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)

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake? 136 65

The regional distribution of [3H]idazoxan and [3H]rauwolscine was studied autoradiographically in human brain. [3H]Idazoxan binds with high affinity to alpha 2 adrenoceptors as well as to non-adrenergic sites (NAIBS). [3H]Rauwolscine, besides binding to alpha 2 adrenoceptors, also binds to 5-HT1A receptors. Both radioligands labelled the same population of alpha 2 adrenoceptors, defined as the epinephrine-displaceable binding component. The highest densities of alpha 2 adrenoceptors occur in the leptomeninges, cerebral cortex and claustrum; lower densities were visualised in the basal ganglia, thalamus, pons, substantia nigra, cerebellum and medulla oblongata; no alpha 2 adrenoceptors were detected in amygdala and nucleus ruber. NAIBS were present in all the examined brain areas, with the highest densities found in the basal ganglia and substantia nigra. The finding that certain brain regions, such as the amygdala, contained NAIBS but no detectable alpha 2 adrenoceptors, suggests that the binding sites are independent from each other. The regional distribution of 5-HT1A receptors labelled by [3H]rauwolscine is in agreement with previous studies using [3H]8-OH-DPAT.
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PMID:Autoradiographic distribution of alpha 2 adrenoceptors, NAIBS, and 5-HT1A receptors in human brain using [3H]idazoxan and [3H]rauwolscine. 166 6

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.
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PMID:The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist. 167 98

Two experiments were performed studying the effects of 8-OH-DPAT and idazoxan on sexual behaviour and ultrasonic communication of male rats. In addition, the reactions of the females towards drug-treated males were studied. 8-OH-DPAT (a very specific 5-HT1A agonist) and idazoxan (an alpha 2-adrenergic antagonist) differentially affected sexual behaviour: 8-OH-DPAT (0.1 and 0.4 mg/kg IP) markedly facilitated ejaculations, a feature indicated by decreased numbers of mounts and intromissions preceding ejaculation and a reduction in ejaculation latency. This drug concomitantly reduced the postejaculatory refractory period. Idazoxan reduced the number of intromissions before ejaculation only at the highest dose (10 mg/kg IP), but did not markedly facilitate other parameters. Both drugs markedly and dose-dependently suppressed the postejaculatory 22 kHz ultrasounds normally recorded during the postejaculatory refractory period. Ultrasound frequencies above 30 kHz first appear at the end of the absolute refractory period, even when the refractory period is shortened by 8-OH-DPAT. Idazoxan increased the number of these 30 kHz ultrasounds, whereas 8-OH-DPAT had no effect on them. No effects were observed on ultrasound production (either 22 kHz or above 30 kHz) before an ejaculation. The behaviour of the females towards 8-OH-DPAT-treated males was also affected, with the females showing more darting and lordosis before and after ejaculation, but less sitting after ejaculation. Idazoxan treatment of the males resulted in more hopping and earwiggling of the females before ejaculation. Following ejaculation, females treated with the antagonist showed more darting, hopping, earwiggling and lordosis, but sitting was decreased. It has been suggested in the rat that the emergence of ultrasounds higher than 30 kHz indicates the end of the absolute refractory period and signals to the female that the male is capable of resuming sexual activity. The significance of 22 kHz ultrasound in sexual behaviour remains puzzling because these vocalizations could be easily uncoupled from the refractory period by drugs acting via different receptor mechanisms without disturbing sexual behaviour per se. A failure to produce postejaculatory sounds appears to disinhibit (proceptive) behaviour by the females.
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PMID:The effects of idazoxan and 8-OH-DPAT on sexual behaviour and associated ultrasonic vocalizations in the rat. 168 88

The effects of the alpha 2-adrenoceptor antagonist idazoxan on 5-hydroxytryptamine (5-HT) neuronal firing and release have been investigated. Idazoxan, administered i.v. (10 micrograms/kg and 0.5 mg/kg) increased dorsal raphe nucleus (DRN)-5-HT neuronal firing rate in a dose-dependent fashion. At the higher dose, a voltammetric study revealed increases in extracellular 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels, there was no effect with the lower dose. Intra-raphe administration of idazoxan (1 ng) also elevated the firing rate of 5-HT neurones in the dorsal raphe, suggesting that idazoxan may produce the increase in firing by a direct effect in the DRN. However, microiontophoretic application of idazoxan did not increase the firing rate of 5-HT neurones in the DRN. Thus the increase in the firing rate of 5-HT neurones in the DRN observed with systemic and local administration of idazoxan is probably not due to a direct action of idazoxan on the 5-HT neurone. Possibly the idazoxan acted at alpha 2-adrenoceptors located on noradrenergic terminals thus stimulating noradrenaline release and consequently increased 5-HT activity. Chronic administration of idazoxan (0.8 mg/kg per h for 14 days), using osmotic mini-pumps, caused an elevation in basal firing rate and an attenuation of the inhibitory response of DRN 5-HT neurones to the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (10 micrograms/kg i.v.). This finding suggests that chronic infusion with idazoxan leads to desensitisation of the 5-HT1A somatodendritic autoreceptor.
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PMID:Effects of idazoxan on dorsal raphe 5-hydroxytryptamine neuronal function. 171 Sep 90

The 5-hydroxytryptamine1A-receptor agonist 8-hydroxy-2-(n-dipropylamino) tetralin (8-OH-DPAT, 0.1 mg kg-1 i.v.) decreased the height of the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak recorded in the suprachiasmatic nucleus (SCN) of the anaesthetized rat by use of differential pulse voltammetry. The decrease in extracellular 5-HIAA produced by 8-OH-DPAT could be partially attenuated by prior administration of the non-selective 5-HT receptor antagonist methiothepin (1 mg kg-1 i.v.). The 5-HT2-receptor antagonist ritanserin (0.2 mg kg-1 i.v.) did not appear to block the effects of 8-OH-DPAT. The selective ligand for 5-HT1A recognition sites TVX Q 7821 (isapirone, 1 mg kg-1 i.v.) decreased the extracellular level of 5-HIAA in the SCN but to a lesser extent than 8-OH-DPAT. The response to 8-OH-DPAT was attenuated by prior administration of TVX Q 7821 to a level suggesting that TVX Q 7821 had blocked the effect of intravenous 8-OH-DPAT. Idazoxan (0.2 mg kg-1 i.v.) an alpha 2-adrenoceptor antagonist, completely blocked the effect of 8-OH-DPAT on the 5-HIAA oxidation peak recorded in the SCN, whilst having no effect on the 5-HIAA oxidation peak when given alone. At a dose of 0.5 mg kg-1 i.v. idazoxan induced a 120% increase in the height of the indole oxidation peak, suggesting that 5-HT release and metabolism in the rat SCN may be influenced by tonic adrenergic inputs. The data in this paper suggest that 5-HT1A- and alpha 2-receptors are involved in the effects of i.v. administered 8-OH-DPAT on 5-HT release and metabolism in the SCN in vivo.
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PMID:Involvement of 5-HT1A- and alpha 2-receptors in the decreased 5-hydroxytryptamine release and metabolism in rat suprachiasmatic nucleus after intravenous 8-hydroxy-2-(n-dipropylamino) tetralin. 243 Jun 56

Previous results from our laboratory indicate that small doses of the alpha-2 adrenergic agonist clonidine increase serotonin (5-HT) neurotransmission by attenuating the release of endogenous norepinephrine (NE), as a result of the activation of alpha-2 adrenergic autoreceptors on NE neurons, and that high doses decrease 5-HT neurotransmission by activating directly alpha-2 adrenergic heteroreceptors on 5-HT terminals. In addition, we have shown that long-term treatments with a monoamine oxidase inhibitor or a selective NE, but not a 5-HT, reuptake inhibitor abolish the effect of a high dose of clonidine, but not that of a small dose of clonidine. The aim of the present study was to determine whether the alpha-2 adrenergic antagonists idazoxan (10 mg/kg/day x 21 days s.c.) and mianserin (5 mg/kg/day x 21 days s.c.), or electroconvulsive shocks (6 or 7 over a 2-week period) would also affect the alpha-2 adrenoceptors modulating 5-HT neurotransmission in the rat hippocampus. The responsiveness of these hetereceptors was tested in parallel with those of the terminal 5-HT1B autoreceptors and of the postsynaptic 5-HT1A and alpha-2 adrenergic receptors. None of the above treatments altered the responsiveness of the 5-HT1B autoreceptors, as assessed by comparing the differential effectiveness of 1 and 5 Hz electrical stimulations of the 5-HT pathway. Idazoxan and mianserin did not affect the responsiveness of the postsynaptic 5-HT1A and alpha-2 adrenergic receptors as indicated by the unchanged suppressant effects of microiontophoretically applied 5-HT and NE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of long-term alpha-2 adrenergic antagonists and electroconvulsive treatments on the alpha-2 adrenoceptors modulating serotonin neurotransmission. 791 78

1. RS-15385-197, a highly potent and selective alpha 2-adrenoceptor antagonist, was examined in a variety of in vitro and in vivo functional tests to assess the selectivity of its interaction with central noradrenergic neurones in the rat. 2. In hypothalamic slices, RS-15385-197 was potent in augmenting K(+)-evoked release of [3H]-noradrenaline, with an EC50 of 9 nM. Idazoxan and yohimbine showed 100 fold less activity. This was due to its antagonist action at presynaptic alpha 2-adrenoceptors, as RS-15385-197 (10 microM), did not directly release [3H]-noradrenaline from cortical slices unlike reserpine (10 microM), and did not inhibit noradrenaline re-uptake into cortical synaptosomes. 3. In vivo, RS-15385-197 (0.5 mg kg-1, p.o.) increased levels of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cerebral cortex without modifying levels of 5-hydroxyindoleacetic acid (5-HIAA). This dose, but not a lower dose (0.1 mg kg-1, p.o.) caused beta-adrenoceptor down-regulation in the cortex when administered once daily for 14 days whereas 5-HT2 receptor number was unaltered, indicating a selective effect on noradrenergic transmission. 4. Selective depletion of cortical 5-HT by administration of p-chlorophenylalanine (PCPA; 100 mg kg-1, i.p. for 14 days) or 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms i.c.v.) prevented the beta-adrenoceptor down-regulation caused by RS-15385-197, indicating that a tonic 5-hydroxytryptaminergic input was required for it to elicit beta-adrenoceptor down-regulation. It was not possible to prevent the loss of activity of RS-15385-197 in these 5-HT-depleted animals by co-administration with the 5-HT1A partial agonist, 8-hydroxy-n-dipropyl aminotetralin (8-OH-DPAT, 0.3 mg kg-1, i.p. twice daily for final 3 days).5. At a dose (1 mg kg-1, p.o.) which completely prevented the hypoactivity produced by clonidine(0.1 mgkg-1, p.o.), RS-15385-197 did not affect behavioural stereotypy induced by 8-OH-DPAT(0.3 mg kg-1, s.c.). Similarly, following chronic dosing with the racemate, RS-15385-196 (3 mg kg-1,p.o., once daily for 14 days), there was no effect on the behavioural and hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Therefore, RS-1 5385-197 was selective for central alpha2-adrenoceptors over 5-HT1A receptors in in vivo functional tests.6. Thus, RS-15385-197 was highly selective in interacting with central noradrenergic neurones in the rat in vitro and in vivo. It is therefore currently the agent of choice for investigations of the role of alpha 2-adrenoceptors in the CNS.
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PMID:Modulation of central noradrenergic function by RS-15385-197. 809 21

1. The contributions of alpha 2-adrenoceptors and 5-HT1A receptors to sexual behaviour in the rat have been re-evaluated by use of a highly potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197), yohimbine, idazoxan and the partial agonist at 5-HT1A receptors, 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT). 2. In a model where naive male rats were introduced to oestrogen-progesterone primed, sexually receptive female rats, delequamine (0.4-6.4 mg kg-1, p.o.) dose-relatedly increased the sexual behaviour score over the entire dose-range whereas yohimbine was effective at only one dose, 2 mg kg-1, p.o.. Idazoxan was active only at 2.5 and 5 mg kg-1, p.o. Yohimbine, but neither delequamine nor idazoxan, decreased ejaculation latency. 8-OH-DPAT (0.1 and 0.25 mg kg-1, s.c.) reduced the time, and the number of intromissions to ejaculation without affecting other parameters. A combination of delequamine (0.4 mg kg-1, p.o.) and 8-OH-DPAT (0.1 mg kg-1 s.c.) increased the percentage of rats mounting, intromitting and ejaculating, and reduced ejaculation latency and the number of intromissions. 3. In orchidectomized, sexually experienced rats exposed to sexually receptive females, delequamine, idazoxan and yohimbine increased the number of rats mounting, and there was a tendency to increase the number of animals intromitting, but no effect on ejaculatory behaviour. 4. In ovariectomized female rats brought to low level receptivity by priming with low dose injections of oestradiol benzoate and progesterone, delequamine, at 1.6 and 6.4 mg kg-1 p.o., increased lordosis, while yohimbine, at 2, 4 and 8 mg kg-1 p.o., reduced lordotic responses to sexually experienced males in a dose-dependent manner. 8-OH-DPAT at 0.1, 0.25 mg kg-1, s.c. reduced lordosis in a dose-dependent manner. 5. These findings may be explained on the basis that yohimbine is an alpha 2-adrenoceptor antagonist with affinity for 5-HT1A receptors and that the effects of 5-HT1A receptors may modulate the sexual behaviour responses to alpha 2-receptor antagonism in some models. Thus, in contrast to yohimbine, the highly-selective alpha 2-adrenoceptor antagonist, delequamine, was very effective in increasing the behavioural score in male and female rats over a wide dose-range.
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PMID:Modulation of sexual behaviour in the rat by a potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197). 873 77

1. In decerebrated, non-spinalized rabbits, intrathecal administration of either of the selective 5-HT1A-receptor antagonists (S)WAY-100135 or WAY-100635 resulted in dose-dependent enhancement of the reflex responses of gastrocnemius motoneurones evoked by electrical stimulation of all myelinated afferents of the sural nerve. The approximate ED50 for WAY-100635 was 0.9 nmol and that for (S)WAY-100135 13 nmol. Intrathecal doses of the antagonists which caused maximal facilitation of reflexes in non-spinalized rabbits had no effect in spinalized preparations. 2. In non-spinalized animals, intravenous administration of (S)WAY-100135 was significantly less effective in enhancing reflexes than when it was given by the intrathecal route. 3. When given intrathecally, the selective 5-HT 2A/2C-receptor antagonist, ICI 170,809, produced a bellshaped dose-effect curve, augmenting reflexes at low doses (< or = 44 nmol), but reducing them at higher doses (982 nmol). Idazoxan, the selective alpha 2-adrenoceptor antagonist, was less effective in enhancing reflex responses when given intrathecally after ICI 170,809 compared to when it was given alone. Intravenous ICI 170,809 resulted only in enhancement of reflexes and the facilitatory effects of subsequent intrathecal administration of idazoxan were not compromised. 4. The selective 5-HT3-receptor blocker ondansetron faciliated gastrocnemius medialis reflex responses in a dose-related manner when given by either intrathecal or intravenous routes. This drug was slightly more potent when given i.v. and it did not alter the efficacy of subsequent intrathecal administration of idazoxan. 5. None of the antagonists had any consistent effects on arterial blood pressure or heart rate. 6. These data are consistent with the idea that, in the decrebrated rabbit, 5-HT released from descending axons has multiple roles in controlling transmission through the sural-gastrocnemius medialis reflex pathway. Thus, it appears 5-HT tonically inhibits transmission between sural nerve afferents and gastrocnemius motoneurones by an action at spinal 5-HT1A-receptors. Spinal 5-HT2A/2C-receptors may mediate a weak inhibition of transmission in the spinal cord, but more convincing evidence was obtained for their involvement in descending facilitatory tone. Further, some of the facilitatory consequences of spinal alpha 2-adrenoceptor blockade may be mediated through 5-HT2 type receptors. Spinal 5-HT3 receptors do not appear to have a major role in tonic modulation of the sural-gastrocnemius medialis reflex.
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PMID:Spinal 5-HT-receptors and tonic modulation of transmission through a withdrawal reflex pathway in the decerebrated rabbit. 893 20


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