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)

Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response. Similarly, NAN-190 (0.1 microM) almost totally prevented the inhibition by 8-OH-DPAT (1 microM) of forskolin-stimulated adenylate cyclase activity in adult rat hippocampal slices but, per se, was without effect on the forskolin response. These results indicate that NAN-190 is a potent antagonist at postsynaptic 5-HT1A receptors in vitro. However, NAN-190 also potently antagonized (IC50 = 0.16 nM) the stimulation by norepinephrine of phosphoinositide turnover in rat cortical slices. In this respect NAN-190 was a 250-fold more potent antagonist than prazosin (IC50 = 49 nM). Thus, in addition to its 5-HT1A receptor antagonist properties, NAN-190 has potent alpha 1-adrenoceptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission. 166 63

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

The present study was undertaken to evaluate the possible functional implications of the previously demonstrated in vitro interactions between galanin and 5-HT1A receptors. To this end we analysed the interactions between galanin and the 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in central cardiovascular regulation. 8-OH-DPAT given intracisternally (i.c.) produced a dose-dependent reduction of blood pressure, the peak action being 32% at 10 nmol of 8-OH-DPAT. Heart rate and respiration rate were not affected. The vasodepressor action of 8-OH-DPAT was counteracted by the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190). A threshold dose (1 nmol) of galanin given i.c. was shown to enhance the vasodepressor effect of both an ED50 dose and a threshold dose of 8-OH-DPAT. Quantitative receptor autoradiography showed that the IC50 values for [125I]galanin binding sites were reduced in the presence of 8-OH-DPAT (10 nM) by approximately 40% in the dorsal region of the nucleus of the solitary tract, the area postrema, and the raphe pallidus and obscurus nuclei. Galanin (10 nM) also significantly increased the IC50 value for [3H]8-OH-DPAT binding sites within the nucleus of the solitary tract. The results provide evidence for a synergistic interaction between 8-OH-DPAT and galanin in cardiovascular regulation after their central administration, an interaction possibly related to the ability of 8-OH-DPAT to enhance the affinity of the galanin receptor within regions of the medulla oblongata involved in cardiovascular control.
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PMID:Centrally coinjected galanin and a 5-HT1A agonist act synergistically to produce vasodepressor responses in the rat. 172 57

The effects of three putative 5-HT1A receptor antagonists (NAN-190, BMY 7378 and WB 4101) were studied on the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In order to control for the alpha 1-adrenoceptor antagonist activity of NAN-190 and WB 4101, the effects of prazosin were also examined. Both NAN-190 and WB 4101 lowered body temperature in the mouse. This effect appeared to be due to their alpha 1-adrenoceptor antagonist effects as prazosin had a similar profile. Neither NAN-190, WB 4101 nor prazosin antagonised the hypothermic effects of 8-OH-DPAT. BMY 7378 slightly lowered body temperature but to a lesser extent than 8-OH-DPAT and, in contrast to the other compounds studied, also prevented a fall in body temperature on injection of 8-OH-DPAT. In the rat there was much less interference from alpha 1-adrenoceptor antagonist activity as both NAN-190 and prazosin only slightly reduced body temperature. In this species, however, NAN-190 showed marked antagonist activity against 8-OH-DPAT hypothermia. This was not due to alpha 1-adrenoceptor antagonist activity as prazosin had no effect. In the rat, as in the mouse, BMY 7378 had a partial agonist profile, whereas WB 4101 behaved essentially as an agonist. These results suggest that NAN-190 is a pure antagonist of 8-OH-DPAT-induced hypothermia in rats and that BMY 7378 and WB 4101 are, respectively, a partial agonist and an agonist in this test.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of putative 5-HT1A receptor antagonists on 8-OH-DPAT-induced hypothermia in rats and mice. 182 67

The putative 5-HT1A receptor antagonist properties of 1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)butyl] piperazine (NAN-190) were studied in mice. The responses studied were hypothermia- and hyperglycemia-induced by the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). NAN-190 (0.3-3 mg/kg) did not antagonize either response, but rather appeared to be additive with the effect produced by 8-OH-DPAT (0.25 mg/kg) alone, at least with respect to temperature. NAN-190, given alone in similar doses, caused hypothermia and hyperglycemia. These results suggest that NAN-190 has similar properties to 8-OH-DPAT with regard to temperature and glucose effects. Therefore, it does not appear to be a effective antagonist for all 5-HT1A-mediated responses.
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PMID:Is NAN-190 an effective antagonist of the hypothermia and hyperglycemia induced by the 5-HT1A receptor agonist, 8-OH-DPAT? 182 70

Pigeons were trained to discriminate the tricyclic antidepressant imipramine (3.0 or 5.6 mg/kg) from saline. The selective 5-HT1A agonist 8-OH-DPAT (0.03-1.0 mg/kg) resulted in dose-dependent increases in responding on the key correlated with imipramine administration. Doses of 8-OH-DPAT from 0.3 to 1.0 mg/kg substituted completely for imipramine. NAN-190 (0.3-3.0 mg/kg), a putative 5-HT1A antagonist with affinity for both 5-HT1A and alpha 1 receptors, blocked the discriminative stimulus effects of imipramine and resulted in saline-key responding. The discriminative stimulus effects of imipramine were also blocked by administration of the alpha 1-adrenoceptor antagonist prazosin, suggesting a dual mediation of imipramine through both 5-HT1A and alpha 1-adrenoreceptor systems. Although antidepressants have not been used frequently as stimuli in drug discrimination studies, it may be possible to arrive at a more complete understanding of their neurochemical and behavioral effects using this procedure.
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PMID:Involvement of 5-HT1A activity in the discriminative stimulus effects of imipramine. 182 31

The present study was conducted to investigate the effects of various 5-hydroxytryptamine (5-HT) agonists and antagonists on motor behaviour in rats and marmosets. Various motor-based responses were assessed after central or peripheral administration of 5-HT agents to rats and marmosets. Drugs acting as agonists at the 5-HT1A receptor (8-OHDPAT, gepirone, BMY-7378, NAN-190, PAPP (LY165163) and flesinoxan) and 5-HT2/1C receptors (DOI) were found to reverse neuroleptic-induced catalepsy in the rat whereas 5-HT2/1C antagonists (mianserin, ritanserin and ICI-170,809) and the 5-HT1 antagonist ((+/-)pindolol) increased catalepsy. Agonists acting at 5-HT3 receptors (phenylbiguanide and 2-methyl-5-HT) had no effect on catalepsy. The putative 5-HT1A antagonist, (+/-) pindolol, attenuated the reversal of catalepsy by 8-OHDPAT. Although both 8-OHDPAT and BMY-7378 were tested, only the latter was found to reduce apomorphine-induced stereotypy. Bilateral or unilateral infusions of 8-OHDPAT, BMY-7378 or pindolol into the substantia nigra of non-lesioned rats had no effect on spontaneous locomotor or rotational activity, respectively. However, 8-OHDPAT and BMY-7378 were found to increase or decrease motor activity, after injection into the median or dorsal raphe nuclei, respectively. Finally, 8-OHDPAT and BMY-7378 were found to be inactive against MPTP-induced bradykinesia in the marmoset. It is concluded that both 5-HT1A and 5-HT2/1C receptors are involved in the anti-cataleptic effects of 5-HT agents. The 5-HT1A receptors are probably situated within the raphe, whereas the location of the 5-HT2/1C receptors remains undetermined.
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PMID:Behavioural effects of serotonin agonists and antagonists in the rat and marmoset. 212 71

The release of serotonin (5-HT) from the terminals of serotonergic (raphe) neurons is under inhibitory feed-back control. 5-HT, acting on raphe cell body autoreceptors, also mediates inhibitory postsynaptic potentials as a result of release from collaterals from neighboring raphe neurons. This may involve a ligand (5-HT)-gated increase in the membrane potassium conductance, leading to a decrease in action potential frequency, which could indirectly reduce calcium influx into nerve terminals. In this report we demonstrate that 5-HT can also directly reduce calcium influx at potentials including and bracketing the peak of calcium current activation. Using acutely isolated, patch-clamped dorsal raphe neurons, we found that low concentrations of 5-HT and the 5-HT1A-selective agonist 8-OH-DPAT reversibly decrease whole-cell calcium current. This effect is antagonized by the putative 5-HT1A-selective antagonist NAN 190. Hence, the inhibition of calcium current may serve a physiological role in these cells and elsewhere in the brain.
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PMID:Serotonin receptor activation reduces calcium current in an acutely dissociated adult central neuron. 214 May 14

The 5-HT1A receptor antagonistic properties of 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl] piperazine (NAN-190) were studied in rats: its effect on the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced behavioural syndrome (flat body posture and reciprocal forepaw treading), hypothermia and secretion of corticosterone, i.e. responses mediated by 5-HT1A receptors, were examined. The drug NAN-190 (1-8 mg/kg) antagonized dose-dependently behavioural effects of 8-OH-DPAT (in both non-reserpinized and reserpine-pretreated animals); however, when administered in doses of 0.5-4 mg/kg, it did not affect the hypothermic or the hormonal response to 8-OH-DPAT. However, NAN-190 (1-8 mg/kg) given alone, produced hypothermia and increased the concentration of corticosterone in serum. The latter effects of NAN-190 were not reduced by (-)pindolol or spiperone. Moreover, the NAN-190-induced secretion of corticosterone was not affected by ketanserin, prazosin or yohimbine. The above results indicate that NAN-190 acts as a 5-HT1A receptor antagonist, only in the model of the 8-OH-DPAT-induced behavioural syndrome. The lack of effect of NAN-190 on the hypothermic or corticosterone response to 8-OH-DPAT most probably results from its own action which mimics the effects of 8-OH-DPAT. The mechanisms responsible for the NAN-190-induced hypothermia and secretion of corticosterone are still unknown, though stimulation of 5-HT1A receptors (either effect), 5-HT2 receptors and alpha 1- and alpha 2-adrenoceptors (corticosterone response) seems to be excluded.
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PMID:The behavioural, but not the hypothermic or corticosterone, response to 8-hydroxy-2-(DI-n-propylamino)-tetralin, is antagonized by NAN-190 in the rat. 214 65

Selective activation of the 5-HT1A receptor induces lower lip retraction (LLR) in rats. 8-Hydroxy-dipropylamino tetralin (8-OH-DPAT)-induced LLR could not be antagonised by the 5-HT antagonists methysergide, metergoline or mesulergine. In fact, some 5-HT antagonists induced LLR. However, 8-OH-DPAT-induced LLR could be antagonised by pindolol, spiperone, spiroxatrine and NAN-190, but not by the beta 1-adrenoceptor antagonist metoprolol, the beta 2-adrenoceptor antagonist butoxamine or the dopamine antagonist haloperidol. This antagonism was competitive as the dose-response curve of 8-OH-DPAT was shifted to the right. Pindolol, spiperone, spiroxatrine and NAN-190 all have a high affinity for the 5-HT1A receptor. This indicates that blockade of 8-OH-DPAT-induced LLR is only possible by selective blockade of 5-HT1A receptors. A possible mechanism of action is discussed. The increased defecation induced by 8-OH-DPAT could be antagonised by pindolol and NAN-190. The effect of spiroxatrine and haloperidol on the 8-OH-DPAT-induced increase in defecation was bimodal: an increase after a low and a decrease after a high dose of 8-OH-DPAT. Metoprolol and butoxamine had no effect on the 8-OH-DPAT-induced increase in defecation, thereby excluding an influence of beta-adrenoceptors.
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PMID:Antagonism of 8-OH-DPAT-induced behaviour in rats. 214 26


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