Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HT1B receptor antagonists such as propranolol and penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5. In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HT1B receptor. 6. In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.7. In the forced swimming test in rats, anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of antidepressant drugs.8. Anpirtoline exhibits both antinociceptive and antidepressant-like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.
 ...
PMID:Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents. 162 59

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC-GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled Gi (but not 5-HT2-coupled Go) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
 ...
PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

Administration of p-chloroamphetamine (PCA, 10 mg/kg i.p. on two occasions) to rats resulted in a severe depletion of [3H]paroxetine binding sites, a measure of presynaptic serotonergic terminals, in both cortex and hippocampus, but did not affect [3H]8-hydroxy-2-(di-n-propylamino)tetralin [( 3H]8-OH-DPAT) binding or 5-hydroxytryptamine (5-HT)-induced inhibition of forskolin-stimulated adenylate cyclase in hippocampal membranes. Administration of either imipramine (15 mg/kg i.p. for 2 weeks) or lithium (0.2% for 2 weeks) to PCA-treated rats did not affect [3H]8-OH-DPAT binding but reduced the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes. It is concluded that the effects of imipramine and Li+ on 5-HT1A receptor-mediated responses in the hippocampus are exerted postsynaptically, possibly at a level distal to the receptor.
 ...
PMID:Chloroamphetamine did not prevent the effects of chronic antidepressants on 5-hydroxytryptamine inhibition of forskolin-stimulated adenylate cyclase in rat hippocampus. 165 66

The cDNA of RDC4, a putative receptor of the G protein-coupled receptor family, has been cloned by PCR methodology. The primary structure of this receptor showed homology with the serotonin 5-HT1A receptor. In this work, RDC4 mRNA has been injected in Y1 adrenal cells and Xenopus oocytes and RDC4 cDNA has been transfected transiently in cos-7 cells. In all these systems serotonin elicited a rise in cyclic AMP levels. Binding studies on membranes of the transfected cos-7 cells using [3H]-LSD showed a pattern of drug affinities consistent with the known properties of a 5-HT1D receptor. RDC4 therefore codes for a 5-HT1D receptor which in the studied systems is positively coupled to adenylate cyclase.
 ...
PMID:The orphan receptor cDNA RDC4 encodes a 5-HT1D serotonin receptor. 165 18

Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response. Similarly, NAN-190 (0.1 microM) almost totally prevented the inhibition by 8-OH-DPAT (1 microM) of forskolin-stimulated adenylate cyclase activity in adult rat hippocampal slices but, per se, was without effect on the forskolin response. These results indicate that NAN-190 is a potent antagonist at postsynaptic 5-HT1A receptors in vitro. However, NAN-190 also potently antagonized (IC50 = 0.16 nM) the stimulation by norepinephrine of phosphoinositide turnover in rat cortical slices. In this respect NAN-190 was a 250-fold more potent antagonist than prazosin (IC50 = 49 nM). Thus, in addition to its 5-HT1A receptor antagonist properties, NAN-190 has potent alpha 1-adrenoceptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission. 166 63

The level of cyclic AMP in NCB-20 cells was increased by serotonin (5-HT), 5-methoxytryptamine and 2-methyl-5-HT with EC50 of 0.5 +/- 0.1, 1.0 +/- 0.1, 10 +/- 0.1 microM, respectively. The 5-HT-mediated increase of cyclic AMP content was completely blocked by metergoline but unaffected by 5-HT3 antagonists, ICS 205-930, MDL 72222, quipazine and 5-HT2 antagonist, ketanserin. Putative 5-HT1A agonists (8-OH-DPAT, ipsapirone, and buspirone) and 5-HT1B agonists (TFMPP and m-CPP) affected neither basal nor forskolin-dependent cyclic AMP accumulation. Receptor binding studies suggest that NCB-20 cells are devoid of 5-HT1A and 5-HT1B receptor sites. Application of 5-HT onto NCB-20 cells resulted in membrane depolarization by an evoked inward current which displayed rapid desensitization. 5-HT-mediated current had a reversal potential around 0 mV and was potently and reversibly inhibited by ICS 205-930. Our data suggest that in NCB-20 cells the 5-HT3 receptor is involved in the generation of inward currents, while the 5-HT receptor coupled to adenylate cyclase does not seem to correspond to any of the known receptor subtypes.
 ...
PMID:Characterization of two distinct 5-HT receptors coupled to adenylate cyclase activation and ion current generation in NCB-20 cells. 168 72

Intracellular recordings in vitro from a variety of central neuronal types have shown both inhibition and excitation to be modulatory consequences of serotonin (5-HT) receptor activation. These responses can be seen in isolation or in some cases (e.g. hippocampal pyramidal cells) as a complex biphasic combination of hyperpolarisation followed by depolarisation, suggesting overall control of neuronal excitability may be dependent on the interaction between activation of more than one post-synaptic receptor and/or mechanism. Our studies have confirmed the 5-HT evoked depolarisation of rat facial motorneurones (FM's) and the hyperpolarisation seen in presumed serotonergic neurones of the dorsal raphe nucleus (DRN) to be the result of opposite effects on K+ ion permeability. Suppression of a resting K+ conductance leads to depolarisation while activation leads to hyperpolarisation. The same mechanisms appear to be responsible for the 5-HT evoked responses in hippocampal pyramidal cells but in addition there is also a suppression of a Ca++ dependent K+ conductance responsible for the long spike after hyperpolarisation (AHP). Data from the hippocampus and DRN indicate the 5-HT induced hyperpolarisation to be sensitive to Pertussis Toxin (PTX) and irreversibly mimicked by GTP gamma S, a non-hydrolysable analogue of GTP, suggesting the involvement of a G protein in K+ channel activation. The mechanism of K+ channel closure is less clear as it is unaffected by PTX or activation of adenylate cyclase, however there is indirect evidence that the phosphoinositide pathway may be involved from the cloned 5-HT1C receptor which also closes a K+ channel in cell lines. The results show that hyperpolarisation evoked by 5-HT in the hippocampus and DRN to be mimicked and blocked by 5-HT1A agonists and antagonists. However, the depolarisations in the hippocampus and FM's are mediated by site-dependent receptors with profiles which do not fit into the current 5-HT receptor subtype classification.
 ...
PMID:Serotonin receptor heterogeneity and the role of potassium channels in neuronal excitability. 175 7

The effects of chronic administration of lithium, short-term administration of lithium, chronic administration of DMI and a combination of short-term administration of lithium and chronic administration of DMI on second messenger responses were studied in the hippocampus of the rat. Lithium reduced the ability of carbachol to inhibit forskolin-stimulated activity of adenylate cyclase in hippocampal membranes but had no effect on carbachol-stimulated formation of inositol phosphate in hippocampal slices. Lithium, however, reduced the degree of stimulation of formation of inositol phosphate, induced by noradrenaline. Desimipramine alone did not affect carbachol- or noradrenaline-mediated reactions and a combination of short-term administration of lithium and chronic administration of DMI did not potentiate the action of lithium on adenylate cyclase. Both lithium and DMI abolished the inhibition by 5-HT of carbachol-stimulated formation of inositol phosphate a 5-HT1A receptor-mediated response. It is concluded that the chronic effects of administration of lithium may be related to actions at the G protein level and that different modes of coupling of receptors to G proteins may be responsible for the variety of effects observed.
 ...
PMID:Effects of lithium and desimipramine on second messenger responses in rat hippocampus: relation to G protein effects. 178 83

The 5-HT1A receptor has been one of the most studied 5-HT receptor subtypes in terms of its pharmacologic profile. Comparisons of various studies of structure-activity relationships (SAR) at this receptor shows an emerging profile for this receptor's pharmacophore. The present discussion focuses on the findings generated with relatively small molecules that can be considered as analogs of serotonin itself and that illustrate some of the structural properties that are important for high-affinity recognition by the receptor. Most of the SAR work has been based on the affinities of compounds for the receptor as determined by the radioligand-binding technique, which has a significant limitation in that it cannot define the intrinsic activity of compounds at the receptor. This problem can be addressed by functional assays, and an example of SAR at the 5-HT1A receptor-coupled adenylate cyclase system is provided.
 ...
PMID:Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity. 181 58

The behavioural and biochemical profile of the sigma ligand and putative antipsychotic agent, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol) has been determined in the mouse and rat. In mice, pretreatment with BMY 14802 attenuated both amphetamine-induced hyperactivity and conditioned avoidance responding, consistent with its previously reported antipsychotic potential. In common with 5-HT1A receptor agonists or partial agonists, BMY 14802 induced (a) a dose-dependent hypothermia in mice; (b) aspects of the 5-HT behavioural syndrome in rats, (c) antagonised mescaline-induced head twitches in mice and (d) generalised to the 8-hydroxy-2-(di-n-propylamino)tetralin discriminative stimulus over the dose range of 3-15 mg/kg. BMY 14802 had appreciable affinity for the 5-HT1A receptor (pIC50 = 6.7 compared to 7.3 for sigma binding) and antagonised forskolin-stimulated adenylate cyclase activity with a pEC50 of 6.2, consistent with an agonist action at this receptor. The results support the involvement of 5-HT1A receptors, but not the sigma binding site, in the behavioural profile of BMY 14802.
 ...
PMID:Behavioural and biochemical evidence of the interaction of the putative antipsychotic agent, BMY 14802 with the 5-HT1A receptor. 183 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>