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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

1. The effects of serotonin (5-HT) on visually identified motoneurones were investigated using the whole-cell recording technique in a neonatal rat spinal cord slice preparation. 2. In current-clamp recordings, bath application of 5-HT depolarized motoneurones. This effect was observed after synaptic inputs were abolished by replacing external Ca2+ with Mg2+. 3. In voltage-clamp recordings at holding potentials of -70 to -90 mV, 5-HT induced an inward current (I5-HT) in motoneurones in a Ca2(+)-free-Mg2+ solution containing tetrodotoxin. This inward current was accompanied by an increase in membrane conductance, which was prominent at voltages negative to the holding potential. 4. The inward I5-HT response declined with repeated short applications of 5-HT. I5-HT produced by a single prolonged application (5 min) was only slightly diminished during the application period. 5. The minimum effective dose of 5-HT for initiating the inward I5-HT was less than 10 nM. At 10 microM, I5-HT approached maximal levels. The averaged dissociation constant (Kd) for 5-HT was approximately 120 nM. 6. Application of spiperone, the mixed 5-HT1A, 5-HT2 receptor antagonist, blocked the inward I5-HT. Application of (+)-8-OH-dipropylaminotetralin (8-OHDPAT), a 5-HT1A agonist, mimicked the action of 5-HT. 7. Various K+ channel blockers including tetraethylammonium chloride (30 mM), 4-aminopyridine (4 mM) and apamin (100 nM) did not abolish I5-HT. Application of extracellular Cs+ (10 mM) blocked I5-HT. 8. Peak inward I5-HT became larger with increasing extracellular K+. With low Cl- pipette solution (less than 1 mM), or in low extracellular Na+ solution (26 mM), the inward I5-HT was not abolished. 9. The current-voltage relation of I5-HT displayed inward rectification. In high external K+ concentration (20 mM), the reversal potential was about -29 mV, which is close to that of the inward rectifier evoked in motoneurones by membrane hyperpolarization. 10. The current generated by 5-HT displayed similar characteristics to the inward rectifying current induced in motoneurones by membrane hyperpolarization. It is thus suggested that the 5-HT-induced current is possibly mediated by the intrinsic inward rectifier conductance.
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PMID:Direct excitation of rat spinal motoneurones by serotonin. 169 89

1. The effects of microinjections (100 nl) into the dorsal motor vagal nucleus of the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan, the 5-HT2 receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), the 5-HT3 receptor agonist phenylbiguanide (PBG), the alpha 2-adrenoceptor agonist clonidine and the excitatory amino acid glutamate on heart rate, blood pressure, tracheal pressure and phrenic nerve activity were investigated in atenolol-pretreated rats anaesthetized with sodium pentobarbitone. 2. Microinjections of glutamate (2.5 nmol) caused decreases in blood pressure, heart rate and phrenic nerve activity. In contrast, microinjections of 5-HT (1.2 nmol), 8-OH-DPAT (1.2 nmol) and flesinoxan (1.3 nmol) all caused a bradycardia but had no effect on blood pressure. In addition, 8-OH-DPAT and flesinoxan caused an increase in phrenic nerve activity. 3. Microinjections of DOI, PBG and clonidine had no significant effect on any of the variables recorded. None of the drugs used had any significant effect on tracheal pressure. 4. These results support the hypothesis that activation of 5-HT1A receptors causes excitation of cardiac vagal motoneurones and suggest that these receptors are also important in the control of central respiratory drive.
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PMID:Microinjections of 5-HT1A agonists into the dorsal motor vagal nucleus produce a bradycardia in the atenolol-pretreated anaesthetized rat. 179 13

Regulation of phosphate uptake was studied in a HeLa cell line after transfection with DNA encoding the human 5-HT1A receptor. In these cells, 5-HT stimulates sodium-dependent phosphate uptake via protein kinase C activation. Endogenous histamine H1 receptors (739 +/- 20 fmol/mg protein) were identified with [3H]pyrilamine. Histamine (i) stimulated phosphoinositide hydrolysis (EC50 = 8.6 +/- 4.1 microM), (ii) activated protein kinase C (2.4-fold increase in activity), and (iii) increased phosphate uptake (EC50 = 3.2 +/- 1.8 microM) by increasing maximal transport (Vmax(basal) = 6.2 +/- 0.3 versus Vmax(histamine) = 9.1 +/- 0.4) without changing the affinity of the transport process for phosphate. Prolonged treatment with 16 microM phorbol 12-myristate 13-acetate completely blocked protein kinase C activation and markedly attenuated the stimulation of phosphate uptake induced by histamine, establishing that 5-HT and histamine stimulate phosphate uptake through the common pathway of protein kinase C activation. The linkages of the histamine H1 and 5-HT1A receptors to G protein pools were assessed in two ways. (i) The stimulation of phosphoinositide hydrolysis, protein kinase C activity, and phosphate uptake associated with histamine were insensitive to pertussis toxin, whereas those associated with 5-HT were very sensitive to pertussis toxin. (ii) The stimulation of phosphoinositide hydrolysis, protein kinase C activity, and phosphate uptake induced by histamine and 5-HT were additive. These findings suggest that distinct receptor types can stimulate phosphoinositide hydrolysis, protein kinase C, and phosphate uptake in an additive fashion through distinct pools of G proteins in a single cell type.
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PMID:5-HT1A and histamine H1 receptors in HeLa cells stimulate phosphoinositide hydrolysis and phosphate uptake via distinct G protein pools. 184 68

Agonist occupancy of the cloned human serotonin (5-HT)1A receptor expressed in HeLa cells stimulates Na+/K+ ATPase activity as assessed by rubidium uptake. The purpose of the study was to determine which of the receptor-associated signaling mechanisms was responsible for this effect. 5-HT stimulated Na+/K+ ATPase 38% at 2 mM extracellular potassium, an effect characterized by a decrease in apparent K0.5 from 2.8 +/- 0.3 to 1.8 +/- 0.3 mM potassium without a significant change in apparent Vmax. The EC50 for the transport effect was approximately 3 microM 5-HT. The response was pertussis toxin-sensitive but did not involve inhibition of adenylate cyclase, as stimulation of Na+/K+ ATPase by 5-HT was observed in the presence of excess dibutyryl cAMP. Protein kinase C was not required for the response since short-term incubation with the phorbol esters phorbol 12 myristate, 13 acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) did not mimic the 5-HT effect. Moreover, 5-HT increased Na+/K+ ATPase activity after inactivation of protein kinase C by overnight incubation with PMA. 5-HT and the sesquiterpene lactone thapsigargin increased cytosolic calcium in this cell model, and the EC50 for 5-HT corresponded with that for stimulation of Na+/K+ ATPase. Both thapsigargin and A23187, a calcium ionophore, also increased Na+/K+ ATPase activity in a dose-responsive fashion. The response to 5-HT, thapsigargin, and A23187 was blocked by conditions that removed the cytosolic calcium response. By two-dimensional gel electrophoresis, we established evidence for a calcium-sensitive but protein kinase C-independent signaling pathway. We conclude that the 5-HT1A receptor, which we have previously shown to stimulate phosphate uptake via protein kinase C, stimulates Na+/K+ ATPase via a calcium-dependent mechanism. This provides evidence for regulation of two separate transport processes by a single receptor subtype via different signaling mechanisms.
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PMID:Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells. 217 7

The neurochemical profile of GBR 12909 (1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)pipera zine) was investigated. GBR 12909 was a potent and selective inhibitor of synaptosomal dopamine uptake (KI = 1 nM), with a 20-fold lower affinity for the histamine H1-receptor and a more than 100-fold affinity for the noradrenaline and 5-HT uptake carriers, the dopamine D-1, D-2, 5-HT2, 5-HT1A and alpha 1-receptors and voltage-dependent sodium channels. GBR 12909 (3 microM) was without effect on muscarinic, alpha 2, beta 1 + 2, gamma-aminobutyric acid (GABA) and benzodiazepine receptors, and on choline and GABA uptake carriers. The selective dopamine uptake inhibitory profile of GBR 12909 was confirmed by ex vivo uptake experiments. GBR 12909 inhibited uptake in vitro in a competitive manner as did cocaine and methylphenidate. [3H]GBR 12935 binding was competitively inhibited by GBR 12909 as well as by dopamine, cocaine and methylphenidate. Off-rate analysis of the [3H]GBR 12935 binding excluded the presence of allosteric binding sites on the dopamine carrier complex. Instead, the data favored the notion that GBR 12909 inhibits dopamine uptake by binding to the dopamine binding site on the carrier protein itself, thereby blocking the carrier process. In conclusion, GBR 12909 is a highly selective inhibitor of dopamine uptake, both in vivo and in vitro. At the moment GBR 12909 is the only compound with this neurochemical profile. The selective effect of GBR 12909 on this neuronal system makes it an interesting experimental tool and a potential antidepressant agent.
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PMID:The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. 253 94

[3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) is thought to label a single population of serotonin (5-HT)1A receptor, but some reports implicate multiple binding sites exist. In addition, while 5-HT1A receptor activates or inhibits adenylate cyclase, 5-HT1A receptor high and low affinity states are not reported. In this experiment, we found that [3H]8-OH-DPAT had multiple binding sites, which contained 5-HT1A receptor high and low affinity states, in rat brain membranes. [3H]8-OH-DPAT saturation binding experiment revealed high and low affinity binding sites existed. High affinity binding site was dense in hippocampus and sparse in striatum. 5-HT agonist and antagonist biphasically displaced [3H]8-OH-DPAT binding in frontocortical, hippocampal, and striatal membranes. These drugs potently displaced high affinity [3H]8-OH-DPAT binding, but clomipramine (5-HT reuptake inhibitor) potently displaced low affinity binding. High affinity [3H]8-OH-DPAT binding site was decreased by guanosine triphosphate and Na+, but increased by divalent cations, implicating coupling with G protein(s). Low affinity [3H]8-OH-DPAT binding site was decreased by cations, especially by monovalent cations and Ca2+. After the destruction of 5-HT neuron by parachloroamphetamine, only the low affinity binding site decreased. These results indicate that [3H]8-OH-DPAT not only labels the 5-HT1A receptor high and low affinity states but has presynaptic binding site relating to 5-HT reuptake site.
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PMID:[Multiple [3H]8-hydroxy-2-(di-n-propylamino)-tetralin binding sites in rat brain: modulation by GTP and cations]. 253 Jul 29

Regulation of phosphate uptake was studied in HeLa cell lines after transfection with DNA encoding the human 5-HT1A receptor. Phosphate uptake was saturable and greater than 90% sodium-dependent, with Vmax approximately 30-35% without changing Km. Treatment with 5-HT or the 5-HT1A-specific agonist 8-OH-2-(di-n-propylamino)1,2,3,4-tetrahydronaphthalene increased Vmax approximately 40% without affecting Km. This effect was blocked by pretreatment with the 5-HT1 antagonists, methiothepine and spiperone, or pertussis toxin. Surprisingly, the stimulation was not secondary to an inhibition of adenylyl cyclase because 5-HT stimulated phosphate uptake approximately 20% in the presence of 1 mM 8-Br-cAMP. Rather, the primary pathway linked to the stimulation of phosphate uptake involved activation of protein kinase C because (i) 5-HT measurably activated protein kinase C in these cells, (ii) activators of protein kinase C (phorbol esters and diacylglycerol analogues) stimulated phosphate uptake in these cells (iii) the half-maximal doses for 5-HT-induced phosphatidylinositol hydrolysis and stimulation of phosphate uptake were virtually equivalent, and both effects were equally sensitive to pertussis toxin, and (iv) the stimulation was markedly attenuated in cells made deficient in protein kinase C. These results demonstrate that the stimulation of phosphatidylinositol hydrolysis by the 5-HT1A receptor can generate physiologically measurable effects on cellular transport and suggest that such accessory pathways may play a prominent role in signal transduction.
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PMID:The human 5-HT1A receptor expressed in HeLa cells stimulates sodium-dependent phosphate uptake via protein kinase C. 255 47

Prompted by previous findings that a p-dimethoxy substitution pattern on an aromatic ring permits retention of dopaminergic agonist effects in certain ring systems, catechol derivatives of which are potent dopaminergic agonists, an 8,11-dimethoxy substitution pattern was introduced into the aporphine ring in place of the 10,11-dihydroxy moiety in apomorphine. Acid-catalyzed rearrangement of an appropriate morphine derivative provided the aporphine ring system with retention of the stereochemical integrity of the 6a asymmetric center. The hydroxyl group at position 10 was removed by catalytic hydrogenolysis of its phenyltetrazoyl ether. The methyl ether of the resulting 11-hydroxyaporphine was iodinated in high yield at position 8 with trifluoroacetyl hypiodite. This is the first account of synthesis of an iodinated aporphine derivative. The 8-iodo substituent was replaced with methoxyl by reaction with sodium methoxide and cuprous iodide. Neither the N-methyl target compound 7 nor the N-n-propyl derivative 8 demonstrated dopaminergic nor serotonergic agonism. However, 7 exhibited receptor-binding characteristics and other pharmacological properties suggesting that it may be a 5-HT1A receptor antagonist.
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PMID:5-HT1A-receptor antagonism: N-alkyl derivatives of (R)-(-)-8,11-dimethoxynoraporphine. 256 41

The ionic mechanism of the inhibitory effect of serotonin was investigated in vitro in the CA1 region of the rat hippocampus by extra- and intracellular recordings. Local or bath applications of serotonin induced a long-lasting reduction of extracellularly recorded synaptic potentials and orthodromic population spikes without affecting the afferent volley or the antidromic population spike. Serotonin can also reduce the frequency of occurrence of spontaneous excitatory and inhibitory postsynaptic potentials without any reduction of input resistance of the pyramidal neuron. During the response to serotonin, the conductance increase evoked by GABA, the inhibitory neurotransmitter, was not changed. A direct postsynaptic effect of serotonin was demonstrated: local or bath applications of serotonin induced a tetrodotoxin-resistant hyperpolarization and conductance increase. The conductance change was not reduced by manual clamp of the neurons to the control resting membrane potential; therefore, a possible involvement of the sodium-potassium electrogenic pump is unlikely. When neurons were loaded with chloride, serotonin could still induce a hyperpolarization with an apparent reversal more negative than the resting membrane potential. When neurons were loaded with caesium, the hyperpolarization and the conductance increase evoked by serotonin were blocked. It is therefore concluded that serotonin increases potassium permeability. Similar effects were induced by a 5-HT1A ligand. The slow after hyperpolarization was reduced by serotonin; the calcium spike was reduced at the same time. In caesium loaded neurons, the spike duration was not modified by serotonin. In the presence of extracellular caesium (4-5 mM), the serotonin-induced hyperpolarization and the conductance change were blocked, but the effect of serotonin on calcium spikes persisted. Tetraethylammonium (5-10 mM) or 4-aminopyridine (0.5 mM) had no effect on the response to serotonin. These data indicate that serotonin has a postsynaptic inhibitory action by an activating potassium conductance. The possibility of a regulation of calcium currents is discussed. The possible role of serotonin on intrinsic synaptic transmission is also discussed.
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PMID:Inhibitory action of serotonin in CA1 hippocampal neurons in vitro. 284 92


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