whereas cells depressed by 5-HT showed high spontaneous firing activity at baseline. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and gepirone caused consistent reduction in the firing rate of cells depressed by 5-HT while they did not change the firing activity of cells excited by 5-HT. The excitatory effects induced by 5-HT on MT neurones were clearly attenuated by concomitant application of ketanserin, a highly specific 5-HT 2 antagonist. Excitatory responses to DL-homoeysteic acid were not affected by ketanserin. Previous administration of zimelidine, a selective 5-HT uptake inhibitor, caused a significant enhancement of the excitatory effects of 5-HT while similar application of gepirone did not affect the size of the excitatory responses to 5-HT. These results give electrophysiological support to the idea that 5-HT neurotransmission operating through 5-HT 2 receptors may exert a phasic control on functional processes in the Mr. It is possible that 5-HT 2 mechanisms in this region may mediate at least part of the therapeutic effects of 5-HT uptake inhibitors in panic disorders.
Journal of Autonomic Pharmacology, 2000
1 In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT 1A and 5-HT 1D receptor subtypes. At the time, we observed that some 5-HT 1 receptors antagonists ± WAY 100,635 and NAN-190 (both 5-HT 1A receptor antagonists), methiothepin (a 5-HT 1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT 1,2 receptor antagonist) ± reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2 The inhibition induced by WAY 100,635 (1000 lg kg )1 , i.v.) was blocked after i.v. treatment with idazoxan, an a 2 -adrenoceptor antagonist (300 and 1000 lg kg )1 ) and was not modi®ed after i.v. treatment with propranolol, a b-adrenoceptor antagonist (1000 lg kg )1 ) and sulpiride, a D 2 receptor antagonist (1000 lg kg )1 ). The inhibition induced by spiperone (500 lg kg )1 i.v.) was signi®cantly blocked by sulpiride (1000 lg kg )1 ) and was not modi®ed by idazoxan or propranolol. 3 Sulpiride (1000 lg kg )1 ) partially blocked the inhibition induced by methiothepin (50 lg kg )1 i.v.). Only pretreatment with idazoxan (300 lg kg )1 ) modi®ed the inhibition induced by NAN-190 (100 lg kg )1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4 All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5 The above results suggest that the inhibitory effects of these 5-HT 1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT 1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT 1 receptor antagonist studied.
Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI
European Journal of Pharmacology, 1991
Systemic, intra-raphe and microiontophoretic administration of the 5hydroxyrryptamine (WIT),,-/MIT, agonist (l-(2,5-dimethoxy-GiodophenyWZaminopropane (DOD inhibited the firing of 5-I-IT neurones in the dorsa! raphe. DOI administered systemically and directly into the raphe also decreased the extracellular concentration of 5-hydroxytryptamine (5-HT) in the frontal cortex. In contrast, the administration of DO1 directly into the frontal cortex did not significantly alter the concentration of frontal cortical extracellular 5-HT. The reduction of the firing rate of 5-I-IT neurones in the dorsal raphe and extracellular 5-HT concentration in the frontal cortex induced by systemic administration of DOI could not be blocked by the 5-HTI antagonist ketanserin, ritanserin (5-HT2/5-HT,c antagonist) or the putative 5-I-IT,, antagonist, pindolol. These results suggest that the inhibition of 5-HT neuronal firing seen with administration of DOI is mediated via an action within the dorsal raphe and at least in close proximity to the 5-HT neurone cell bodies. The decrease in frontal cortical extracellular concentration of 5-HT release was not due to a direct action in the frontal cortex itself and may possibly be as a result of the decrease in the firing rate of the 5-HT neurones in the dorsal raphe. The mechanism of action of DO1 to produce these effects is, however, unclear and warrants further investigation. DO1 (l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropanek Dorsal raphe; Frontal cortex; Neuronal firing; 5-HT release --Correspondence lo: CA. Marsden.