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)

The purpose of the present study was to characterize the cardiorespiratory effects of activation of 5-HT1A, 5-HT1B and 5-HT2 receptor subtypes at the intermediate area of the ventral surface of the medulla. The agonists (+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (8-OH-DPAT), 1-[3-(trifluoromethyl)phenyl]-piperazine hydrochloride (TFMPP) and (+/-)-1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) were used to activate these receptor subtypes, respectively. Application of each drug to the intermediate area produced a different profile of cardiorespiratory effects. 8-OH-DPAT (0.0625-4.0 micrograms) produced dose-dependent hypotension and bradycardia, which were antagonized by the 5-HT1A antagonists spiperone and spiroxatrine. The bradycardia was blocked by bilateral vagotomy. No significant changes in respiratory motor outflow to the larynx or diaphragm were observed after application of 8-OH-DPAT. TFMPP (10-1000 micrograms) also produced a dose-dependent hypotension and bradycardia. However, these effects were not antagonized by spiperone or blocked by vagotomy. A decrease in the amplitude of the recurrent laryngeal and phrenic nerve signals was observed after application of the highest dose of TFMPP. In contrast to the effects of 8-OH-DPAT and TFMPP, DOI (0.3-100 micrograms) produced an increase in blood pressure without any change in heart rate. Recurrent laryngeal and phrenic nerve activities were depressed, as was respiratory rate, after application of DOI. Both the cardiovascular and respiratory effects of DOI were blocked by the 5-HT2 antagonist ketanserin. These results indicate that activation of ventral medullary 5-HT receptor subtypes produces unique effects on cardiorespiratory activity.
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PMID:Characterization of the effects of activation of ventral medullary serotonin receptor subtypes on cardiovascular activity and respiratory motor outflow to the diaphragm and larynx. 213 22

1. Intracellular recordings were made from neurones of the nucleus prepositus hypoglossi (PH) in slices of guinea-pig brain. Focal stimulation evoked an inhibitory postsynaptic potential (IPSP) that was typically 10-25 mV in amplitude and 1 s in duration. The IPSP reversal potential showed a Nernstian dependence on the external potassium concentration ([K+]o). 2. Spiperone blocked the IPSP with an IC50 of 40 nM, while ketanserin and (-)sulpiride had no effect. Cocaine (1 microM) prolonged the IPSP half-duration by 157%, and increased the amplitude by 28%. 3. 5-Hydroxytryptamine (5-HT, serotonin) hyperpolarized PH cells with an EC50 of 8.5 microM in control, and 135 nM in cocaine (10 microM). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) also hyperpolarized PH cells with an EC50 of 16 nM, although the maximal effect was only 81% of the maximum 5-HT hyperpolarization. Spiperone produced a parallel, right shift of the 5-HT concentration-response curve; Schild analysis gave a Kd of 10 nM. Application of 5-HT to neurones voltage-clamped near their resting potential (about -55 mV) caused an outward current and an increase in membrane conductance. 4. The amplitude of the IPSP was reversibly decreased by non-hyperpolarizing concentrations of 5-HT and by the 5-HT1 receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP). The IC50 values for the latter two compounds were 50 nM and 1.5 microM, respectively; the maximal effect was a 90% inhibition. Neither compound affected the membrane potential nor changed the hyperpolarization induced by 5-HT. Quipizine competitively antagonized TFMPP with an estimated Kd of 165 nM. 5. When trains of stimuli were applied, an inhibition of the IPSP was observed following the first stimulus. At a frequency of 1 Hz, the inhibition was approximately 75%. This frequency-dependent 'run-down' of the IPSP was markedly attenuated by pre-treatment with TFMPP (1 microM). 6. It is concluded that the IPSP in PH cells is caused by 5-HT acting on 5-HT1A receptors to activate a potassium conductance. The release of 5-HT can be inhibited by activation of a presynaptic 5-HT1D receptor. This presynaptic receptor appears to be at least partly responsible for the run-down phenomenon, and may be involved in the physiological regulation of 5-HT synaptic transmission.
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PMID:Serotonin-mediated inhibitory postsynaptic potential in guinea-pig prepositus hypoglossi and feedback inhibition by serotonin. 214 Oct 79

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

1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5-HT receptor subtypes was studied. 2. Hypothermia and hypoactivity in mice induced by the 5-HT1A-agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) could be attenuated by the preferential 5-HT1C-agonists MK 212, 1-(meta-chlorophenyl)-piperazine (mCPP) and m-trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5-HT2/1C-agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The mixed 5-HT1A/1B-agonist CGS 12066B at 10 mg kg-1 potentiated hypothermia and had no effect on hypoactivity. 3. Forepaw treading in rats induced by the 5-HT1A-agonist 8-OH-DPAT was attenuated by the 5-HT1C-agonists MK 212 and mCPP. The 5-HT1C-agonist TFMPP had a bimodal effect: at low doses (less than 1 mg kg-1) it potentiated, and at higher doses (greater than 2.2 mg kg-1) it attenuated forepaw treading, the mixed 5-HT2/1C-agonist DOI produced 5-HT2-related behaviours and potentiated 8-OH-DPAT-induced forepaw treading. This indicates an attenuating effect of 5-HT1C-receptor activation and a potentiating effect of 5-HT2-receptor activation. CGS 12066B had no effect in this respect. 4. Head shakes in rats induced by DOI could be attenuated by 8-OH-DPAT, TFMPP, mCPP and MK 212. The ID50S were 0.03, 0.7, 0.1 and .2 mg kg-1, respectively. This suggests that a 5-HT2-receptor-mediated effect may be attenuated by activation of 5-HT1A- or 5-HT1c-receptors. CGS 12066B attenuated the head shake response but only at 10mg kg- '. 5. The results suggest that interactions exist between the different 5-HT receptor subtype-mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5-HT-receptor subtype.
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PMID:Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. 215 Jan 80

The role of the 5-hydroxytryptamine (5-HT) receptor subtypes in the spinal cord in the regulation of nociception is unknown. This study examined whether administration of different 5-HT1 receptor agonists into the spinal subarachnoid space of mice modulates the nociceptive tail-flick reflex, and whether effects on the tail-flick reflex involve changes in tail skin temperature. The tail-flick latencies (the time needed to evoke the tail-flick reflex by noxious radiant heat) were significantly increased after intrathecal (i. th.) injection of 5-HT (10-20 micrograms), the 5-HT1A/5-HT1B receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 10-20 micrograms), the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 20 micrograms) and after i.th. injection of 1(m-chlorophenyl)piperazine (mCPP, 5-20 micrograms) and 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 5-20 micrograms) which have high affinity for the 5-HT1B receptors. None of the 5-HT1 receptor agonists had the ability to change the tail skin temperature. The results show that in the mouse i.th. injection of both 5-HT1A and 5-HT1B receptor agonists has the ability to inhibit the tail-flick reflex without interfering with the tail skin temperature.
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PMID:The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex. 215 Jul 69

In rats lightly restrained in plastic cylinders, subcutaneous administration of the selective, high efficacy 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), induced spontaneous tail-flicks, that is, tail-flicks in the absence of extraneous stimulation. The putative 5-HT1B receptor agonist, CGS 12066B, the mixed 5-HT1B/1C receptor agonists, 1-((3-(trifluoromethyl)phenyl]piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP), the 5-HT1C/2 receptor agonist, [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1B/1C/2 receptor agonist, quipazine, did not, in contrast, elicit tail-flicks when applied alone. However, TFMPP, mCPP, DOI and quipazine, but not CGS 12066B, each potentiated the action of 8-OH-DPAT. Further, in the presence of TFMPP, mCPP and DOI, the dose-response curve for the induction of tail-flicks by 8-OH-DPAT was both steeper and shifted to the left. Tail-flicks induced by another high efficacy 5-HT1A receptor agonist, lisuride, were also enhanced by TFMPP, mCPP and DOI. The 5-HT1A receptor partial agonists, buspirone and (+/-)-flesinoxan, evoked tail-flicks only in the presence of TFMPP, mCPP or DOI. The mixed 5-HT1C/2 receptor antagonists, ritanserin and ICI 169,369, did not modify the action of 8-OH-DPAT alone but abolished the potentiation of 8-OH-DPAT-induced tail-flicks by DOI and TFMPP. Further, the selective 5-HT1A receptor antagonist, BMY 7378, blocked tail-flicks induced by both 8-OH-DPAT alone and 8-OH-DPAT plus DOI or TFMPP. A common property of those drugs potentiating 8-OH-DPAT-induced tail-flicks is an agonist action at 5-HT1C receptors and the data indicate that it is this mechanism which underlies the facilitation of tail-flicks.
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PMID:Agonist action at 5-HT1C receptors facilitates 5-HT1A receptor-mediated spontaneous tail-flicks in the rat. 215 Aug 18

Obsessive-compulsive disorder (OCD) is emerging very clearly as a serotonin specific illness. The evidence for this comes from a variety of clinical sources. Firstly the efficacy of 5-HT uptake inhibitors, especially clomipramine, is consistent and strong. Secondly clomipramine has not merely been found to be effective against placebo in 9 placebo controlled studies, it is also found to be more effective in some studies than reference tricyclic antidepressants and monoamine oxidase inhibitors. In other studies tricyclic antidepressants do not appear to be better than placebo. The lack of efficacy of general antidepressants, neuroleptics and benzodiazepines supports the specificity of the serotonin effect. Thirdly the evidence of the efficacy of clomipramine in OCD without concomitant depression reported by Montgomery 1980 and supported by other studies suggests that 5-HT uptake inhibitors have a specifically anti-obsessional effect. The lack of response of depressive symptoms in OCD to other antidepressants suggests that these depressive symptoms are integral to OCD and will only respond when the OCD is treated. Many of the studies found efficacy for 5-HT uptake inhibitors compared with placebo despite both groups being treated with concomitant behaviour therapy. This argues either for behaviour therapy being relatively ineffective or for there being a synergistic effect with the 5-HT uptake inhibitor which is more likely. Results from studies with selective serotonergic probes with a worsening of OCD symptoms in response to the 5-HT1A agonist, m-chlorophenyl piperazine, add support to the serotonergic hypothesis of OCD but further investigation is needed.
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PMID:[Biological treatments in obsessive-compulsive disorder]. 220 92

5-Hydroxytryptamine (serotonin, 5-HT) stimulates basal adenylyl cyclase activity in membranes from guinea pig or rat hippocampi, but 5-HT inhibits forskolin-stimulated adenylyl cyclase activity in these same membranes. The opposing effects of 5-HT on adenylyl cyclase activity indicate that distinct 5-HT receptors, positively and negatively coupled to adenylyl cyclase, are present in these membranes. Stimulation of adenylyl cyclase activity is mediated by two distinct 5-HT receptors. The receptor with lower affinity for 5-HT, designated as RL, is apparently homologous with a 5-HT receptor present in rat collicular membranes, but it is not homologous with the stimulatory receptor characterized in neuroblastoma hybrid cell (NCB-20) membranes. The receptor with higher affinity for 5-HT is homologous with the 5-HT1A binding site. The magnitude of stimulation by 5-HT1A receptors is variable with respect to stimulation by RL and is sometimes completely absent. Inhibition of forskolin-stimulated adenylyl cyclase activity, in membranes from either rat or guinea pig hippocampus or rat cortex, is a functional correlate of the 5-HT1A binding site. This inhibitory response was used to determine the pharmacological characteristics of drugs that reportedly have high affinity for 5-HT1A binding sites, such as 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) and (-)pindolol. PAPP inhibited adenylyl cyclase activity in guinea pig hippocampal membranes with an EC50 value of 27 +/- 3 nM. (-)Pindolol was a partial agonist in inhibiting adenylyl cyclase activity in guinea pig and rat hippocampal membranes. Because of the low intrinsic activity of (-)pindolol, it was tested as an antagonist of the inhibition produced by 5-HT1A receptor agonists in rat hippocampal membranes. The Kb of (-)pindolol was 40 nM as measured by a Schild plot. (-)Propranolol was a simple competitive antagonist at the rat hippocampal receptor with a Kb value of 550 nM. In summary, guinea pig and rat hippocampal membranes possess two distinct populations of 5-HT receptors, a 5-HT receptor that mediates inhibition of adenylyl cyclase activity and is pharmacologically homologous with the 5-HT1A binding site, and a stimulatory receptor that appears to be homologous with the 5-HT receptor first characterized in infant rat collicular membranes.
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PMID:Stimulation and inhibition of adenylyl cyclase by distinct 5-hydroxytryptamine receptors. 222 10

Feeding or food withdrawal can affect the supply of tryptophan to the brain and hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which releases 5-HT to postsynaptic receptors suppresses appetite, and there are reports that tryptophan can have a similar effect. Furthermore, feeding is reported to release hypothalamic 5-HT. Therefore 5-HT could have a role in the normal termination of feeding and perhaps also in disorders of appetite. The recognition of various 5-HT receptor subtypes has stimulated research in this area. We have now investigated the involvement of the subtypes in the pharmacological control of feeding. Thus, 5-HT1A agonists (8-OHDPAT, buspirone, gepirone, etc.) stimulate intake in freely feeding rats, probably by activating autoreceptors on the cell bodies of 5-HT neurons so that 5-HT release at terminals is decreased. The hyperphagia is not explicable by increased activity or gnawing and is strikingly manifest against carbohydrate in carbohydrate vs. protein choice experiments. Feeding in previously food-deprived rats is decreased by the 5-HT agonists RU 24969, 1-(3-chlorophenyl) piperazine (mCPP) and 1-(3-trifluoromethyl) phenyl) piperazine (TFMPP). Effects of antagonists on these properties suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors only, while mCPP and TFMPP induce hypophagia at 5-HT1C sites, though this effect also requires 5-HT1B receptors for its expression. Responsible sites occur in the paraventricular nucleus of the hypothalamus as infusing either RU 24969 or TFMPP therein causes hypophagia. On systemic injection, the hypophagic drugs are particularly active in female rats, an effect of conceivable relevance to human anorexic illness.
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PMID:Serotonin and appetite. 225 31

1-[3-(trifluoromethyl) phenyl] piperazine (TFMPP), a putative 5-HT1B, 5-HT1C and 5-HT2 agonist decreased dose-dependently food intake over 4 h in freely feeding rats. The TFMPP-induced anorexia was blocked by mesulergine (a 5-HT1C and 5-HT2 antagonist), metergoline (a 5-HT1A, 5-HT1B, 5-HT1C and 5-HT2 antagonist), mianserin (a 5-HT1C and 5-HT2 antagonist) and attenuated by ketanserin and ritanserin (5-HT2 antagonists). The examined anorexia was not antagonized by cyanopindolol and compound 21009 (5-HT1A and 5-HT1B antagonists). These results indicate that the TFMPP-induced anorexia in freely feeding rats is probably mediated by 5-HT2--and, may be also by 5-HT1C receptors.
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PMID:Anorexia induced by M-trifluoromethylphenylpiperazine (TFMPP) in rats. 228 Oct 17


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