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)

Treatment of rats with the serotonin 5-HT1A agonist 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT, 1 mg/kg s.c.) markedly elevated plasma levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH) and prolactin (PRL); the levels of growth hormone were unaffected. Pretreatment with the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg s.c.) greatly attenuated the increase in plasma CORT produced by 8-OH-DPAT (0.3 mg/kg s.c.). Prevention of EEDQ-induced 5-HT1A receptor inactivation by prior treatment with the reversible mixed 5-HT1A/beta-adrenergic antagonist (+/-)pinodolol (30 mg/kg s.c.) blocked the reduction of the CORT response to 8-OH-DPAT. In contrast, prevention of EEDQ-induced inactivation of 5-HT2, alpha-1- and alpha-2-adrenergic and D1 and D2 dopamine receptors by a cocktail of selective antagonists of these receptors did not block the attenuation of the CORT response to 8-OH-DPAT. Dose-response curves were obtained for 8-OH-DPAT (0.01-3 mg/kg s.c.)-induced elevation of plasma CORT, ACTH and PRL after treatment (24 hr earlier) with vehicle or EEDQ (6 mg/kg s.c.) and analyzed for the extent of receptor reserve. Whereas substantial receptor reserves were observed for the 8-OH-DPAT rise in plasma CORT (80%) and ACTH (50%), no receptor reserve was seen for the increase in plasma PRL. The results are discussed with regard to potential differences in the receptors, G proteins, effectors and/or stoichiometric relationships between these components of the signal transduction pathway, leading to elevation of these plasma hormones after treatment with 8-OH-DPAT.
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PMID:Differential receptor reserve for 5-HT1A receptor-mediated regulation of plasma neuroendocrine hormones. 799 33

Previous studies [Meller et al. (1990) Mol. Pharmacol., 37:231-237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5-HT1A receptor activation, i.e., the inhibition of dorsal raphe cell firing. Intravenous dose-response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg, s.c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 micrograms/kg, 8-OH-DPAT; 30.0 micrograms/kg, ipsapirone; 17.5 micrograms/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose-response curves were shifted to the right (ED50's: 10.1 micrograms/kg, 6.7-fold shift, 8-OH-DPAT; 139.9 micrograms/kg, 4.7-fold shift, ipsapirone; 53.8 micrograms/kg, 3.1-fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8-OH-DPAT > ipsapirone > BMY 7378), a large (> 50%) receptor reserve was estimated for all three drugs in this electrophysiological system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists. 824 53

The present study investigates the inactivation and recovery of brain serotonin (5-HT) recognition sites by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2,-dihydroquinoline). Adult male Sprague-Dawley rats were given a single s.c. injection of vehicle (1:1 EtOH/H2O) or EEDQ (1-20 mg kg-1) and sacrificed at 4 h and 7 days (10 mg kg-1 dose) post-injection. EEDQ dose-dependently reduced the Bmax of 5-HT1A(3H-DPAT),5-HT1B(125I-CYP),5-HT2(3H-ketanserin) and 5-HT2/1C(125I-DOI) receptors in cortical homogenates. In contrast, EEDQ was without effect on the 5-HT transporter recognition site (3H-paroxetine). No significant changes in affinity were observed for 5-HT1B, 5-HT2 or 5-HT2/1C receptors. The rank order of sensitivity to EEDQ inactivation was: 5-HT1A > 5-HT1B > 5-HT2 approximately 5-HT2/1C >>> 5-HT uptake sites. This study demonstrates: (1) differential EEDQ inactivation and recovery of 5-HT receptors and (2) lack of EEDQ inactivation of the 5-HT transporter.
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PMID:In vivo EEDQ dose-dependently inactivates rat brain 5-HT receptors but not 5-HT uptake sites. 828 Aug 61

In this study, the relationship between the expression of 5-HT1A receptors and level of receptor mRNA in discrete regions of rat brain was examined by inactivation of 5-HT1A receptors with the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; i.p., 10 mg/kg) and measurement of the time-course of receptor recovery and changes in receptor mRNA levels. Inactivation of 5-HT1A receptors ranged from 84% in the dorsal raphe to 97% in the cortex 12 h after administration of EEDQ. Receptor levels returned to 62-100% of control levels by day 7 and the rate of recovery was uniform across all regions examined. The rate of recovery of 5-HT1A receptors labeled by the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and by the putative antagonist [125I]4-(2'-methoxy)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamido] ethylpiperazine ([125I]p-MPPI) did not differ across regions, suggesting that the ratio of high versus low affinity states of the 5-HT1A receptor remains relatively constant during receptor recovery. However, there did appear to be a short lag in the recovery of sites labeled with the agonist. Significant increases in 5-HT1A receptor mRNA levels were observed as early as 12 h after treatment in all regions but the magnitude of these increases varied. The time-courses of recovery of 5-HT1A receptors and changes in mRNA levels were not parallel in individual regions. Moreover, inactivation of low (8-26%) to moderate (29-57%) levels of 5-HT1A receptors produced no change in mRNA levels, whereas inactivation of greater than 90% elicited a robust increase in mRNA levels. Thus, changes in 5-HT1A receptor expression are not mediated exclusively by changes in mRNA levels and extensive receptor inactivation is required to trigger transcriptional regulation.
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PMID:Time-course of recovery of 5-HT1A receptors and changes in 5-HT1A receptor mRNA after irreversible inactivation with EEDQ. 879 11

The in vivo labelling of 5-hydroxytryptamine (5-HT)1A receptors in the mouse brain was studied with the novel selective 5-HT1A receptor antagonist, NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide hydrogen (2R,3R)-tartrate monohydrate). 3H-NAD-299 was injected in a tail vein and the radioactivity in various brain regions was determined. More than 90% of the radioactivity in hippocampus, 15 min after the injection, was intact NAD-299. At this time the amount of 3H-NAD-299 was highest in hippocampus followed by frontal cortex, mesencephalon, hypothalamus, striatum and cerebellum. The specific accumulation of radioactivity (after subtracting cerebellum values) in frontal cortex and hippocampus was maximal 10 to 30 min after the injection and had almost disappeared after 2 h. Saturation kinetics derived Bmax (pmol/g wet weight tissue) values of 19.6+/-2.0 in frontal cortex and 38.0+/-3.5 in hippocampus. The apparent Kd values expressed in nmol/kg 3H-NAD-299 injected, were 12.3+/-2.2 in frontal cortex and 20.3+/-3.1 in hippocampus. The 5-HT1A receptor antagonist, WAY-100,635 competitively inhibited the specific accumulation of 3H-NAD-299 and was about equipotent with unlabelled NAD-299 with ED50 values of 20-30 nmol/kg s.c. These compounds were about 10 times more potent than the 5-HT1A receptor antagonists, p-MPPI and NDL-249 and 100 times more potent than (S)-UH-301. 5-HT1A receptor agonists, e.g. 8-OH-DPAT and flesinoxan and partial agonists, e.g. pindolol, buspirone and ipsapirone had low potency in this in vivo assay. Spiperone and methiothepin inhibited the 3H-NAD-299 accumulation at 10 micromol/kg s.c. The alpha1-adrenoceptor antagonist, prazosin at 2 micromol/kg s.c. increased significantly the specific accumulation of 3H-NAD-299. Pretreatment of the mice with the non-selective, irreversible receptor antagonist, EEDQ produced a dose related long-lasting decrease in the accumulation of 3H-NAD-299. It is concluded that NAD-299 is a very suitable ligand for studies of 5-HT1A receptors in the brain in vivo.
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PMID:In vivo labelling of the mouse brain 5-hydroxytryptamine1A receptor with the novel selective antagonist 3H-NAD-299. 965 Aug 1

The present study has examined several characteristics of the release of 5-HT in the median raphe nucleus in terms of its dependence of nerve impulse, provenance of a vesicular storage fraction as well as the regulatory role played by 5-HT1A receptors. Tetrodotoxin (1 microM) and reserpine (5 mg kg(-1), i.p.) virtually suppressed the output of 5-HT. The administration of EEDQ (10 mg kg(-1), i.p.) did not alter the basal release of 5-HT but abolished the reduction of 5-HT release induced by 8-OH-DPAT (0.1 mg kg(-1), s.c.). The perfusion of 1-100 microM of 8-OH-DPAT or the novel 5-HT1A agonist BAY x 3702 decreased the efflux of 5-HT, whereas the perfusion of the 5-HT1A antagonist WAY-100635 failed to alter 5-HT release. The decrease in dialysate 5-HT induced by 100 microM 8-OH-DPAT was reversed by the concurrent perfusion of 100 microM WAY-100635. Also, the perfusion of 100 microM WAY-100635 for 2 h inhibited partly the reduction of 5-HT release evoked by the systemic administration of 8-OH-DPAT (0.1 mg kg(-1)). These results indicate that extracellular 5-HT in the median raphe nucleus is stored in vesicles and released in an impulse-dependent manner. Also, the basal release of 5-HT in the median raphe nucleus does not appear to be under the tonic control of somatodendritic 5-HT1A receptors by endogenous 5-HT. Instead, this feedback mechanism seems to be triggered when an excess of the transmitter or a 5-HT1A agonist is present in the extracellular space of the median raphe nucleus.
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PMID:A microdialysis study of the in vivo release of 5-HT in the median raphe nucleus of the rat. 986 68