Evidence that central 5-HT 2A and 5-HT 2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat (original) (raw)
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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.
Characterization of DOI, a putative 5-HT2 receptor agonist in the rat
European Journal of Pharmacology, 1989
DOI (1-100/xg/kg i.v.) induced an increase in mean blood pressure in the anaesthetized rat. Similarly, in the pithed rat, DOI (1-100 /~g/kg i.v.) induced a dose-dependent increase in mean blood pressure, as did 5-HT. However, in contrast to 5-HT, DOI did not change the heart rate in either intact or pithed rats. In the pithed rat, the dose-pressor response curves to both 5-HT and DOI were unaffected by MDL 72222 (5-HT 3 receptor antagonist), spiroxatrine or (+)-pindolol (5-HT1A receptor antagonists), idazoxan (a2-adrenoceptor blocking agent) and AR-C 239 (cq-adrenoceptor blocking agent). Only the selective 5-HT 2 receptor antagonist, LY 53857, significantly and dose dependently shifted to the right the dose-reponse curves to both 5-HT and DOI. These results indicated that DOI possesses 5-HT 2 agonistic properties and that the pressor response induced by DOI in the pithed rat is mediated via 5-HT 2 receptors.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2003
Most studies of 5-HT 2 receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT 2A and 5-HT 2C receptors); very few in vitro studies have addressed the peripheral receptors 5-HT 2A and 5-HT 2B. The aim of this investigation was to compare the possible short-and long-term processes regulating these peripheral receptors in the rat. The in vitro contractile response elicited by serotonin (5-HT, 10 µM) in the rat gastric fundus (5-HT 2B receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT 2A receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI, 1 or 2.5 mg/ kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (±)DOI (2.5 mg/ kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (±)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E max (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E max was lower in animals treated with (±)DOI (2.5 mg/ kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E max between experimental and control animals. After chronic treatment with (±)DOI (2.5 mg/kg), clozapine and cyproheptadine, E max was lower than in controls. In the gastric fundus, E max 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E max was significantly lower than in controls for each drug used. These findings suggest first, that regulation of peripheral 5-HT 2 receptors (5-HT 2A and 5-HT 2B) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT 2 receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT 2B receptors in rat gastric fundus are more sensitive to druginduced regulation than the 5-HT 2A rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer. Keywords (±)DOI • Clozapine • Cyproheptadine • Rauwolscine • Rat thoracic aorta • Rat gastric fundus • 5-HT 2A receptor • 5-HT 2B receptor • Ex vivo treatments
British Journal of Pharmacology, 1990
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 a-methyl-5-hydroxytryptamine (a-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 a-Me-5-HT, when applied by microiontophoresis. The antagonists nonselectively reduced the excitatory responses evoked by 5-HT, 5-CT, a-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.
Synapse, 1990
The dorsal and median raphe 5-HT neurons give rise to projections that differ in axon morphology and in vulnerability to certain amphetamine derivatives. The present study was undertaken to determine if these two 5-HT systems possess different functional properties. To this end, we studied the effects of selective 5-HT1A or 5-HT1A/5-HT1B receptor agonists and of p-chloroamphetamine on extracellular levels of indoleamines, as measured by differential pulse voltammetry with extracellular levels of indoleamines, as measured by differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes, in cell body and nerve terminal regions of these subsets of 5-HT neurons in the rat brain. The selective 5-HT1A agonist 8-OH-DPAT produced a gradual decrease in the height of the 300 mV oxidation peak in the dorsal raphe and in the frontal cortex, reaching a maximum of 60% 3 h after the i.v. injection of 30 micrograms/kg. However, the same dose of 8-OH-DPAT was ineffective in the median raphe and in the dentate gyrus that receives its 5-HT innervation exclusively from the median raphe. A higher dose of 8-OH-DPAT (150 micrograms/kg, i.v.) produced a 60% decrease in the height of the 300 mV oxidation peak in the median raphe, whereas only a 20% decrease was obtained in the dentate gyrus. In contrast, the non-selective 5-HT1 agonist RU 24,969 (10 mg/kg, i.p.) caused a 70% reduction of the 300 mV peak height in both the dorsal and median raphe and a 50% decrease in both the frontal cortex and the dentate gyrus. Moreover, although a high dose of 8-OH-DPAT (150 micrograms/kg, i.v.) given alone reduced by 20% the amplitude of the oxidative peak in the dentate gyrus, subsequent administration of RU 24,969 (10 mg/kg, i.p.) caused a further 30% diminution of the oxidative peak height. The greater responsiveness of dorsal as compared to median raphe 5-HT systems to 5-HT1A receptor agonists was confirmed in two further series of experiments. First, the microiontophoretic application of 8-OH-DPAT directly onto 5-HT neurons was three times more potent in suppressing the firing rate of dorsal raphe 5-HT neurons than that of their median raphe congeners. Second, 8-OH-DPAT and buspirone were ten and four times, respectively, more potent in decreasing 5-HT synthesis in the frontal cortex than in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)
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.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000
5-HT 1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurones. In this study we report on the effect of a selective and potent 5-HT 1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'piperidine] hydrochloride), on extracellular 5-HT levels in the cortex and dentate gyrus of the freely-moving guineapig, using the technique of in vivo microdialysis.
British Journal of Pharmacology, 1997
The receptor mediating the long-lasting hypotensive eect of intravenous (i.v.) 5-hydroxytryptamine (5-HT) in the rat was originally classi®ed as 5-HT 1-like. Since some pharmacological properties of this receptor are closely similar to those for the cloned 5-ht 7 receptor, the present study investigated the eects of several 5-HT receptor agonists and antagonists showing high anity for the cloned 5-ht 7 receptor in pithed rats with arti®cially raised blood pressure. 2 I.v. bolus administration of 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, lisuride and sumatriptan to bilaterally vagotomized pithed rats pretreated with ketanserin (0.18 mmol kg 71 , i.v.), the diastolic blood pressure of which had been raised by a continuous i.v. infusion of methoxamine (60 ± 80 nmol kg 71 min 71), produced dose-dependent hypotensive responses; only 5-HT and 5-CT displayed similar maximum eects. In addition to mimicking the hypotensive action of 5-HT with a lower maximum eect, lisuride strongly antagonized the 5-CT-induced hypotensive responses thus suggesting a partial agonist eect. The rank order of hypotensive agonist potency was 5-CT 44 5-HT 5 5methoxytryptamine 5 lisuride 44 sumatriptan. 3 In experiments with antagonists, i.v. treatment with metergoline (2.48 mmol kg 71), mesulergine (2.76 mmol kg 71), methysergide (2.13 mmol kg 71), lisuride (0.22 mmol kg 71), methiothepin (0.68 mmol kg 71), mianserin (10.6 mmol kg 71), or the atypical antipsychotic drugs, clozapine (11.0 mmol kg 71) or risperidone (78.0 nmol kg 71), produced signi®cant rightward displacements of the dose-response curve for 5-CT in methoxamine-infused pithed animals pretreated with ketanserin (0.18 mmol kg 71 , i.v.); lisuride, methiothepin and risperidone behaved as non-competitive antagonists as they elicited a signi®cant reduction of the maximum eect to 5-CT. In contrast, blockade of 5-HT 1 , 5-HT 3 and 5-HT 4 receptors with i.v. propranolol (3.38 mmol kg 71), MDL-72222 (1.59 mmol kg 71) and GR125487 (1.91 mmol kg 71), respectively, did not alter 5-CT-induced hypotensive responses; ketanserin (0.18 mmol kg 71 , i.v.) failed to modify the dose-response curve for 5-CT in saline-pretreated animals. Lastly, inhibition of the prostaglandin-forming cyclo-oxygenase and nitric oxide synthase with indomethacin (14 mmol kg 71 , i.v.) and N G-nitro-L-arginine methyl ester (L-NAME, 120 mmol kg 71 , i.v.), respectively, had no signi®cant eects on 5-CT-induced hypotensive eects. 4 Taken together, the present pharmacological data suggest that the long-lasting vasodepressor action of 5-HT in the rat involves activation of receptors closely similar to the cloned 5-ht 7 subtype. Since no evidence for an indirect mechanism could be obtained, these receptors may be primarily located in the vascular smooth muscle of the systemic resistance vessels. These ®ndings represent further evidence favouring the functional role of the 5-ht 7 receptor.