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)

Spontaneous tail-flicks (STFs) in the rat are mediated by postsynaptic serotonin (5-HT)1A receptors in lumbar spinal cord (Bervoets et al., 1993). In this study, we examined the role of alpha 1- as compared with alpha 2-adrenoceptors in their modulation. STFs elicited by the 5-HT1A agonist 8-OH-DPAT were potently blocked by the alpha 1-adrenoceptor antagonist prazosin, as well as by WB 4101 and 5-methylurapidil, antagonists with a preference for the alpha 1A-subtype of adrenoceptor. In contrast, several alpha 2-antagonists, for example, idazoxan and the preferential alpha 2D-antagonist BRL 44408, (biphasically) potentiated 8-OH-DPAT-induced STFs. Whereas STFs were unaffected by the alpha 1-adrenoceptor agonist cirazoline, they were blocked both by the alpha 2-agonist UK 14,304 and by the preferential alpha 2D-agonists guanfacine and guanabenz. The intrathecal administration onto lumbar spinal cord of prazosin or of the preferential alpha 1A-antagonist benoxathian (which does not cross the blood-brain barrier) blocked STFs evoked by s.c. injection of 8-OH-DPAT. Intrathecal UK 14,304 acted similarly. Conversely, STFs elicited by intrathecal 8-OH-DPAT were blocked by s.c. prazosin or UK 14,304. Cirazoline and the preferential alpha 1A-agonist methoxamine (which does not cross the blood-brain barrier) elicited STFs upon intrathecal administration onto lumbar but not cervical spinal cord. The action of cirazoline was blocked by s.c. prazosin but not by 5-HT1A antagonists such as (-)-alprenolol, indicating that the alpha 1-adrenoceptors mediating STFs lie downstream of 5-HT1A receptors. Further, cirazoline-induced STFs were not affected by alpha 2-agonists and -antagonists, suggesting that the alpha 2-adrenoceptors inhibiting STFs are localized presynaptically to these alpha 1-adrenoceptors. In rats in which lumbar spinal cord pools of noradrenaline were depleted by 6-hydroxydopamine, STFs evoked by cirazoline were potentiated, indicating supersensitivity of postsynaptic alpha 1-adrenoceptors. In contrast, 8-OH-DPAT-induced STFs were diminished. In conclusion, spinal populations of alpha 1 (alpha 1A)- and alpha 2 (alpha 2D)- adrenoceptors respectively mediate and inhibit the induction of STFs by 5-HT1A receptor agonists, the actions of which depend on a functionally intact, descending, noradrenergic projection to lumbar spinal cord.
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PMID:5-HT1A receptors and the tail-flick response. V. Opposite modulation of 5-HT1A receptor-induced spontaneous tail-flicks by alpha 1A- as compared with alpha 2D-adrenoceptors in rat lumbar spinal cord. 790 54

The effects of one 5-HT1A serotonin agonist (8-OH-DPAT) and of two alpha 2 noradrenaline agonists (tizanidine and B-HT 933) were tested on the transmission between group II muscle afferents and spinal neurons in the sacral segments of the spinal cord in the cat. These agonists have previously been found to depress transmission from group II muscle afferents either in the dorsal horn or in the intermediate zone of midlumbar segments, and this study addressed the question of whether their actions in the sacral segments are similarly selective. The drugs were applied ionophoretically and their effects were tested on field potentials evoked from group II muscle afferents. As judged by changes in the amplitude of the early components of these field potentials, the transmission is effectively depressed by the serotonin agonist (to 56 +/- 26% after 2 min of ionophoresis of 8-OH-DPAT) but not by the noradrenaline agonists (to 97 +/- 12% after 6 min of ionophoresis of B-HT 933 and to 95 +/- 17% after 6 min of ionophoresis of tizanidine). These data suggest that transmission from group II muscle spindle afferents in the sacral segments is under control of serotonin releasing neurons, as in the dorsal horn of midlumbar segments, but leave open the question of the similarities or differences in the mechanisms (pre- and/or postsynaptic) of this control.
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PMID:Effects of monoamines on transmission from group II muscle afferents in sacral segments in the cat. 795 76

Here we have studied the effect of various 5-HT1A and 5-HT2 receptor-selective drugs on noradrenaline release in the hippocampus on anaesthetized and awake rats using microdialysis. In the anaesthetized rat, administration of the 5-HT1A agonists buspirone, gepirone and ipsapirone increased noradrenaline levels in the microdialysates. However, the common metabolite of these compounds, 1-PP (an alpha-2 adrenoceptor antagonist with low affinity for 5-HT1A receptors), also increased noradrenaline efflux whilst the 5-HT1A receptor agonist 8-OH-DPAT and MDL 73005EF, which are not metabolized to 1-PP, did not. In the awake rat, buspirone but also 8-OH-DPAT increased noradrenaline efflux. A similar effect was observed in response to MDL 73005EF and the 5-HT1A ligand NAN-190. Since the latter two drugs have weak intrinsic activity at the post-versus presynaptic 5-HT1A receptor, a presynaptic mechanism (inhibition of 5-HT release) was implicated. The 5-HT2 receptor may be important to this mechanism as noradrenaline increased following administration of the 5-HT2 receptor antagonists, ritanserin and ICI 170,809. In conclusion, our data indicate that there are clear differences in the effects of 5-HT1A and 5-HT2 receptor-selective drugs on noradrenaline efflux in hippocampus of the anaesthetized versus awake rat. Our findings are reconcilable with the hypothesis that in the awake (but not anaesthetized) rat, release of noradrenaline in hippocampus is influenced by an inhibitory tone mediated via 5-HT2 receptors. If this inhibitory tone is removed, either by decreasing 5-HT release through activation 5-HT1A autoreceptors or by blocking postsynaptic 5-HT2 receptors, noradrenaline release increases.
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PMID:Biochemical evidence for the regulation of central noradrenergic activity by 5-HT1A and 5-HT2 receptors: microdialysis studies in the awake and anaesthetized rat. 798 79

The ability of 5-HT receptor agonists to modulate the electrically evoked release of [3H]noradrenaline was tested on preloaded slices of the rat brain. The 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) (10-100 microM) concentration-dependently enhanced the electrically evoked release of [3H]noradrenaline in the hippocampus and the hypothalamus, but only at 100 microM in the frontal cortex. The enhancing effect of 2-methyl-5-HT was blocked by the 5-HT3 receptor antagonist ondansetron. Elevated levels of endogenous 5-HT, achieved through selective reuptake blockade with paroxetine, as well as the addition of exogenous 5-HT in the medium, also enhanced [3H]noradrenaline release. Furthermore, this effect of paroxetine was blocked by nanomolar concentrations of the 5-HT3 receptor antagonists ondansetron, tropisetron and (S)-zacopride. Only high concentrations of the 5-HT3 receptor agonist m-chlorophenylbiguanide increased [3H]noradrenaline release from hippocampal slices, and this effect was not blocked by ondansetron nor by (S)-zacopride. The possibility that the enhancing effect of 2-methyl-5-HT could have been due to the antagonism of alpha 2-autoreceptors of noradrenergic terminals was ruled out by the unaltered effectiveness of the alpha 2-adrenoceptor agonist UK-14,304 (1 microM) to attenuate [3H]noradrenaline release in the presence of 100 microM of 2-methyl-5-HT. Moreover, in pseudo-one-pulse experiments 100 microM of 2-methyl-5-HT increased [3H]noradrenaline release in the absence of autoinhibition through alpha 2-adrenergic autoreceptors. The 5-HT1A and 5-HT1B receptor agonists 8-hydroxy-2(di-n-propyl-amino)tetralin and CP-93,129, respectively, as well as the 5-HT1 receptor agonist 5-carboxyamidotryptamine, were devoid of effect on the release of [3H]noradrenaline. The 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased the release of [3H]noradrenaline, but this effect was not blocked with the 5-HT3 receptor antagonist ondansetron. Lesioning 5-HT fibers with the neurotoxin 5,7-dihydroxytryptamine did not alter the action of 2-methyl-5-HT on [3H]noradrenaline release, indicating that this effect is not attributable to an action of this 5-HT3 receptor agonist on 5-HT terminals.
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PMID:Activation of 5-HT3 receptors enhances the electrically evoked release of [3H]noradrenaline in rat brain limbic structures. 804 71

The effects of chronic administration of desipramine, citalopram, and electroconvulsive shocks (ECS) on changes in rat motility after intraaccumbens (NAS) injections of selective serotonergic drugs were studied in intact and 5.7-DHT lesioned animals. It was shown that local injections of 8-OHDPAT and DOI-HCl depressed rat locomotor activity. Their effects appeared to be mediated postsynaptically, and could be antagonized by NAN-190 and ritanserin, respectively. Chronic but not acute pretreatment of rats with antidepressants (21 days long; the experiment was performed 24 h after the last dose) as well as repeated ECS (shocks were applied five times every second day), antagonized behavioral depression after 8-OHDPAT and DOI-HCl. The influence of antidepressant treatment was prevented by serotonergic lesions. Chronic administration of antidepressants and ECS did not equivocally affect the levels or metabolism of 5-HT, dopamine, and noradrenaline in the rat limbic forebrain. It is concluded that the present data indicate diminished activity of 5-HT systems related to the 5-HT1A and 5-HT2 receptors in the limbic nucleus, after chronic antidepressant treatment. This effect of drugs and ECS concerns nervous processes linked with the function of postsynaptically localized 5-HT receptor subtypes, and it probably depends on intact presynaptic 5-HT innervation.
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PMID:Antidepressant treatment and limbic serotonergic mechanisms regulating rat locomotor activity. 809 Jul 97

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

The 5-HT1A ligand, spiroxatrine, displays very low affinity for alpha 1-adrenergic binding sites and a relatively high affinity for alpha 2-adrenergic binding sites. Nonetheless, recent functional studies indicate that spiroxatrine is a potent antagonist of the alpha 1-adrenoceptor mediating contraction in the rat isolated aorta. On the basis of the widely studied heterogeneous interaction of drugs with alpha-adrenoceptors in several experimental models, the present study was designed to analyze the alpha-adrenoceptor antagonist properties of spiroxatrine in the pithed rat. Animals were prepared for recording of arterial blood pressure and intravenous (i.v.) administration of drugs. Norepinephrine and the alpha 1- and alpha 2- adrenoceptor agonists methoxamine and clonidine, respectively, elicited pressor responses in a dose-related fashion. Spiroxatrine (1 mg/kg, i.v.) produced a moderate--but significant--rightward displacement of the dose-response curves to all agonists. The present data lead us to suggest that, though spiroxatrine exhibits alpha 1- and alpha 2-adrenoceptor antagonist properties in the pithed rat, its potency does not seem to correlate with that found in rat aorta. The potential involvement of alpha 1-adrenoceptor subtypes is discussed.
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PMID:[The alpha-antiadrenergic properties of spiroxatrine, a ligand of serotonergic 5-HT1A receptors]. 810 62

The 5-HT1A receptor agonists buspirone, 8-hydroxy-N,N-dipropyl-2-aminotetralin, gepirone and ipsapirone were evaluated for their receptor binding profiles and their effects on firing rates of 5-HT, dopamine (DA) and noradrenaline (NA) neurons in the dorsal raphe, substantia nigra pars compacta and the locus ceruleus, respectively. All agents bound to 5-HT1A receptors with high affinities. All agents also bound to dopamine D2 receptors but, with the exception of buspirone, affinities were usually much lower than for 5-HT1A receptors. All agents depressed 5-HT neurons, with 8-hydroxy-N,N-dipropyl-2-aminotetralin having a potency about 8 to 12 times those for the other three. All agents also antagonized the inhibition of DA neurons by amphetamine, an index of DA antagonist properties. Buspirone reversed amphetamine's effects with doses similar to those for depressing 5-HT neurons, but the remaining three required much higher doses to affect DA neuron function. All four 5-HT1A agonists excited NA neurons. In each case, doses required for excitation of NA cells were similar to those reversing amphetamine's effects on DA cells, but not to those for depressing 5-HT cells. Haloperidol also stimulated NA cells. It is concluded that excitation of NA neurons by 5-HT1A agonists may be due to interactions with dopaminergic, rather than serotonergic, receptors.
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PMID:Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties. 813 43

The neurochemical profile of the selective 5-HT1A receptor antagonist WAY100135 [N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride] and its enantiomers at the somatodendritic 5-HT1A receptor was determined by studying the effects of these compounds on 5-HT (5-hydroxytryptamine, serotonin) release in the rat hippocampus using in vivo microdialysis. (+/-)-WAY100135, (+)-WAY100135 and (-)-WAY100135 (all at 10 mg/kg s.c.) had no significant effect on extracellular levels of 5-HT in the hippocampus demonstrating that these compounds are devoid of 5-HT1A receptor agonist properties. In contrast, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1 mg/kg s.c.) and the partial agonists BMY 7378 (1.0 mg/kg s.c.) and buspirone (5 mg/kg s.c.) significantly decreased hippocampal 5-HT. Pretreatment with (+/-)-WAY100135 (at 10 mg/kg s.c.) and (+)-WAY100135 (at 1.0-10 mg/kg s.c.) completely blocked the 8-OH-DPAT-induced decrease in 5-HT release demonstrating that these compounds are antagonists at the somatodendritic 5-HT1A autoreceptor. (-)-WAY100135 at a dose of 10 mg/kg s.c. had no significant effect on the 8-OH-DPAT-induced inhibition of 5-HT release. (+/-)-WAY100135 had no significant effect on extracellular levels of dopamine in the rat hippocampus but significantly increased extracellular levels of noradrenaline. The mechanism underlying the increase in noradrenaline is unknown at present.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurochemical profile of the selective and silent 5-HT1A receptor antagonist WAY100135: an in vivo microdialysis study. 822 94

The effect of 5-HT receptor agonists and antagonists to inhibit [3H]5-HT uptake was investigated in rat cortical synaptosomes. The 5-HT (5-hydroxytryptamine) uptake inhibitors paroxetine and fluoxetine yielded pKi values of 8.41 +/- 0.12 and 7.43 +/- 0.06 respectively. The 5-HT3/5-HT4 receptor antagonist tropisetron and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) had similar inhibitory potencies to cocaine (pKi values of 6.58 +/- 0.04, 6.47 +/- 0.14 and 6.45 +/- 0.12 respectively). The dopamine and noradrenaline uptake inhibitors GBR12909 and desipramine had comparable values of 6.5 +/- 0.05 and 6.13 +/- 0.07. Other 5-HT receptor ligands had pKi values less than 6.0 (R(+)-zacopride, MDL72222, R(+)/S(-)-zacopride) or 5.0 (5-methoxytryptamine, m-chlorophenylbiguanide, S(-)-zacopride, SDZ205-557, ondansetron and renzapride). It is concluded, with the possible exception of tropisetron and 8-OH-DPAT, that it is unlikely that the effects of the 5-HT receptor ligands to inhibit 5-HT uptake contribute to their effects in vivo.
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PMID:The effect of 5-HT receptor ligands on the uptake of [3H]5-hydroxytryptamine into rat cortical synaptosomes. 822 95


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