Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2. 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (< or = 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3. The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3-10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4. The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response. Antagonists at 5-HTlc/5-HT2 receptors (ketanserin; 0.1-3.0 mg kg-1, p.o.),5-HT3 receptors (ondansetron; 0.03-10mg kg-1, p.o.), at-adrenoceptors (prazosin; 1-3mgkg-1, p.o.),alpha2 -adrenoceptors (idazoxan; 3-30mg kg-1, p.o.), alpha 1-adrenoceptors (metoprolol; 1-30mgkg-1, p.o.),beta 2-adrenoceptors (ICI 118,551; 1-30 mg kg-1, p.o.), dopamine D2 receptors (sulpiride; 10-300mg kg-',p.o.) and opiate receptors (naloxone; 3-100 mg kg-', p.o.) had no effect on the 8-OH-DPAT response.5. Selective destruction of 5-HT neurones with 5,7-dihydroxytryptamine or inhibition of 5-HT synthesis with p-chlorophenylalanine did not change the 8-OH-DPAT response in the Porsolt test. This response was also unaltered by pretreatment with the noradrenergic neurotoxin, DSP-4.6. Administration of 8-OH-DPAT (3 mg kg-1, s.c.) twice-daily for 10 days attenuated the hypothermia,but not the increased mobility, induced by 8-OH-DPAT (3 mg kg-1, s.c.). Similarly, repeated administration of amitriptyline (3-30 mg kg-1), desipramine (3-30 mg kg-1) or dothiepin (10-100 mg kg-1) also attenuated the former, but not the latter, response.7. We conclude that 8-OH-DPAT produces an antidepressant-like effect in the Porsolt test which is mediated via postsynaptic 5-HT1A receptors.
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PMID:Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors. 846 55

1. The effect of 7 days of isolation were observed in mice on behavioural models involving 5-HT2 and 5-HT1A receptors. 2. The sensitivity of 5-HT2 receptors as assessed through L-5-HTP or 5-MeODMT induced head-twitches was reduced. 3. The sensitivity of the 5-HT1A receptors implicated in the 8-OH-DPAT induced feeding was unchanged. 4. The sensitivity of the 5-HT1A receptors involved in the 8-OH-DPAT induced hypothermia was diminished. 5. On the whole, these results show that after 7 days of isolation, the responses to the stimulation of serotonergic receptors is unchanged or diminished according to both the receptor's subtype and the model used.
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PMID:Effect of isolation on behavioural models involving serotonergic 5-HT2 and 5-HT1A receptors. 853 29

WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride) is an achiral phenylpiperazine derivative that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a standard antagonist in further studies of 5-HT1A receptor function.
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PMID:A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. 856 21

The alpha 1-adrenoceptor agonist, SDZ NVI-085 ((-)-(4aR,10aR)-3,4,4a,5,10,10a-hexahydro-6-methoxy-4- methyl-9-(methylthio)-2H-naphth[2,3-b]-1,4-oxazine.HCl; 1 mg/kg i.p.), decreased body temperature of guinea-pigs. Two 5-HT1D receptor antagonists, GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl- 1,2,4-oxadiazol-3yl)[1,1-biphenyl]-4-carboxamide) and PAPP (p-aminophenylethyl-m-trifluoromethylphenyl piperazine; both compounds at 1 mg/kg i.p., -30 min) blocked this response, whilst the alpha 1-adrenoceptor blocker prazosin (1 mg/kg i.p.) and the 5-HT1A receptor antagonist, SDZ 216-525 (methyl 4-(-[4-(1,1m3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl ]-1-piperazinyl)1H- indole-2-carboxylate; 1 mg/kg i.p.) were inactive. Another alpha 1-adrenoceptor agonist, St 587 (2-(2-chloro-5-trifluoromethylphenylimino)-imidazoline; 1 mg/kg i.p.) did not alter body temperature. SDZ NVI-085-induced hypothermia in guinea-pigs is probably mediated by 5-HT1D receptors.
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PMID:Evidence for a 5-HT1D receptor-mediated hypothermic effect of the alpha 1-adrenoceptor agonist, SDZ NVI-085, in guinea-pigs. 857 20

Mechanisms of tryptophan (a 5-HT precursor)-induced changes in body temperature were investigated in rats pretreated with pargyline, a monoamine oxidase inhibitor (MAO-I). Tryptophan (100 mg/kg, i.p.) did not affect the body temperature in rats, but it produced significant hypothermia followed by marked hyperthermia and higher mortality in the pargyline-pretreated rats. 5-HT depletion with p-chlorophenylalanine (p-CPA, 100 mg/kg/day for 3 days) significantly suppressed not only the body temperature change but also the mortality and 5-HT syndrome following tryptophan plus pargyline administration. Although propranolol (10 mg/kg, i.p.), a beta-adrenoceptor antagonist, did not alter the hypothermia caused by tryptophan in the pargyline-pretreated rats, pindolol (2 mg/kg, S.C.), a 5-HT1A receptor and beta-adrenoceptor antagonist, suppressed the hypothermia but not the hyperthermia or mortality caused by the same treatment. On the other hand, spiperone and ketanserin, 5-HT2 receptor antagonists, at doses of 3 mg/kg, potentiated the hypothermia and completely suppressed the hyperthermia and mortality caused by tryptophan in the pargyline-pretreated rats. These results suggest that tryptophan-induced hypo- and hyperthermia are mediated by 5-HT1A and 5-HT2 receptors, respectively, in the pargyline-pretreated pretreated rats.
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PMID:5-HT1A and 5-HT2 receptors mediate hypo- and hyperthermic effects of tryptophan in pargyline-pretreated rats. 857 5

The effect of total alkaloid extracted from Peganum harmala seeds collected in Egypt on body temperature was studied in rats. Intraperitoneal administration of the Peganum harmala extract produced significant and dose-dependent hypothermia. Similarly, harmine and harmaline, major constituents of the harmala alkaloid, lowered the body temperature. Pretreatment with p-chlorophenylalanine (100 mg/kg/day for 3 days), a 5-HT synthesis inhibitor, significantly attenuated the hypothermic effect of the total alkaloid and harmine, while it tended to block the hypothermic action of harmaline. Methysergide (2 mg/kg), a 5-HT antagonist, significantly attenuated the hypothermia induced by harmala alkaloids. Pindolol (0.05-2 mg/kg), a 5-HT1A receptor and beta-adrenoceptor antagonist, partly blocked the hypothermic effect of the harmala alkaloids in a dose-dependent manner, whereas propranolol (10 mg/kg), a beta-adrenoceptor antagonist, failed to alter it, suggesting that beta-adrenoceptor is not involved in the hypothermia caused by the alkaloids. Pretreatment with a dopamine receptor antagonist haloperidol (5 mg/kg, s.c. and 2 mg/kg, i.p. 24 and 2 h before the experiment, respectively) significantly attenuated the hypothermic effect of harmala alkaloids. Moreover, in haloperidol pretreated rats, methysergide (2 mg/kg, i.p.) and pindolol (0.05 and 2 mg/kg) completely attenuated the hypothermic effect of the alkaloids. These data suggest that harmala alkaloids produce hypothermic effect mainly through endogenous 5-HT stimulation of 5-HT1A receptor.
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PMID:Hypothermic effect of harmala alkaloid in rats: involvement of serotonergic mechanism. 857 10

The effects of the selective 5-HT1A receptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flesinoxan (7 and 14 micrograms/kg), administered intravenously in 11 healthy volunteers, elicited a dose-related decrease in body temperature and increases in growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels. In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1A antagonist pindolol (30 mg, PO), the nonselective 5-HT1/2 antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV). The growth hormone response to flesinoxan was blocked by pindolol but not by methysergide, whereas the prolactin response was blocked by methysergide but not by pindolol. The ACTH and cortisol responses to flesinoxan were potentiated by methysergide. The flesinoxan-induced hypothermia was attenuated by both methysergide and pindolol, although the latter effects did not reach statistical significance. The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1A receptor function in humans.
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PMID:Serotonin1A receptor activation by flesinoxan in humans. Body temperature and neuroendocrine responses. 859 27

p-MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido] ethylpiperazine] and p-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine] competitively antagonized 5-HT1A receptor activation in the rat, as measured by hypothermia, forepaw treading and 5-HT turnover; they exhibited to partial agonist activity on any of these measures. When given i.p., p-MPPI and p-MPPF dose-dependently antagonized the hypothermia induced by 8-hydroxy-2- (di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg), with approximate ID50 of 5 and 3 mg/kg, respectively. The inhibitory effect caused by a fixed dose of p-MPPI (6 mg/kg) or p-MPPF (3 mg/kg) was surmounted by higher doses of 8-OH-DPAT. p-MPPI and p-MPPF also attenuated the hypothermia induced by gepirone. Forepaw treading caused by 8-OH-DPAT (2 mg/kg) in reserpine-pretreated rats (1 mg/kg, s.c., 18-24 hr before the experiment) was dose-dependently antagonized by p-MPPI and p-MPPF with approximate ID50 of 3 and 0.7 mg/kg, respectively. p-MPPI also antagonized forepaw treading induced by 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) (5 mg/kg) and this antagonism was competitively overcome by higher doses of 5-methoxy-N,N,-dimethyltryptamine. p-MPPI and p-MPPF were able to antagonize the 8-OH-DPAT-(0.5 mg/kg) induced reduction in the 5-HIAA/5-HT ratio, a measure of 5-HT turnover in the hippocampus or striatum. No hypothermia or reciprocal forepaw treading was produced by either drug when given at doses as high as 10 mg/kg. Neither p-MPPI nor p-MPPF (10 mg/kg) given alone significantly altered the ratio of 5-HIAA/5-HT in the hippocampus or striatum. Also, binding of [3H]p-MPPF to hippocampal membranes was unaltered by the addition of 100 microM guanylyl-imidodiphosphate to the incubation medium. In conclusion, p-MPPI and p-MPPF behave, in vivo, as competitive antagonists of both postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors.
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PMID:4-(2'-Methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] piperazine and 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p- fluorobenzamido]ethyl]piperazine, two new antagonists at pre- and postsynaptic serotonin-1A receptors. 862 43

The present communication reports on the efficacy of (R)-8-OH-DPAT ((R)-8-hydroxy-2-(di-n-propylamino)tetralin) and (S)-LY-41 ((S)-8-acetyl-2-(di-n-propylamino)tetralin) in displaying the 5-HT1A syndrome and decreasing body temperature after administration of the compound subcutaneously into the gastric ventricle or into the oral cavity in the rat. The dose range eliciting a clear-cut HT1A syndrome and hypothermia after oral cavity administration was 1/10-1/30 that of the gastric ventricle dose range, but 10-30 times higher than the dose range used for subcutaneous administration of both (R)-8-OH-DPAT and (S)-LY-41. Determination of the concentrations of (R)-8-OH-DPAT in plasma and brain tissue confirmed a higher bioavailability after oral cavity than after gastric ventricle administration; plasma and brain tissue concentrations of the drug were found to be approximately 3 times those after 10 mumol/kg-1 orally than after 100 mumol/kg-1 gastroventrically at 15-60 min after administration of (R)-8-OH-DPAT. These findings suggest that the oral cavity may be an important site for drug delivery of 8-OH-DPAT, LY-41 and other compounds with a low gastrointestinal bioavailability.
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PMID:Oral cavity absorption of (R)-8-hydroxy-2-(di-n-propylamino)tetralin and (S)-8-acetyl-2-(di-n-propylamino)tetralin in the rat. 872 93

Biochemical alterations of serotoninergic parameters have been demonstrated in experimental thiamine deficiency. In addition, hypophagia and hypothermia, two physiological processes associated with changes in the serotonin [5-hydroxytryptamine (5-HT)] system, are manifest early during the progression of thiamine deficiency. The binding of selected 5-HT radioligands was therefore investigated in discrete brain regions of pyrithiamine-induced thiamine-deficient rats. Using quantitative receptor autoradiography, the binding of 8-hydroxy-2-(di-n-[3H]propylamino) tetralin, a ligand used to label the somatodendritic 5-HT1A autoreceptor of the dorsal raphe nucleus, was found to be unaffected in this region, suggesting that the structural integrity of the 5-HT cell bodies is maintained throughout the course of pyrithiamine treatment. Increased binding of [3H]-ketanserin was observed in regions considered vulnerable as well as in some considered to be nonvulnerable during the course of thiamine deficiency. These binding changes, which appear to represent changes in the density of the postsynaptic 5-HT2A receptor population rather than the "tetrabenazine-sensitive" vesicular monoamine transporter, are evident before the appearance of histopathologic lesions and coincide with altered tissue concentrations of 5-HT. These data suggest that 5-HT neurons, although structurally intact, are functionally affected early during the progression of thiamine deficiency. These alterations, which are likely a part of adaptive neuronal change consequent to thiamine dysfunction, may be important in the physiological manifestations and the learning deficits commonly encountered in experimental thiamine deficiency.
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PMID:Alterations in serotonin parameters in brain of thiamine-deficient rats are evident prior to the appearance of neurological symptoms. 875 18


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