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 cardiovascular effects of the 5-HT1A receptor agonists MDL 73,975 (8-[2-(2,3-dihydro-8-methoxy-1,4-benzodoxin-2-yl)methylaminol++ +]-ethyl]-8- azaspiro[4,5]decane-7,9-dione hydrochloride) and flesinoxan (10-300 micrograms/kg subcutaneously, s.c.), the 5-HT1A receptor antagonist NAN 190 (2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)- dione,1,2-ethanedioate), and the alpha 1-adrenoceptor antagonist prazosin have been investigated in conscious normotensive and renal hypertensive dogs. In normotensive dogs the increases in heart rate and respiratory rate induced by both agonists were dose-related, as were the decreases in systolic and diastolic blood pressure induced by MDL 73,975. Both compounds caused a dose-related increase in the intensity of the '5-HT syndrome'. After pretreatment with NAN 190 (100 micrograms/kg s.c.) the increases in heart rate, respiratory rate and symptoms of the '5-HT syndrome' were significantly reduced but the decreases in systolic and diastolic pressure were additive. Pretreatment with prazosin (100 micrograms/kg s.c.) antagonized the '5-HT syndrome' and the increase in respiratory rate. Similar responses were evident in renal hypertensive dogs. Tolerance did not develop to the increases in heart rate, respiratory rate and manifestations of the '5-HT syndrome' in normotensive dogs during 5 days of treatment with MDL 73,975 or flesinoxan. In conclusion, MDL 73,975 and flesinoxan induced a 5-HT1A receptor-mediated fall in blood pressure but the changes in heart rate, respiratory rate and the '5-HT syndrome' are probably mediated by alpha 1-adrenoceptors.
Eur J Pharmacol 1994 Sep 12
PMID:Are the cardiovascular effects and '5-HT syndrome' induced by MDL 73,975 and flesinoxan in the dog mediated by 5-HT1A receptors? 781 85

Previously it was shown that acute cocaine administration dose dependently reduces the 5-HT2-receptor-mediated DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced head-twitch response (HTR) in mice via indirect stimulation of the inhibitory adrenergic alpha 2- and serotonergic 5-HT1A receptors. In addition, the inhibitory capacity of cocaine was enhanced fourfold in mice with 5-HT2-receptor supersensitivity induced by a single injection of DOI 48 h prior to experimentation. The aim of the present investigation was to determine the inhibitory capacity of cocaine in reserpinized mice. A single injection of reserpine 48 h prior to DOI administration caused supersensitivity in the DOI-induced HTR. Two reserpine injections did not further enhance this supersensitivity effect. Once reserpinized 5-HT2-receptor supersensitive animals were less responsive to the inhibitory effects of cocaine on the DOI-induced behavior than were the mice, as reported previously, that were made supersensitive by DOI pretreatment. The inhibitory capacity of cocaine was further attenuated when mice were reserpinized twice prior to determination of its effects on the DOI-induced behavior. Taken together with previously published data, the present investigation lends further support for the importance of endogenous levels of 5-HT and norepinephrine on the ability of cocaine to attenuate the DOI-induced HTR.
Pharmacol Biochem Behav 1994 Sep
PMID:The effects of acute cocaine administration on the DOI-induced head-twitch response in reserpinized mice. 781 79

The densities of serotonin1A (5-HT1A) receptors, labeled with [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined in the CNS of alcohol-naive adult male alcohol-preferring (P) and -nonpreferring (NP) rats using quantitative autoradiography. The densities of sites labeled with 2 nM [3H]8-OH-DPAT were a) 20-30% higher in the medial prefrontal, frontal (layers 1, 2, and layers 3-6), parietal (layers 3-6), and cingulate cortex; b) 35-40% higher in the retrosplenial, occipital (all layers), temporal (all layers) cortex; and c) 15% higher in the entorhinal cortex of the P compared with the NP rat. Within the hippocampus, significant differences between the rat lines were observed only in the posterior portion where the densities of [3H]8-OH-DPAT labeled sites were a) 10-15% higher in the dorsal dentate gyrus, dorsal CA1, and dorsal CA3 regions; and b) 15-25% higher in the anterior ventral hippocampal area and ventral dentate gyrus of the P relative to the NP line. In contrast to the above results, the densities of [3H]8-OH-DPAT labeled sites were 15-20% lower in the dorsal, paradorsal, and median raphe nuclei of the P compared with the NP rat. No differences in [3H]8-OH-DPAT binding between the rat lines were found in several basal ganglia, limbic, and brain stem regions. The data indicate that there are greater numbers of postsynaptic 5-HT1A receptors in certain parts of the cerebral cortex and hippocampus of the P compared with the NP rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacol Biochem Behav 1994 Sep
PMID:Regional serotonin1A receptors in the CNS of alcohol-preferring and -nonpreferring rats. 781 92

Cholinergic neurons in the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei are implicated in the generation of rapid eye movement sleep (REM) and ponto-geniculo-occipital (PGO) waves. Serotonin (5-HT) has a role in sleep-wake regulation and appears to inhibit PGO wave generation. We studied the effects of the central infusion of the relatively specific 5-HT1A receptor agonist 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) and the less specific 5-HT1 receptor agonist 1(3-chlorophenyl)piperazine (mCPP) on the regulation of REM and on PGO wave generation. DPAT (0.0, 0.002, 0.01, 0.08, and 0.8 microgram/0.5 microliter normal saline) and mCPP (0.0, 0.02, 0.2, 2.0, and 20.0 micrograms/0.5 microliter normal saline) were infused unilaterally into the peribrachial region of PPT (PB) in cats. Additionally, DPAT (0.01 microgram/0.5 microliter) was infused bilaterally into PB in a separate experiment. Low dosages of DPAT (unilateral or bilateral) decreased successful entrances into REM (0.01 microgram) and time spent asleep (0.002 microgram and 0.01 microgram) without affecting outward behavior. No dosage of mCPP significantly decreased the number of REM episodes, and neither drug decreased REM episode duration once REM had been entered. Neither drug affected the rate of PGO waves independently of modulating behavioral state. We propose that 5-HT1A receptor mechanisms have an inhibitory role in actual REM initiation, possibly by facilitating endogenously generated excitation of brainstem startle mechanisms at the onset of REM.
Pharmacol Biochem Behav 1994 Sep
PMID:Central administration of two 5-HT receptor agonists: effect on REM sleep initiation and PGO waves. 781 96

In previous studies, we showed that localized perfusion of the SCN region with serotonin (5-HT) or the non-selective serotonergic, quipazine, using the microdialysis technique significantly reduced the extracellular concentration of the excitatory amino acid (EAA), glutamate. The present investigation was undertaken to extend these findings by characterizing the effects of various classes of 5-HT receptor ligands on the extracellular glutamate concentration in the SCN. Localized SCN application or i.p. injection of the 5-HT1A receptor agonist, 8-OH-DPAT, during the dark phase (6 h after lights-off) significantly reduced the extracellular glutamate concentration in the SCN region from baseline levels (38.7 +/- 8.7 and 53.4 +/- 11.2%, respectively, of pretreatment values; P < 0.05). The effect of systemically applied 8-OH-DPAT was abolished by i.p. injection of the 5-HT1A receptor antagonist, NAN-190, administered 20 min before the 8-OH-DPAT. Localized perfusion of the SCN with the 5-HT1B receptor agonist, TMFPP, also reduced extracellular glutamate but to a lesser degree than 8-OH-DPAT (80.1 +/- 3.9% of pretreatment levels; P < 0.05). This effect was prevented by i.p. injection of the non-selective 5-HT receptor antagonist, metergoline 20 min before TFMPP perfusion. Localized perfusion of the SCN region with the 5-HT2 and 5-HT3 receptor agonists, alpha-methyl 5-HT and 1-phenylbiguanide, respectively, had little effect on extracellular glutamate (both P > 0.1 vs. baseline). Systemic treatment with NAN-190 alone had little effect on extracellular glutamate, however, similar treatments with metergoline or the 5-HT2 receptor antagonist, ritanserin, induced significant increases extracellular glutamate levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res 1994 Sep 12
PMID:Serotonergic inhibition of extracellular glutamate in the suprachiasmatic nuclear region assessed using in vivo brain microdialysis. 782 May 91

The role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated by using the shock titration test in rats. A subcutaneous injection of 300 micrograms/kg 8-OH-DPAT significantly raised the threshold for flinching, jumping and vocalization whereas 100 micrograms/kg only inhibited the flinch response. l-Propranolol and (+)-[N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl propanamide dihydrochloride], (+)-WAY100135, two antagonists at 5-HT1A receptors at 10 mg/kg s.c. antagonized the effect of 300 micrograms/kg 8-OH-DPAT on all measures. The effect of 300 micrograms/kg 8-OH-DPAT on the three measures was unmodified in rats which had received 150 micrograms 5,7-dihydroxytryptamine intracerebroventricularly 10 days before testing. The results suggest that 8-OH-DPAT inhibits nociceptive responses by stimulating postsynaptic 5-HT1A receptors.
Eur J Pharmacol 1994 Sep 22
PMID:Role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n- propylamino)tetralin in the rat. 782 51

5-Hydroxytryptamine (5-HT)-induced increase of intracellular Ca2+ concentration ([Ca2+]i) was monitored in cultured canine tracheal smooth muscle cells (TSMCs) using a fluorescent Ca2+ indicator Fura-2. Stimulation of TSMCs by 5-HT produced an initial transient peak followed by a sustained, concentration-dependent elevation of [Ca2+]i. The log (EC50) values of 5-HT for the peak and sustained plateau responses were -7.43 and -7.60 M, respectively. 5-HT1A and 5-HT3 receptor antagonists, NAN-190 and metoclopramide, inhibited the 5-HT-stimulated increase in [Ca2+]i with pKB values of 6.3 and 6.2, respectively, indicating that the 5-HT receptors mediating Ca2+ signal had low affinity for these receptor antagonists. In contrast, 5-HT2A receptor antagonists, ketanserin and mianserin, had high affinity in antagonizing the changes in [Ca2+]i response to 5-HT with pKB values of 8.3 and 8.3, respectively. The sustained elevation of [Ca2+]i was dependent on the presence of extracellular Ca2+. Removal of extracellular Ca2+ by addition of 2 mM EGTA during the sustained phase caused a rapid decline in [Ca2+]i to the resting level. In the absence of extracellular Ca2+, only an initial peak was observed which then declined to the resting level; the sustained elevation of [Ca2+]i could then be evoked by addition of 1.8 mM Ca2+ in the continued presence of 5-HT. Ca2+ influx was required for the changes of [Ca2+]i, since the Ca(2+)-channel blockers, diltiazem, verapamil, and Ni2+, decreased both the initial and sustained elevation of [Ca2+]i in response to 5-HT. These Ca(2+)-channel blockers also decreased the sustained elevation of [Ca2+]i when applied during the plateau phase. In conclusion, these findings indicate that the initial increase in [Ca2+]i stimulated by 5-HT acting on 5-HT2A receptors is due to the release of Ca2+ from internal stores, followed by the influx of external Ca2+ into the cells. The influx of extracellular Ca2+ partially involves a diltiazem and verapamil sensitive Ca2+ channel.
Cell Calcium 1994 Sep
PMID:5-Hydroxytryptamine-stimulated calcium mobilization in cultured canine tracheal smooth muscle cells. 782 73

The elevated "zero-maze" is a modification of the elevated plus-maze model of anxiety in rats which incorporates both traditional and novel ethological measures in the analysis of drug effects. The novel design comprises an elevated annular platform with two opposite enclosed quadrants and two open, removing any ambiguity in interpretation of time spent on the central square of the traditional design and allowing uninterrupted exploration. Using this model, the reference benzodiazepine anxiolytics, diazepam (0.125-0.5 mg/kg) and chlordiazepoxide (0.5-2.0 mg/kg) significantly increased the percentage of time spent in the open quadrants (% TO) and the frequency of head dips over the edge of the platform (HDIPS), and reduced the frequency of stretched attend postures (SAP) from the closed to open quadrants. In contrast, the anxiogenic drug m-chlorophenyl-piperazine (mCPP; 0.25-1.0 mg/kg) induced the opposite effects, decreasing %TO and HDIPS, and increasing SAP. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.001-0.1 mg/kg) had no effects on either %TO or HDIPS, but did decrease SAP at 0.01 mg/kg although not at higher or lower doses. Similarly, the 5-HT3 receptor antagonist, ondansetron (0.0001-1.0 mg/kg) decreased SAP and increased %TO at 0.01 mg/kg, but not at other doses. The present data suggest that a combination of the novel "zero-maze" design and a detailed ethological analysis provides a sensitive model for the detection of anxiolytic/anxiogenic drug action.
Psychopharmacology (Berl) 1994 Sep
PMID:Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety. 786 31

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.
Psychopharmacology (Berl) 1994 Sep
PMID:Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (-)S 20500. 786 33

This study was designed to determine if alpha 1-adrenoceptors are involved in the vascular responses to 5-HT1A receptor agonists. Buspirone (3.1 x 10(-7)-3.1 x 10(-5) M) and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT; 3.1 x 10(-6)-10(-4) M) elicited contractions of rabbit aorta rings which were blocked by prazosin (10(-9)-5.6 x 10(-9) M), but which were unaffected by reserpine pretreatment (1 mg/kg i.p.). 5-Methylurapidil (10(-7) and 10(-6) M) blocked contractions elicited by 8-OH-DPAT and by buspirone, whereas chloroethylchonidine (10(-5) and 10(-4) M) inhibited only the effect of buspirone. In addition, these 5-HT1A receptor agonists relaxed arteries precontracted with alpha-adrenoceptor agonists in a similar range of concentrations in which they elicited contraction. Moreover, 8-OH-DPAT and buspirone protected the alpha-adrenoceptors from the irreversible blockade provoked by phenoxybenzamine (10(-7) M), as judged by the norepinephrine contraction and stimulated phosphatidylinositol labeling. According to these results the contractile and relaxant effects elicited by 5-HT1A receptor agonists are a consequence of a direct interaction with alpha 1-adrenoceptors. The contraction elicited by 8-OH-DPAT may be mediated by alpha 1A-adrenoceptors, whereas both alpha 1A- and alpha 1B-adrenoceptors may mediate the effect of buspirone in rabbit aorta.
Eur J Pharmacol 1993 Sep 14
PMID:Pharmacological evidence for interactions between 5-HT1A receptor agonists and subtypes of alpha 1-adrenoceptors on rabbit aorta. 790 87


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