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 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.
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PMID:The orphan receptor cDNA RDC4 encodes a 5-HT1D serotonin receptor. 165 18

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.
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PMID:Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission. 168 46

The (R)- and (S)-2-butylamides of d-lysergic acid were prepared and evaluated in behavioral and biochemical assays of 5-HT2 agonist activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, both isomers completely substituted for the training stimulus. Similarly, both isomers were found to possess very high affinity in displacing [125I]-(R)-DOI ([125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane) from rat cortical homogenate 5-HT2 receptors and in displacing [3H]-8-OH-DPAT ([3H]-8-hydroxy-2-(di-n-propylamino)tetralin) from rat hippocampal 5-HT1A receptors. The difference in activity between the two isomeric amides was significant in both the behavioral and binding assays, with the R isomer possessing greater potency. Molecular mechanics were used to predict the active geometries of the subject compounds. It was found that the (R)-2-butylamide has a conformation quite similar to LSD, while the (S)-2-butylamide does not. These results suggest that stereochemical properties of the amide substituent of hallucinogenic lysergamides may exert a critical influence on activity. It is concluded that the conformation of the amide function may directly affect binding through stereoselective interactions with a hydrophobic region on the receptor, indirectly by inducing conformational changes elsewhere in the molecule, or by a combination of these two mechanisms.
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PMID:Stereoselective LSD-like activity in d-lysergic acid amides of (R)- and (S)-2-aminobutane. 173 37

The hallucinogenic agent d-lysergic acid diethylamide (d-LSD) interacts with a number of serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes in the central nervous system. It has been hypothesized that hallucinosis is produced by agonist activity at 5-HT2 receptors. There exist, however, numerous data from radioligand binding, cellular, smooth muscle, and behavioral studies that suggest that d-LSD is a potent 5-HT2 antagonist. These data are reviewed in this report. In addition, d-LSD displays agonist activity at 5-HT1A and 5-HT1C receptor subtypes, as determined in biochemical studies. At the present time, agonist interactions at 5-HT1C receptors, as opposed to 5-HT2 receptors, appears to be a more likely "common mechanism of action" of hallucinogenic agents.
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PMID:Antagonist properties of d-LSD at 5-hydroxytryptamine2 receptors. 207 83

5-Hydroxytryptamine (5-HT; 10(-4) M) produces an initial depolarization, followed by a long-lasting hyperpolarization, when focally applied to pyramidal neurons in the somatosensory cortex of the rat. Application of the selective 5-HT1A agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT; 10(-6) M) or d-lysergic acid diethylamide (d-LSD; 10(-6) M), produced only a hyperpolarizing response which was larger than the response to 5-HT. Application of 8-OH-DPAT (10(-6) M) and 5-HT (10(-4) M) together produced an initial depolarizing response, similar to the response with 5-HT alone, followed by a hyperpolarizing response which was 23 +/- 3% larger than with 5-HT alone. By contrast, the application of d-LSD (10(-6) M) and 5-HT (10(-4) M) together produced either no depolarization (7 of 13 cells) or a significantly smaller depolarizing response (36 +/- 4% of the response to 5-HT alone), as well as a hyperpolarizing response which was 33 +/- 4% larger than with 5-HT alone. Therefore, d-LSD displayed a unique pharmacological ability to both mimic and block the effect of 5-HT on single neurons in somatosensory cortex of the rat.
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PMID:d-Lysergic acid diethylamide differentially affects the dual actions of 5-hydroxytryptamine on cortical neurons. 214 13

The effect of different serotonin (5-HT) agonists and antagonists on the discriminative stimulus properties (cue) induced by 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT), 1-(m-trifluoromethylphenyl)piperazine (TFMPP) and d-LSD (d-lysergic acid diethylamide) has been investigated. The 8-OHDPAT cue was mimicked by the 5-HT1A agonists ipsapirone, buspirone, gepirone and partially by 5-methoxy-N,N-dimethyltryptamine and d-LSD. 5-HT1B (TFMPP and RU 24969) and 5-HT2 agonists (DOM, DOI and quipazine) were ineffective and induced disruption of responding. The 8-OHDPAT cue was antagonized by spiroxatrine and partially by (-)-alprenolol, whereas selective antagonists of 5-HT2 (ketanserin and ritanserin), 5-HT3 (ICS 205-930), alpha 1-adrenergic (prazosin) and beta-adrenergic receptors (ICI 118.551) were ineffective. The TFMPP cue was mimicked by RU 24969 and partially by quipazine. Other compounds were ineffective. Only (-)-alprenolol antagonized the effect of TFMPP. The d-LSD cue was mimicked by DOM, DOI, quipazine, 5-methoxy-N,N-dimethyltryptamine and partially by ipsapirone, TFMPP and RU 24969. The 3 latter compounds and 5-HT1A agonists induced disruption of responding. The d-LSD cue was antagonized by ketanserin and ritanserin, but not by the other antagonists mentioned above. The specific inhibitor of 5-HT uptake citalopram was not able to substitute for any of the 3 agonists. It is concluded that the drug discrimination technique can be used to identify selective agonists and antagonists of 5-HT receptor subtypes. Compounds with mixed effects on 5-HT receptor subtypes can also be identified. These show additional effects on reaction time and often disrupt responding at higher dosages.
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PMID:Characterization of the discriminative stimulus properties induced by 5-HT1 and 5-HT2 agonists in rats. 252 50

The 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induced a dose-dependent reduction in latency to withdraw the tail from noxious hot water (48 degrees C). However, a similar apparent 'hyperalgesia' was seen at a non-noxious temperature of 38 degrees C. Indeed, 8-OH-DPAT induced spontaneous 'tail-flicks' in the absence of external stimulation. This property was shared by lisuride and LSD, which also have high intrinsic activity at 5-HT1A sites. Agonists at other serotonin (5-HT) receptor types (5-HT1B, 5-HT1C, 5-HT2, 5-HT3) were inactive. Tail-flicks induced by 8-OH-DPAT could be antagonised by the 5-HT1 2 antagonist, methiothepin, but not by ritanserin or GR-38032F, which are antagonists at 5-HT2 and 5-HT3 sites, respectively. Ipsapirone and buspirone, partial 5-HT1A agonists, acted as antagonists. Further, BMY 7378, a proposed selective antagonist at 5-HT1A sites, also blocked the tail-flicks. Thus, the apparent 'hyperalgesia' induced by 8-OH-DPAT may reflect induction of spontaneous tail-flicks. These flicks appear to be mediated by 5-HT1A receptors and represent a novel model of 5-HT1A function in the rat.
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PMID:Apparent hyperalgesic action of the 5-HT1A agonist, 8-OH-DPAT, in the rat reflects induction of spontaneous tail-flicks. 253 34

The binding affinities of four hallucinogenic agents were analyzed at nine neurotransmitter binding sites in human cortex. d-Lysergic acid diethylamide (d-LSD), N,N-dimethyltryptamine (DMT), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB) display highest affinity for the recently identified "DOB binding site" labeled by 77Br-R(-)DOB. The phenalkylamines, DOI and DOB, display subnanomolar affinity for the 77Br-R(-)DOB-labeled site, whereas the indolealkylamines, d-LSD and DMT, display nanomolar affinity for this site. d-LSD was the most potent of the four hallucinogens at six of the other eight sites analyzed in this study. All four hallucinogens also display high affinity for the 5-hydroxytryptamine2 (5-HT2) receptor subtype, with potencies ranging from 4 to 360 nM. Marked differences in relative affinities were observed between the indolealkylamines and the phenalkylamines at the 5-HT1A, 5-HT1D, and DOB binding sites. These rank-order differences in affinities are likely to account for the differing effects of these agents in various biochemical and physiological assays.
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PMID:Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex. 254 May 5

The radioligand binding characteristics of 125I-R-(-)4-iodo-2,5-dimethoxyphenylisopropylamine [125I-R-(-)DOI] and 3H-ketanserin were compared in rat and bovine cortical membranes. In rat cortex, 125I-R-(-)DOI labels a relatively low density of binding sites (Bmax = 2.5 +/- 0.2 pmol/gm tissue) with high affinity (KD = 0.63 +/- 0.09 nM). In bovine cortex, specific binding of 125I-R-(-)DOI represents less than 20% of total binding at radioligand concentrations above 0.6 nM, and, therefore, the data cannot be analyzed adequately by Scatchard transformation. By contrast, 3H-ketanserin displays saturable, specific high-affinity binding in both rat cortex (KD = 1.0 +/- 0.1 nM; Bmax = 11 +/- 0.4 pmol/gm tissue) and bovine cortex (KD = 1.2 +/- 0.2 nM; Bmax = 5.3 +/- 0.4 pmol/gm tissue). Ki values for 30 drugs were determined for 125I-R-(-)DOI-labeled sites in rat cortex and 3H-ketanserin-labeled sites in bovine cortex. 5-Hydroxytryptamine (5-HT) displays 250-fold higher selectivity for the 125I-R-(-)DOI-labeled sites (Ki = 3.0 +/- 0.7 nM) than for the 3H-ketanserin-labeled sites (Ki = 750 +/- 50 nM). Structural congeners of R-(-)DOI display 80- to 160-fold higher affinity for the 125I-R-(-)DOI binding site than for the 3H-ketanserin-labeled binding site. d-LSD and putative 5-HT2 antagonists are approximately equipotent at both sites. Significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and putative 5-HT2A sites labeled previously by 77Br-R-(-)DOB (r = 0.93, p less than 0.01), putative 5-HT2B sites labeled by 3H-ketanserin in bovine cortex (r = 0.63, p less than 0.01), and 5-HT1C binding sites that have been characterized by other investigators (r = 0.78, p less than 0.01). No significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and 5-HT1A, 5-HT1B, 5-HT1D, or 5-HT3 sites, as determined by previous investigators. We conclude that 125I-R-(-)DOI labels a novel 5-HT binding site subtype (tentatively designated the 5-HT2A binding site) that is present in rat cortex but is either absent or minimally present in bovine cortex. By contrast, 3H-ketanserin labels both the putative 5-HT2A site in rat cortex as well as a separate, distinct recognition site that is present in both rat and bovine cortex, tentatively designated the 5-HT2B site.
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PMID:Differentiation of 5-hydroxytryptamine2 receptor subtypes using 125I-R-(-)2,5-dimethoxy-4-iodo-phenylisopropylamine and 3H-ketanserin. 279 35

Short-term lithium administration to rats has previously been shown to enhance 5-HT neurotransmission through a modification of 5-HT neuron properties. In the first part of the present study, the effect of lithium on the function of terminal 5-HT autoreceptors was assessed by comparing in controls and lithium-treated rats the differential effect of two frequencies of stimulation (0.8 and 5 Hz) and that of methiothepin, a terminal 5-HT autoreceptor antagonist, on the effectiveness of the electrical activation of the ascending 5-HT pathway in suppressing dorsal hippocampus pyramidal neuron firing activity. Both procedures produced similar effects in controls and lithium-treated rats. In the second part of the study, the function of somatodendritic 5-HT autoreceptors was studied. The effect of intravenous LSD, an agonist of the somatodendritic 5-HT autoreceptor, on the firing activity of 5-HT neurons was not modified by the lithium treatment, whereas that of intravenous 8-OH-DPAT, a 5-HT1A receptor agonist, was increased two-fold. However, lithium did not alter the responsiveness of 5-HT neurons to direct microiontophoretic applications of 8-OH-DPAT as well as of LSD and 5-HT. It is concluded that short-term lithium treatment does not alter the function of terminal and somatodendritic 5-HT autoreceptors and that it enhances the sensitivity of a subset of postsynaptic 5-HT1A receptors involved in controlling 5-HT neuron firing activity, presumably through a feedback loop.
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PMID:Short-term lithium treatment enhances responsiveness of postsynaptic 5-HT1A receptors without altering 5-HT autoreceptor sensitivity: an electrophysiological study in the rat brain. 285 Jun 22


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