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)

A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods. Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors. Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors. It did not interact with histamine (H1), alpha-1 adrenergic and 5-HT3 receptors in smooth muscle preparations. No inhibition of the uptake of norepinephrine, dopamine or 5-HT was seen. Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action. Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile.
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PMID:Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist. 150 Nov 21

The psychotropic effects of a calcium channel blocker (Ca antagonist) were examined in behavioral studies following changes in 45Ca2+ influx in synaptosomal fractions of brain tissues using spontaneously hypertensive rats (SHR). Under a novel circumstance utilizing 85-dB noise, SHR demonstrated hyperactivity and a significant increase in 45Ca2+ uptake into synaptosomal fractions of frontal cortex (FC) and hippocampus. Such hyperactivity may be caused not only be seeking behavior but also by stress-induced anxiety. Such hyperactivity was significantly blocked after 10 days of repeated administration of diazepam (DZP), tandospirone (SM-3997; SM), a 5-HT1A anxiolytic, and nitrendipene (Nit), a Ca antagonist. Moreover, repeated administration of DZP, SM and Nit reduced the maximum binding density of 3H-PN200-110 and reduced the 45Ca2+ uptake in FC of SHR. In hippocampus, midbrain, hypothalamus and striatum, the increased ratio of 45Ca2+ uptake was reduced after repeated administration of Nit or SM. These results suggest that the hyperactivity induced by this novel circumstances was reduced by DZP, SM and Nit and may be attributed to inhibition of voltage-dependent Ca channel activities in FC. In addition, Nit may induce anti-anxiety through the modulation of Ca2+ mobilization in the central nervous system.
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PMID:Neuropsychopharmacological studies of a Ca2+ channel blocker on the modulation of brain Ca2+ mobilization of spontaneously hypertensive rats under mild stress. 166 79

Exposure of bovine adrenal chromaffin cells to ethanol [50 mM], alprazolam [10(-7) M] and buspirone [10(-7) M] inhibited basal and carbachol-induced release of catecholamines from these cells. The inhibition produced by alprazolam was prevented, and that produced by ethanol inhibited, by the presence of the benzodiazepine receptor antagonist, flumazenil [10(-8) M]. The inhibition produced by buspirone was unaffected by flumazenil, but was mimicked by the selective 5-HT1A receptor agonist, 8-OH DPAT and prevented by the 5-HT receptor antagonist spiperone [10(-6) M]. These results suggest that bovine adrenal chromaffin cells express GABAA receptors, containing a benzodiazepine recognition site and also 5-HT1A receptors. Ethanol and alprazolam appear to inhibit the excitability of bovine adrenal chromaffin cells by an action related to the former, while buspirone probably inhibits these cells through the latter. Maintaining bovine adrenal chromaffin cells for several days in culture medium, containing inhibitory concentrations of ethanol alprazolam or buspirone, produced a marked increase in binding sites for a [3H]dihydropyridine [DHP] calcium channel antagonist, on cell membranes. The increase in binding sites produced by alprazolam was greater than that produced by the other two agents and was almost completely prevented by the concomitant presence of flumazenil. The effects of ethanol and buspirone on the binding of DHP were not prevented by flumazenil. The results suggest that drugs which decrease excitability of bovine adrenal chromaffin cells by different mechanisms, may evoke a similar adaptive response involving an increase in DHP-sensitive calcium channels.
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PMID:Chronic exposure to anxiolytic drugs, working by different mechanisms causes up-regulation of dihydropyridine binding sites on cultured bovine adrenal chromaffin cells. 167 64

Only 25 years ago, tobacco dependence was believed to be a simple overuse problem. Research in the last 5 years has demonstrated a much more complex and profound neurochemical and behavioral disorder. Nicotine receptors in the locus coeruleus and the midbrain mesolimbic dopaminergic system activate both arousal state and enhance cognitive functioning (locus coeruleus) and activate the brain's "pleasure center" (mesolimbic system). Pharmacologic treatments, which must be completely integrated into the behavioral treatment plan, alter these profound central nervous system nicotine effects. Currently the only agent with clear scientific evidence for treatment efficacy is nicotine itself. Available only in a transmucosally delivered ion-exchange resin as nicotine polacrilex (Nicorette), nicotine should soon be available in other delivery forms that will have different absorption kinetics: transdermal patch, nasal spray, and vapor inhaler. Other agents in various phases of preclinical and clinical evaluation include 5-HT1A partial agonists such as buspirone; alpha 2-noradrenergic agonists such as clonidine; tricyclics such as doxepin; serotonin re-uptake antagonists such as fluoxetine; ACTH; 5-HT2 antagonists such as ritanserin; central excitatory amino acid inhibitors such as kynurenate; and calcium channel blockers.
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PMID:Pharmacologic approaches to smoking cessation. 174 93

The interactions of antimigraine agents with serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes were analyzed in human frontal cortex membranes. The drugs studied included 5-HT antagonists, beta-adrenergic antagonists, and calcium channel blockers. At 5-HT1A sites labeled by 3H-8-hydroxy-2-(N,N-dipropylamino)-tetralin, (-)pindolol, alprenolol, (-)propranolol, methysergide, cyproheptadine, and pizotifen are similar in that they display affinities of approximately 100 nM for this receptor. By contrast, only methysergide displays relatively high affinity (120 +/- 60 nM), whereas all other drugs have affinities greater than 1,000 nM for non-5-HT1A sites labeled by 3H-5-HT in human cortex. Finally, at 5-HT2 receptors labeled by 3H-spiperone, cyproheptadine, methysergide, and pizotifen are extremely potent agents (affinity constants of 1 to 10 nM), whereas amitriptyline (23 +/- 4 nM), verapamil (140 +/- 50 nM), and nifedipine (320 +/- 80 nM) are moderately potent. All other drugs are inactive at concentrations below 1,000 nM. These data demonstrate that most antimigraine drugs display high affinity for the 5-HT1A and/or 5-HT2 receptor subtypes in human brain. However, antimigraine efficacy cannot be explained by drug interactions with a single 5-HT receptor subtype.
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PMID:Antimigraine drug interactions with serotonin receptor subtypes in human brain. 289 16

The serotonin-1A agonists buspirone (BU) and ipsapirone (IPSA) have been demonstrated to exert antidepressant and anxiolytic effects. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, the interaction of BU and IPSA with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+ induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. BU and IPSA reduced the frequency of occurrence of low magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose dependent manner. The subthreshold concentrations which yielded no effect were 5 mumol/l for BU and IPSA, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that BU and IPSA behave additively with verapamil and carbamazepine, which may be due to a common action on the same subtype of calcium channels. It may be assumed that besides their action on 5-HT1A receptors BU and IPSA may also have calcium antagonistic properties.
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PMID:Effects of the serotonin-1A agonists buspirone and ipsapirone on field potentials in the hippocampus slice: comparison with carbamzepine and verapamil. 761 4

In this study, serotonin (5-HT) was found to diminish the intracellular calcium, [Ca2+]i, concentrations in a dose-dependent manner in Fura-2-loaded human leukemia (K 562) cells. Prior addition of verapamil (a calcium channel blocker) to the cells abolished the serotonin-induced response, suggesting that the diminution of free [Ca2+]i contents was due to the opening of calcium channels. Thapsigargin (an agent which increases [Ca2+]i via its action on endoplasmic reticulum) augmented the [Ca2+]i contents. Addition of serotonin before or after thapsigargin (THAP) curtailed the THAP-stimulated increases in [Ca2+]i, supporting the notion that 5-HT acts on the calcium channels and that it empties, in part, the THAP-stimulated calcium contents. Spiperone and NAN-190, antagonists to 5-HT1A receptor subtype, abolished the serotonin effects on calcium signaling, whereas an agonist to 5-HT1A receptor, 8OHDPAT, mimicked the serotonin-like action on the diminution of the intracellular calcium contents. These results indicate that the 5-HT response is mediated via 5-HT1A serotonergic receptors in these cells. Furthermore, we characterized the 5-HT receptors in K 562 cells. The specific binding of serotonin to these cells was saturable and hyperbolic. The Kd and the Bmax of serotonin binding were 100 nM and 1690 fmol/10(6) cells, respectively. 8-[3H]OH-DPAT also labeled these cells with a Bmax of 2.8 fmol/10(6) cells and a Kd of 20 nM. The specific binding of 8-[3H]OH-DPAT to K 562 cells was displaced by serotonin, 8OH-DPAT, and NAN-190. These results suggest that K 562 cells possess functional 5-HT1A receptors coupled with calcium signaling.
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PMID:Serotonin-induced calcium signaling via 5-HT1A receptors in human leukemia (K 562) cells. 767 19

This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal (Fig. 1).
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PMID:Benzodiazepine withdrawal: behavioural pharmacology and neurochemical changes. 791 Jul 43

The effect 5-HT1A receptor activation on the temperature dependence of HVA calcium channel currents has been studied in acutely isolated DR neurones, using barium as the charge carrier. 8-OH-DPAT caused a reduction in the temperature dependence of the peak current amplitude. However the most dramatic effect of 8-OH-DPAT was a large reduction in Q10 for the current activation rate. This also occurred with direct G-protein activation using GTP gamma S. In the presence of GTP gamma S, current activation became bi-exponential, rather than mono-exponential as in the control situation. The time constants of both components were significantly slower than the controls, and the Q10 for both components was significantly lower. GDP beta S had no effect on the temperature dependence or kinetics of activation of HVA current. Depolarizing prepulses applied prior to test pulses were able to reverse the action of 8-OH-DPAT on the Q10 of the activation rate. When prepulses were applied to cells containing GTP gamma S, the activation rate Q10 was similar to control values. We postulate that the highly significant reduction in activation rate Q10, seen with both 8-OH-DPAT and GTP gamma S, is as a result of a change in the mechanism underlying activation of HVA channels on depolarization. Contrary to previous models of calcium current modulation our results show that the mechanisms responsible for slowed activation by transmitters and facilitation of the residual current by depolarizing prepulses have little in common. We present a new model of transmitter modulation of HVA current, consistent with a mechanistic approach to channel subunit structure.
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PMID:The modulation of calcium channel currents recorded from adult rat dorsal raphe neurones by 5-HT1A receptor or direct G-protein activation. 860 96

We characterized whole cell barium currents through calcium channels and investigated the effects of serotonin (5-HT) on calcium channel currents and firing behavior in visualized caudal raphe neurons of the neonatal rat in brain stem slices (n = 201). A subpopulation of recorded neurons was recovered after staining for tryptophan hydroxylase (TPH), the 5-HT synthesizing enzyme (n = 21); of those cells, 86% were TPH immunoreactive, suggesting that the majority of recorded neurons was serotonergic. Calcium channel currents began to activate at about -40 mV in caudal raphe neurons and showed a peak amplitude of 952.2 +/- 144.2 (SE) pA at -10 mV. A small low-voltage activated current was also observed (approximately 22 pA). Calcium channel currents were potently inhibited by bath-applied 5-HT in most cells tested (approximately 90%). The EC50 for inhibition of calcium current by 5-HT was 0.1 microM; a saturating concentration (1.0 microM) blocked approximately 40% of the current evoked at 0 mV from a holding potential of -70 mV (n = 101). Current inhibition was associated with a slowing of activation kinetics and a shift in the peak of the current-voltage relationship, and was partially relieved by strong depolarizations. Current inhibition by 5-HT was mimicked by 8-OH-DPAT, a specific 5-HT1A agonist, and blocked by the 5-HT1a antagonists NAN 190 and (+) WAY 100135, but was unaffected by ketanserin, a 5-HT2A/C antagonist. omega-Conotoxin GVIA (omega-CgTx)-sensitive N-type channels and omega-agatoxin IVA (omega-AgaIVA)-sensitive P/Q-type channels together accounted for most of the calcium current (36 and 37%, respectively). Nimodipine had no effect on the calcium current, indicating that caudal raphe neurons do not express dihydropyridine-sensitive L-type currents. A substantial residual current (27%) remained after application of omega-CgTx, omega-AgaIVA, and nimodipine. Most of the 5-HT-sensitive calcium current was blocked by omega-CgTx and omega-AgaIVA; 5-HT had little effect on the residual current. Inhibition of calcium current by 5-HT was irreversible when GTP gamma S, a nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue, was substituted for GTP in the pipette. In addition, the effects of 5-HT were blocked by pretreating slices with pertussis toxin (PTX). Together these data indicate that inhibition of N- and P/Q-type calcium current in serotonergic caudal raphe neurons is mediated by a 5-HT1A receptor via PTX-sensitive G proteins. Under current clamp, calcium channel toxins (omega-CgTx and omega-AgaIVA) and 5-HT each caused a decrease in the spike afterhyperpolarization and enhanced the repetitive firing response to injected current. The similar effects of 5-HT and the calcium channel toxins on firing behavior suggest that those effects of 5-HT were secondary to inhibition of N- and P/Q-type calcium channels.
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PMID:Effects of serotonin on caudal raphe neurons: inhibition of N- and P/Q-type calcium channels and the afterhyperpolarization. 908 3


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