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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low doses of the selective 5-HT1A agonist 8-OH-DPAT increase ethanol intake in a limited access paradigm following peripheral injection. This may be due to a reduction in 5-HT neurotransmission following activation of raphe somatodendritic autoreceptors. In order to test this hypothesis, and to determine the effects of selective reductions in raphe 5-HT activity, experiments examined the effects of injecting 8-OH-DPAT into the dorsal raphe (0, 0.02, 0.1, 1 and 2.5 micrograms) or the median raphe (0, 0.1, 1 and 5 micrograms) in rats trained to drink 12% ethanol for 40 min each day. The effects of the GABAA agonist, muscimol, on ethanol intake were also examined. Ethanol intake was increased at the highest dose of 8-OH-DPAT following injection into either site, with no change in water intake. Thus, the effects of 8-OH-DPAT are selective for ethanol. The selective 5-HT1A antagonist, (+)-WAY100135 (0.3, 1 and 3 mg/kg), blocked the effect of 8-OH-DPAT, showing that activation of 5-HT1A receptors underlies the ethanol drinking induced by 8-OH-DPAT. These results are consistent with the idea that reduced 5-HT function increases ethanol intake. Several behavioral mechanisms for this effect are discussed. Muscimol (50-100 ng) also increased ethanol drinking. Following injection into the median raphe, muscimol also stimulated water intake. These effects are probably due to non-specific behavioural activation induced by this treatment. However, the effect of muscimol in the dorsal raphe was specific for ethanol since water intake was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Median and dorsal raphe injections of the 5-HT1A agonist, 8-OH-DPAT, and the GABAA agonist, muscimol, increase voluntary ethanol intake in Wistar rats. 798 73

Changes in the extracellular concentration of 5-HT evoked by electrical stimulation of brain slices containing either dorsal raphe nucleus (DRN) or suprachiasmatic nucleus (SCN) from rats treated for 21 days with fluoxetine (5 mg/kg; i.p.) or water were monitored using fast cyclic voltammetry (FCV). Stimulated 5-HT overflow was enhanced significantly in both brain regions after 21 days treatment with fluoxetine but there was no change in the half time for re-uptake (t1/2). Concentration response curves for inhibition of electrically stimulated 5-HT overflow by 8-OH-DPAT (5-HT1a receptor agonist) or RU24969 (5-HT1b receptor agonist) in the DRN or SCN respectively were obtained in slices prepared from both groups of animals. There was a significant shift to the right in the dose-response curve for RU24969 in the SCN in fluoxetine treated animals but a shift to the left for the dose-response curve for 8-OH-DPAT in the DRN. These data suggest that down regulation of the 5-HT1b autoreceptors occurs in an axon terminal region (SCN) but that there is a sensitisation of 5-HT1a autoreceptor mechanisms controlling 5-HT overflow in the DRN.
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PMID:Effects of 21 days treatment with fluoxetine on stimulated endogenous 5-hydroxytryptamine overflow in the rat dorsal raphe and suprachiasmatic nucleus studied using fast cyclic voltammetry in vitro. 800 61

1. The present study was designed to examine the effects of a centrally acting 5-HT1A receptor agonist, flesinoxan, on the cardiovascular system and renal haemodynamics and excretory function. 2. In chloralose-urethane anaesthetized Wistar rats, i.v. administration of bolus doses of flesinoxan, at 30, 100, 300 and 1000 micrograms kg-1, caused significant, dose-dependent decreases in mean arterial pressure, of 33 +/- 2 mmHg (P < 0.001) and heart rate of 57 +/- 9 beats min-1 (P < 0.001) at the highest dose used. Despite this substantial fall in perfusion pressure there were no meaningful changes in the renal excretion of water and sodium. In a second group of rats, reduction of renal perfusion pressure mechanically to the same values as observed in rats given flesinoxan (i.e. 100, 92, 84 and 76 mmHg) produced reductions in urine flow, absolute and fractional sodium excretions reaching a maximum of 74, 86 and 84% respectively (all P < 0.001) at the lowest pressure. These reductions were significantly larger than those seen in the previous group of animals. 3. In the group of rats subjected to renal denervation, flesinoxan produced changes in blood pressure and heart rate which were not different from those observed in intact animals. However, the reduction in pressure was accompanied by significant decreases in urine flow of 71%, absolute sodium excretion of 68% and fractional sodium excretion of 67% (all P < 0.001) at the highest dose, which were all significantly greater than the changes seen in the innervated animals but were not different from those observed when renal perfusion pressure was reduced mechanically. 4. The findings of this investigation showed that flesinoxan was effective in lowering blood pressure and heart rate in the anaesthetized rat, which was probably due to decreased sympathetic nerve activity.Renal excretion of water and sodium was well preserved in the face of the flesinoxan-induced hypotension.The maintenance of fluid excretion with flesinoxan appeared to be mediated via changes in renal nerve activity, since it did not occur when the kidney was denervated.
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PMID:The renal functional responses to 5-HT1A receptor agonist, flesinoxan, in anaesthetized, normotensive rat. 803 44

Rats were trained to discriminate the 5-HT receptor agonist m-chlorophenylpiperazine (mCPP; 1 mg/kg) from saline using a two-lever, water-reinforced drug discrimination task. The antidepressant trazodone (1-8 mg/kg), the 5-HT1B/2C receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.25-1 mg/kg) and MK 212 (0.125-1 mg/kg), and the mixed 5-HT1A/B receptor agonist RU 24969 (0.25-2 mg/kg) substituted fully for mCPP. The 5-HT2A/2C receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.25-1 mg/kg) and d-lysergic acid diethylamide (LSD; 0.02-0.08 mg/kg) and the 5-HT releaser fenfluramine (0.5-2 mg/kg) also mimicked mCPP. Agonists selective for the 5-HT1A or 5-HT3 receptor or the 5-HT reuptake site produced saline-lever responding. The ergoline derivative mesulergine (0.5-4 mg/kg) produced a partial agonist/antagonist profile. The 5-HT1/2 receptor antagonist metergoline (0.125-1 mg/kg) completely blocked the mCPP cue whereas the 5-HT2A/2C receptor antagonists ketanserin and LY 53857 as well as all other 5-HT receptor antagonists failed to block the mCPP cue. The dopamine receptor antagonists SCH 23390 and haloperidol were also ineffective mCPP antagonists. Following pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA; 100 mg/kg/day) for 3 consecutive days, the discriminability of low doses of mCPP increased, whereas the effects of fenfluramine decreased. The present results suggest that the discriminative stimulus effects of mCPP in rats are mediated primarily by postsynaptic 5-HT2C receptors.
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PMID:Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP). 808 4

We tested the ability of SR 48968, (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloropheny l)butyl ) benzamide, a non-peptide antagonist highly selective for tachykinin NK2 receptors, to prevent defecation induced in rats by several agents. The tachykinin agonists substance P, [MePhe7]neurokinin B and [beta-Ala8]neurokinin A (4-10) all promoted defecation and increased faecal water content, the last compound being over ten times more potent than the other two (intraperitoneal dose inducing the excretion of 1 g faeces dry weight = 6.7 micrograms kg-1). SR 48968 given either orally (p.o.) or subcutaneously (s.c.) was similarly potent in dose-dependently inhibiting faecal output stimulated by the selective NK2-agonist [beta-Ala8]neurokinin A (4-10) (doses causing 50% inhibition 0.4 microgram kg-1, p.o. and 0.3 microgram kg-1, s.c.). This inhibition was long-lasting (more than 18 h after 1 microgram kg-1 SR 48968 either s.c. or p.o.). At the higher doses tested, SR 48968 also significantly prevented the increase in faecal water content produced by [beta-Ala8]neurokinin A (4-10). In rats treated with SR 48968, stimulation of faecal output by the alpha 2-adrenergic antagonist idazoxan and by salmonella endotoxin (LPS), but not by the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin, 5-HT, carbachol or platelet-activating factor, was partially prevented. The present results suggest that activation of intestinal NK2 receptors, either directly by the selective agonist [beta-Ala8]neurokinin A (4-10) or indirectly through the release of endogenous neurokinin A (by idazoxan or LPS), promotes defecation, presumably as a consequence of increased gut motility or secretion, or both. SR 48968 should therefore be useful for studying the role of neurokinin A-dependent mechanisms in health and disease, including those of the gastrointestinal system, and possibly for developing new therapeutic agents.
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PMID:SR 48968 selectively prevents faecal excretion following activation of tachykinin NK2 receptors in rats. 808 13

Acute stimulation of 5-HT1A receptors has been reported to diminish some 5-HT2 receptor-mediated responses in the rat, but there is controversy as to whether repeated stimulation of 5-HT1A receptors leads to identical changes. In this study, we tested the influence of repeated treatment with the 5-HT1A receptor agonist ipsapirone (0.5 g/l in drinking water for 21 days) on some 5-HT2 receptor-mediated responses elicited by the acute injection of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These responses included hyperglycemia, corticosterone release, and head shakes; cortical 5-HT2 receptor number and DOI-induced prolactin release (a 5-HT1C/5-HT2 receptor-mediated event) were also analyzed. In a first series of experiments, ipsapirone administration for 1, 8, 15, and 20 days reduced the duration fo shock-induced ultrasonic vocalization. Ipsapirone administration for 21 days reduced fluid intake and decreased body weight, but did not affect baseline plasma glucose, corticosterone, and prolactin levels or cortical 5-HT2 receptor number. The increases in plasma glucose levels elicited by acute injection of either DOI (0.1-1 mg/kg i.v.) or clonidine (an alpha 2-adrenoceptor agonist; 0.05 mg/kg i.v.) were reduced in ipsapirone-pretreated rats. The maximal effects of DOI and clonidine on plasma corticosterone or prolactin levels were not affected by ipsapirone pretreatment. Ipsapirone decreased the area under the corticosterone curve in both DOI- and clonidine-treated rats. Lastly, the head-shake response to DOI (0.5-2 mg/kg s.c.) was similar in vehicle- and ipsapirone-pretreated rats. These data indicate that a 3-week treatment with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not desensitize 5-HT2 receptors.
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PMID:Subchronic treatment with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not affect 5-HT2 receptor sensitivity in the rat. 809 65

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), gepirone, buspirone and ipsapirone dose-dependently antagonized the head-shakes induced by 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) (1.0 mg kg-1) in mice, when these agents were given i.p. 10 min beforehand. 2. para-Chlorophenylalanine (pCPA) abolished the effect of 8-OH-DPAT (0.1 mg kg-1) and of buspirone (1.0 mg kg-1). (+/-)-Pindolol (5.0 mg kg-1) also antagonized the effect of 8-OH-DPAT (0.1 mg kg-1). 3. The alpha 2-adrenoceptor antagonists, RX811059 (1.0 mg kg-1), idazoxan (0.5 mg kg-1), yohimbine (1.0 mg kg-1) and 1-(2-pyrimidinyl)-piperazine (1-PP) (2.0 mg kg-1) i.p. prevented the antagonistic effect of 8-OH-DPAT (0.1 mg kg-1) on DOI-head-shakes. 4. Orally-administered buspirone, given 60 min beforehand, only reduced DOI-head-shakes at doses of 60 mg kg-1 and above. However, when buspirone (1.0 mg kg-1) was administered orally twice daily for 21 days, DOI-head-shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. 5. A single oral dose of buspirone (1.0 mg kg-1) strongly antagonized DOI-head-shakes when given 24 h after the last of 4 daily doses of 1-PP (2.0 mg kg-1, p.o.) but had no effect on DOI-head-shakes 24 h after the last of 4 daily doses of water (p.o.). 6. A single oral dose of 1-PP (2.0 mg kg-1) abolished the inhibitory effect of i.p. buspirone(1.0 mg kg-1) on DOI-head-shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1-PP (2.0mg kg-1, p.o.) on these days.7. The ability of 5-HT1A receptor agonists to antagonize DOI-head-shakes may be due to an effect at presynaptic 5-HT receptors. It is suggested that 1-PP, formed from buspirone, may act at a2-adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI-head shakes, but that tolerance occurs to this effect of I-PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.
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PMID:The effects of alpha 2-adrenoceptor antagonists on the inhibition of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes by 5-HT1A receptor agonists in the mouse. 810 40

The present study examined the effects of a centrally acting 5-HT1A receptor agonist flesinoxan on the renal sympathetic nerve control of the kidney while left renal perfusion pressure (RPP) was controlled at 80 mm Hg. In groups of chloralose/urethane-anesthetized Wistar rats, reduction in left kidney RPP significantly decreased the glomerular filtration rate (GFR), with much larger decreases in urine flow (UV) and absolute (UNaV) and fractional (FENa) sodium excretions, but raised systemic pressure as well as right kidney GFR and water and sodium excretion. In intact time-control rats, there were no time-dependent changes in left or right kidney GFR, UV, UNaV or FENa. Administration of bolus doses of flesinoxan at 30, 100 and 300 micrograms/kg i.v. in intact rats caused significant, dose-dependent decreases in mean systemic arterial pressure (23%) and heart rate (10%) (both P < .001). Although RPP was unchanged, there were significant increases in left kidney UV (118%), UNaV (385%) and FENa (277%) (all P < .005). Despite the substantial decrease in RPP at the right kidney, excretion of water and sodium was well preserved. In bilaterally renal-denervated rats, flesinoxan produced similar changes in blood pressure and heart rate but did not increase left kidney UV or sodium excretion, and the reduction in pressure caused significant decreases in right kidney UV, UNaV and FENa. These findings are consistent with the hypothesis that flesinoxan causes suppression of renal sympathetic tone, which leads to increased sodium and water excretion.
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PMID:Renal functional responses to the 5-HT1A receptor agonist flesinoxan: effects of controlled renal perfusion pressure. 816 28

A 3-D model of the human 5-HT1a receptor was constructed from its amino acid sequence by computer graphics techniques, molecular mechanics calculations and molecular dynamics simulations. The model has seven alpha-helical membrane spanning segments, which form a central core containing a putative ligand binding site. Electrostatic potentials 1.4 A outside the water accessible surface were mainly negative on the synaptic side of the receptor model and at the postulated ligand binding site, and positive in the cytoplasmic domains. The negative electrostatic potentials around the synaptic domains indicate that positively charged ligands are attracted to the receptor by electrostatic forces. Molecular dynamics simulations of the receptor model with serotonin, ipsapirone, R(-)-methiothepin or S(+)-methiothepin in the central core suggested that up to 22 different amino acid residues may form a ligand binding pocket, and contribute to the specificity of ligand recognition and binding.
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PMID:Molecular dynamics of the 5-HT1a receptor and ligands. 824 92

The present study investigates the inactivation and recovery of brain serotonin (5-HT) recognition sites by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2,-dihydroquinoline). Adult male Sprague-Dawley rats were given a single s.c. injection of vehicle (1:1 EtOH/H2O) or EEDQ (1-20 mg kg-1) and sacrificed at 4 h and 7 days (10 mg kg-1 dose) post-injection. EEDQ dose-dependently reduced the Bmax of 5-HT1A(3H-DPAT),5-HT1B(125I-CYP),5-HT2(3H-ketanserin) and 5-HT2/1C(125I-DOI) receptors in cortical homogenates. In contrast, EEDQ was without effect on the 5-HT transporter recognition site (3H-paroxetine). No significant changes in affinity were observed for 5-HT1B, 5-HT2 or 5-HT2/1C receptors. The rank order of sensitivity to EEDQ inactivation was: 5-HT1A > 5-HT1B > 5-HT2 approximately 5-HT2/1C >>> 5-HT uptake sites. This study demonstrates: (1) differential EEDQ inactivation and recovery of 5-HT receptors and (2) lack of EEDQ inactivation of the 5-HT transporter.
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PMID:In vivo EEDQ dose-dependently inactivates rat brain 5-HT receptors but not 5-HT uptake sites. 828 Aug 61


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