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)

This preliminary study has analyzed the potential ability of the 5-HT1A ligand spiroxatrine to interact with vascular alpha 1-adrenoceptors. Norepinephrine and the selective alpha 1-adrenoceptor agonist, methoxamine, elicited concentration-dependent contractions of rat aortic rings. In contrast, (+/-)-spiroxatrine (from 10(-8) to 3.1X10(-7) M) was devoid of any effect on vascular tone per se, but shifted the concentration-response curves of norepinephrine and methoxamine to the right in a concentration-dependent manner with pA2 values of 8.48 +/- 0.22 and 8.93 +/- 0.33, respectively. Endothelium removal did not significantly affect the above pA2 values of (+/-)-spiroxatrine. These data, taken in concert, support the contention that (+/-)-spiroxatrine displays alpha 1-adrenoceptor blocking properties in rat aortic rings.
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PMID:Alpha 1-adrenoceptor blocking properties of spiroxatrine in rat aorta. 135 25

A fourteen-days treatment (twice a day) of male Wistar rats with the putative anxiolytic ipsapirone (10 mg/kg po) and the selective 5-HT1A agonist 8-OH-DPAT (1 mg/kg ip) induced changes in the turnover of serotonin and catecholamines in various regions of the brain. In contrast to 8-OH-DPAT, ipsapirone stimulated the development of tolerance in serotonin neurons in the hypothalamus, hippocampus, cortex and striatum. Nevertheless, adaptative changes were not produced by ipsapirone in dopamine neurons in the striatum or nucleus accumbens, or in noradrenaline neurons in the hypothalamus, hippocampus or cortex. The centrally active metabolite of ipsapirone 1-PP, which has adrenolytic properties, seems to be responsible for the effects on the dopamine and noradrenaline turnover.
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PMID:Effect of acute and chronic treatment of rats with the putative anxiolytic drug ipsapirone on the turnover of monoamine transmitters in various brain regions. A comparison with the 5-HT1A agonist 8-OH-DPAT. 135 15

Intrathecal (i.th.) administration of substance P (SP, 6.5 nmol) at the Th 8-10 level in conscious rats increased blood pressure (carotid artery), heart rate and plasma catecholamine concentrations. The responses were antagonized by the intravenous (i.v.) but not i.th. pretreatment with the 5-HT2-receptor antagonists ketanserin and ritanserin and intrathecally administered serotonin (5-HT, 10 micrograms). The pressor response and the increase in plasma noradrenaline concentrations were also antagonized by i.v. or i.th. pretreatment with the 5-HT1A-agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). In contrast the pressor response to SP was facilitated by the 5-HT1A-antagonist 1-pindolol (i.v. or i.th). Pretreatment with SP (i.th) reduced the hypotensive response to i.v. 8-OH-DPAT. These results demonstrate functional interactions between SP and serotonergic mechanisms in the central system, but the precise location and nature were not elucidated.
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PMID:Cardiovascular effects of intrathecal administration of substance P in the rat: interactions with serotonergic mechanisms. 137 13

1 We have examined the actions of the 5-HT1A-receptor ligand 8-OH-DPAT at alpha 2-adrenoceptor ligand binding sites in human platelet and rat kidney membranes and at functional pre- and postjunctional alpha 2-adrenoceptors in rat atrium and human saphenous vein, respectively. 2 8-OH-DPAT had low affinity for the alpha 2A ligand binding site of human platelet but showed 10 times higher affinity for the alpha 2B ligand binding site of rat kidney (K1 of 6.41, -log M). 3 In functional studies, 8-OH-DPAT had low potency as an antagonist of noradrenaline-induced contractions in human saphenous vein, with a KB of 5.40 (-log M). 4 In rat atria preincubated with [3H]-noradrenaline, 8-OH-DPAT potentiated stimulation-evoked overflow of tritium with an EC30 (concentration producing 30% increase in the stimulation-evoked overflow) of 6.37 (-log M). 5 It is concluded that 8-OH-DPAT shows selectively for the alpha 4B ligand binding site of rat kidney and for the functional prejunctional alpha 2-adrenoceptor of rat atrium, which resembles the alpha 2B ligand binding site.
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PMID:Actions of 8-hydroxy-2-(N-dipropylamino) tetralin (8-OH-DPAT) at alpha 2-adrenoceptors. 165 7

Trimipramine has been reported to differ from other typical tricyclic antidepressant drugs in several aspects, for instance it does not inhibit neuronal transmitter uptake and does not cause down-regulation of beta-adrenoceptors. Moreover, it may possess antipsychotic activity in schizophrenic patients. In the present investigation it was found that trimipramine did not alter the electrically-induced release of [3H]noradrenaline and [3H]5-hydroxytryptamine, from slices of the cerebral cortex of the rat, in concentrations of less than 1 microM. It did not antagonize the inhibitory effect of noradrenaline and 5-hydroxytryptamine on the release of transmitter, mediated by presynaptic autoreceptors. In radioligand binding studies, D,L-trimipramine showed fairly high affinities (KI 10-60 nM) for some dopamine (DA), noradrenaline and 5-hydroxytryptamine (5-HT) receptor subtypes (5-HT2 receptors = alpha 1A/B-adrenoceptors greater than or equal to D2 receptors), intermediate affinities (300-550 nM) for D1 receptors, alpha 2B-adrenoceptors and 5-HT1C receptors but only low affinities (greater than 1000 nM) for alpha 2A-adrenoceptors, 5-HT1A, 5-HT1D and 5-HT3 receptors. It may thus be classified as an atypical neuroleptic drug. Especially, its affinities for dopamine receptors, alpha 1-adrenoceptors and 5-HT2 receptors closely resembled the values measured for clozapine. The L-enantiomer of trimipramine showed higher affinities for these binding sites than D-trimipramine. The present findings may explain the mechanism of the potential antipsychotic action but not the antidepressant effect of trimipramine.
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PMID:Trimipramine: pharmacological reevaluation and comparison with clozapine. 166 93

1. The actions of serotonin (5-HT) and noradrenaline (NA) in the cat perigeniculate nucleus (PGN) and the guinea-pig nucleus reticularis thalami (NRT) were investigated with extracellular and intracellular recordings obtained from neurones in thalamic slices maintained in vitro. 2. Single, local application of either 5-HT or NA resulted in pronounced (5-50 Hz) and prolonged (2-10 min) excitation associated with the occurrence of single-spike activity. Serotoninergic excitation was specifically blocked by the 5-HT2/5-HT1C antagonists ketanserin and ritanserin, but not by the 5-HT1A antagonist pindolol or the 5-HT3 antagonist ICS 205-930. Furthermore, the 5-HT response was mimicked by alpha-methyl-5-HT, but not by the 5-HT1A agonist 8-hydroxydipropylaminotetralin (8-OHDPAT) or the 5-HT3 agonist 2-methyl-5-HT. Together, these results indicate that this excitatory response is mediated through 5-HT2 receptors with the possible involvement of 5-HT1C receptors. 3. Noradrenergic excitation was specifically blocked by the alpha 1-antagonist prazosin, but not by the beta-antagonist propranolol or the alpha 2-antagonist yohimbine. Similarly, the response was mimicked by the alpha-agonist phenylephrine, but not by the beta-agonist isoprenaline. These results indicate that the noradrenergic excitation is mediated by alpha 1-adrenoceptors. 4. Block of synaptic transmission either by lowering external calcium concentration ([Ca2+]o) to 0.5 mM and raising external magnesium concentration ([Mg2+]o) to 10 mM or by local application of tetrodotoxin failed to block the excitatory or depolarizing response to 5-HT or NA indicating that these responses are direct and not mediated through the release of other neurotransmitters. 5. Intracellular recordings revealed that the 5-HT- and NA-induced excitations are mediated by a pronounced slow depolarization associated with an apparent decrease in input conductance and an increase in the membrane time constant. Current versus voltage plots obtained under voltage clamp before and during the presence of 5-HT and NA revealed that these neurotransmitters induced an inward current which reversed to an outward current at -107 and -110 mV, respectively, in 2.5 mM external potassium concentration ([K+]o). This reversal potential was identical to that associated with an increase in potassium conductance activated by acetylcholine (-110 mV) in the same neurones. Plots of the amplitude of the 5-HT- or NA-induced current versus membrane potential revealed a linear relationship in the voltage range from -140 to -60 mV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. 166 58

In rats lightly restrained in horizontal cylinders, (+/-)-3,4-methylenedioxymethamphetamine (MDMA) dose dependently (0.16-10.0 mg/kg, s.c.) elicited spontaneous tail-flicks; that is, tail-flicks in the absence of extraneous stimulation. In contrast, amphetamine over a similar dose-range was inactive. Selective inhibitors of 5-hydroxytryptamine (5-HT) uptake and carrier-mediated 5-HT release, paroxetine and citalopram, did not induce spontaneous tail-flicks themselves and blocked those induced by MDMA. In distinction, maprotiline and bupropion, selective inhibitors of noradrenaline and dopamine uptake, respectively, failed to modify the action of MDMA. Spontaneous tail-flicks elicited by MDMA were unaffected by the selective 5-HT3 receptor antagonists, ICS 205,930 and GR 38032F. They were attenuated by the mixed 5-HT1/5-HT2 receptor antagonist, methiotepin, the mixed 5-HT1A/5-HT1B receptor antagonist, (-)-alprenolol and the mixed 5-HT1A/5-HT2 receptor antagonist, spiperone, but not by the selective 5-HT1C/5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ketanserin. The novel 5-HT1A receptor antagonists, BMY 7378 and NAN-190, each abolished MDMA-evoked spontaneous tail-flicks. Selective D1, D2, alpha 1, alpha 2, beta 1 and beta 2 antagonists had little influence upon induction of spontaneous tail-flicks by MDMA. These data indicate that MDMA evokes spontaneous tail-flicks in the rat via a release of 5-HT which acts at 5-HT1A receptors. Thus, 5-HT1A receptors appear to be involved in the acute functional actions of MDMA.
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PMID:Methylenedioxymethamphetamine induces spontaneous tail-flicks in the rat via 5-HT1A receptors. 167 9

A new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D2-receptors combined with negligible binding to D1-receptors in binding assays in vitro. However, in tests in vivo for central D2-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p.o. administration, striatal L-DOPA accumulation in intact rats was unchanged up to 100 mg/kg p.o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s.c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal L-DOPA accumulation, suggest that EMD 45609 is a partial dopamine D2-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s.c. In accordance with its high affinity for D2-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurochemical profile of EMD 45609 (carmoxirole), a dopamine DA2-receptor agonist. 168 17

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study. 168 86

The vasodilator mechanism of the putative serotonin1A (5-HT) receptor agonists, urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated in constant-pressure perfused rat kidneys. The compounds (10(-12)-10(-7) mol bolus injection) neither enhanced basal flow nor evoked vasodilatation in kidneys preconstricted by 27 mM KCl, 1.5 mM BaCl2 or 10(-6) M prostaglandin (PG)F2 alpha, but evoked a dose-dependent, reversible and spiroxatrine-resistant increase in vasodilatation of organs preconstricted by 6 x 10(-7) M noradrenaline. 5-Carboxamidotryptamine and sumatriptan did not reverse the vasoconstriction induced by all stimuli or that induced by noradrenaline in the presence of 5-HT2 plus 5-HT3 receptor blockade. No correlation for the vasorelaxant drugs was found between their -log ED50 in rat kidney and pKi values at 5-HT1A binding sites in pig cortex as determined in radioligand experiments. The relaxation in rat kidney induced by 5-HT1A receptor agonists and alpha 1A-adrenoceptor-selective antagonists (WB 4101 and (+)-niguldipine) was significantly correlated with pKi values at alpha 1A binding sites in rat cortex and the pA2 values derived from contraction studies for competitive antagonism at alpha 1-adrenoceptors in prostatic portions of the rat vas deferens, but differed from pKi values for alpha 1B binding sites in rat cortex. Thus, the vasodilator effect of the 5-HT1A receptor agonists urapidil, 5-methyl-urapidil, ipsapirone, flesinoxan and 8-OH-DPAT in the noradrenaline-perfused rat kidney appears to be mediated by their concomitant alpha 1A-adrenoceptor blockade. No evidence for a vasodilator effect mediated through 5-HT1A receptors was found under our experimental conditions.
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PMID:Vasodilatation elicited by 5-HT1A receptor agonists in constant-pressure-perfused rat kidney is mediated by blockade of alpha 1A-adrenoceptors. 168 54


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