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)

Spinal serotonin1 (5-HT1)(labelled by [3H]5-HT), 5-HT1A (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT)), mu- (labelled by [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol ([3H]DAGO) and [3H]naloxone) and delta-opiate (labelled by [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr [( 3H]DSTLE] receptor binding sites were studied in adult rats using quantitative autoradiography after either neonatal treatment with capsaicin or unilateral cervical dorsal rhizotomy. Both treatments produced a significant loss of 5-HT (-20 to -30%) and opiate (-30 to -45%) binding sites within the superficial layers of the dorsal horn, suggesting they are partly located presynaptically on primary afferent fibres. Thus, 5-HT, as well as opiates, might generate analgesia by acting--at least partly--on primary afferent nociceptive fibres at the spinal level.
Neurosci Lett 1987 Dec 16
PMID:Autoradiographic evidence of serotonin1 binding sites on primary afferent fibres in the dorsal horn of the rat spinal cord. 344 2

1. The actions of serotonin (5-HT) on pyramidal cells of the CA1 region of the rat hippocampus were characterized using intracellular recording in in vitro brain slices. 2. 5-HT typically evokes a biphasic response consisting of a hyperpolarization which is followed by a longer-lasting depolarization. These effects on membrane potential are accompanied by a decrease in the calcium-activated after-hyperpolarization (a.h.p). 3. Detailed analysis using 5-HT antagonists and agonists indicates that the hyperpolarization is mediated by a 5-HT1A receptor. Spiperone is the most effective antagonist of the response and the selective 5-HT1A agonist, 8-OHDPAT, behaves as a partial agonist at this receptor. In agreement with the distribution of 5-HT1A binding sites, responses to 5-HT were most prominent in the stratum radiatum. 4. The hyperpolarizing response is associated with a decrease in input resistance, is blocked by extracellular barium and intracellular caesium, is unaffected by the chloride gradient, and its reversal potential shifts with the extracellular concentration of potassium as predicted for a response mediated by a selective increase in potassium permeability. 5. The depolarizing response and reduction in the a.h.p. could be studied in isolation by blocking the hyperpolarizing response with either pertussis toxin or spiperone. The pharmacology of these responses did not correspond to that of any of the 5-HT binding sites reported in C.N.S. tissue. Although the depolarization and blockade of the a.h.p. have the same time course it is unclear if they are mediated by the same or different receptors. 6. The depolarization most likely results from a decrease in resting potassium conductance. However, neither a blockade of the M current nor the a.h.p. current can account for the depolarization. 7. Blockade of phosphodiesterase activity by 3-isobutyl-1-methylxanthine (IBMX) did not enhance the depressant action of 5-HT on the a.h.p., making it unlikely that this action is mediated by cyclic AMP. 8. Blockade of the a.h.p. by 5-HT reduces spike frequency adaptation and counteracts the inhibitory action of 5-HT on 5-HT1A receptors. This excitatory action outlasts the hyperpolarizing action. 9. In summary 5-HT acts on at least two distinct receptors on hippocampal pyramidal cells, one coupled to the opening of potassium channels and a second coupled to a decrease in a resting potassium conductance and a decrease in the a.h.p.
J Physiol 1987 Dec
PMID:Pharmacologically distinct actions of serotonin on single pyramidal neurones of the rat hippocampus recorded in vitro. 344 77

The 5-hydroxytryptamine (5-HT) autoreceptors mediating inhibition of [3H]5-HT release in rat hippocampus have been characterized pharmacologically in terms of 5-HT receptor subtype by using superfused synaptosomes depolarized with 15 mM KCl. Exogenous 5-HT inhibited in a concentration-dependent way (pEC30 = 8.74) the K+-evoked release of [3H]5-HT. Methiothepin shifted the concentration-response curve of 5-HT to the right (pA2 = 8.62). The 5-HT2 receptor antagonists, ketanserin, methysergide or spiperone were ineffective against 5-HT. The 5-HT1 receptor agonist, 5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole (RU 24969) mimicked 5-HT and was equipotent as an inhibitor of the release of [3H]5-HT. In contrast, the putative 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was almost ineffective at 1 microM. Finally, (-)propranolol, used as a non-selective 5-HT1A/5-HT1B receptor antagonist, shifted to the right (pA2 = 7.91) the concentration-response curve of 5-HT whereas the 5-HT1C receptor antagonist mesulergine was ineffective. In conclusion, 5-HT nerve terminals of rat hippocampus possess autoreceptors which appear to belong to the 5-HT1B subtype.
Naunyn Schmiedebergs Arch Pharmacol 1986 Dec
PMID:Serotonin autoreceptor in rat hippocampus: pharmacological characterization as a subtype of the 5-HT1 receptor. 382 24

A superfusion system employed to measure the K+-stimulated release of [3H]5-hydroxytryptamine [(3H]5-HT, [3H]serotonin) from a synaptosomal-rich spinal cord tissue preparation was carefully characterized, then used to examine the regulation of spinal 5-HT release. Spinal 5-HT release is apparently modulated by an autoreceptor. Exogenous 5-HT depressed, in a concentration-dependent manner, the K+-stimulated release of [3H]5-HT. Similarly, lysergic acid diethylamide (LSD) produced a concentration-dependent decrease in [3H]5-HT release. Methiothepin and quipazine blocked the inhibition of release induced by exogenous 5-HT. The 5-HT2 receptor antagonists spiperone and ketanserin failed to alter the action of 5-HT at the spinal 5-HT autoreceptor. Spiperone and ketanserin were shown, however, to alter the storage of [3H]5-HT. When used in concentrations greater than 10 nM, the drugs evoked increases in basal [3H]5-HT and [3H]5-hydroxyindoleacetic acid ( [3H]5-HIAA) effluxes which were independent of the presence of calcium ions. A good agreement existed between the potencies of drugs for modifying autoreceptor function and their abilities to compete for high-affinity [3H]5-HT binding in the spinal cord (designated 5-HT1). Furthermore quipazine, in concentrations that preferentially interact with the 5-HT1B subtype, antagonized the actions of exogenous 5-HT on K+-stimulated release. Spiperone, in a concentration that approximated the affinity constant of 5-HT1A sites for the drug, was ineffective in altering the ability of exogenous 5-HT to modulate K+-stimulated [3H]5-HT release. These results suggest that 5-HT1B sites are associated with serotonergic autoreceptor function in the spinal cord.
J Neurochem 1985 Dec
PMID:Demonstration of an autoreceptor modulating the release of [3H]5-hydroxytryptamine from a synaptosomal-rich spinal cord tissue preparation. 387 46

A series of 2-(dipropylamino)tetralin derivatives in which the C8 substituent is varied has been prepared and evaluated pharmacologically to explore the importance of the C8 substituent in the interaction of 2-aminotetralin-based ligands with serotonin (5-HT1A) receptors. Enantiopure derivatives were prepared by facile palladium-catalyzed reactions of the triflates of the enantiomers of 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 1). The affinity of the compounds for the 5-HT1A receptors was evaluated by competition experiments with [3H]-8-OH-DPAT in rat hippocampal and cortical tissue. In addition, the compounds were evaluated for central 5-HT and dopamine receptor stimulating activity in vivo by use of biochemical and behavioral assays in rats. With the exception of the carboxy-substituted derivative which is devoid of 5-HT1A receptor affinity, the compounds have moderate to high affinities (K(i) values range from 0.7 to 130 nM) for 5-HT1A receptors. Surprisingly, several of the derivatives do not produce any apparent effects in vivo although they have fairly high 5-HT1A receptor affinities. However, the methoxycarbonyl- and acetyl-substituted derivatives are potent 5-HT1A receptor agonists in vivo and exhibit in vitro affinities in the same range as the enantiomers of 1.
J Med Chem 1993 Dec 24
PMID:Derivatives of 2-(dipropylamino)tetralin: effect of the C8-substituent on the interaction with 5-HT1A receptors. 750 12

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H1, D2, alpha 1 and alpha 2 receptors became occupied (ED50 = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H1 and alpha 1 receptors at low doses (ED50 = 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, alpha 2, cholinergic muscarinic and 5-HT1A receptors at higher doses (ED50 = 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D2 and alpha 1 receptors at low doses (ED50 = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol.(ABSTRACT TRUNCATED AT 400 WORDS)
Brain Res 1993 Dec 24
PMID:Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography. 751 May 74

Intracerebroventricular (i.c.v.) injection of highly selective mu opioid receptor agonist ohmefentanyl (OMF) to rats produced dose-dependent antinociception as assessed with the tail flick test. This analgesia could be blocked by intrathecal (i.t.) injection of the 5-HT1A receptor antagonist spiperone or the 5-HT1C/2 receptor antagonist mianserin, but not by the 5-HT2 receptor antagonist 1-NP or the 5-HT3 receptor antagonist ICS 205-930. The results suggest that the descending 5-HT system is involved in mediating spinal mu opioid analgesia via spinal 5-HT1A and 5-HT1C/2 receptors.
Neuroreport 1994 Dec 20
PMID:Spinal serotonin IA and IC/2 receptors mediate supraspinal mu opioid-induced analgesia. 769 28

N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) is a potent and selective 5-HT1A receptor antagonist in a slice preparation of the guinea pig dorsal raphe nucleus: the inhibitory actions on 5-HT neuronal firing of 5-hydroxytryptamine (5-HT, serotonin), 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), but not those of baclofen, were abolished by 30 nM WAY-100635. The selective 5-HT1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'- methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide (GR127935, 300 nM) did not attenuate the 5-HT induced inhibition, indicating that 5-HT1D receptors do not contribute to the inhibitory action of exogenous 5-HT on 5-HT neurones.
Eur J Pharmacol 1994 Dec 12
PMID:WAY-100635 and GR127935: effects on 5-hydroxytryptamine-containing neurones. 769 89

Proestrous rats were infused unilaterally into the median raphe nucleus with 200-2,000 ng of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Inhibition of the lordosis to mount ratio occurred within 15 and 10 min, respectively, following infusion with 1,000 or 2,000 ng of the drug. Infusion of 2,000 ng of the 5-HT2 agonist, (+/-)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), or 4,000 ng 5-HT (creatinine sulfate) failed to substantially reduce lordosis behavior.
Brain Res 1994 Dec 30
PMID:Agonist activation of 5-HT1A receptors in the median raphe nucleus and female rat lordosis behavior. 770 14

The novel selective 5-HT1A receptor antagonist radioligand [3H]WAY 100635 ([O-methyl-3H]N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridyl)cyclohexane-carboxamide) was injected i.v. to mice in an attempt to label in vivo central 5-HT1A receptors. Although 5 min after the i.v. injection of [3H]WAY 100635 (4-7.6 muCi per mouse) the amount of tritium found in the whole brain only accounted for 1.5-1.8% of the injected radioactivity, regional differences in 3H accumulation already corresponded to those of 5-HT1A receptor density. Optimal data were obtained 1 h after [3H]WAY 100635 injection as the distribution of 3H in brain was exactly that of 5-HT1A receptor binding sites in mouse brain sections labelled in vitro with [3H]WAY 100635. In particular, high level of labelling was found in the lateral septum, gyrus dentatus and CA1 area of Ammon's horn in the hippocampus, dorsal raphe nucleus and entorhinal cortex. No labelling was found in he substantia nigra, and 3H accumulated in the cerebellum represented only 12-14% of that found in the hippocampus. Pretreatment with various drugs indicated that only 5-HT1A receptor ligands were able to decrease the accumulation of 3H in all the brain areas examined except in the cerebellum. Assuming that only non-specific binding took place in the latter structure, it was possible to calculate the ID50 values of 5-HT1A receptor agonists (8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl+ ++)piperazine) and S 20499 ((+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8- azaspiro-(4,5)-decane-7,9-dione)) and antagonists (spiperone, (-)-tertatolol, (+)-WAY 100135 (N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl- propanamide)) as inhibitors of 3H accumulation in the hippocampus of [3H]WAY 100635-injected mice. Comparison of these values with the in vitro affinity of the same ligands for hippocampal 5-HT1A receptors revealed marked variations in the capacity of 5-HT1A receptor agonists and antagonists to reach the brain when injected via the subcutaneous route in mice.
Eur J Pharmacol 1994 Dec 27
PMID:Selective in vivo labelling of brain 5-HT1A receptors by [3H]WAY 100635 in the mouse. 770 51


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