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)

IMR-32 and SK-N-MC cells were found to contain [3H]quinuclidinyl benzilate specific binding sites inhibited by pirenzepine in a manner suggesting the presence of both M1-type and M2-type muscarinic receptor recognition sites. Neither cell had detectable [3H]8-OH-DPAT binding sites. Carbachol stimulated the rate of inositol phospholipid breakdown in IMR-32 and SK-N-MC human neuroblastoma cells with an EC50 value of about 50 microM in both cases. Pirenzepine inhibited the carbachol (100 microM)-stimulated inositol phospholipid breakdown in both cells with Hill slopes of unity and IC50 values of 15 nM (IMR-32) and 12 nM (SK-N-MC). The 5-HT1A receptor agonist 8-OH-DPAT competitively inhibited carbachol-stimulated inositol phospholipid breakdown with pA2 values of 5.78 (IMR-32) and 5.61 (SK-N-MC). These values are consistent with the inhibitory potency of 8-OH-DPAT towards [3H]quinuclidinyl benzilate binding in these cells. The 5-HT agonists 5-MeODMT and buspirone at micromolar concentrations inhibited carbachol-stimulated breakdown in IMR-32 cells. The inhibition by 8-OH-DPAT and 5-MeODMT was not affected by preincubation with (-)alprenolol. 5-HT (10-100 microM) was without effect on either basal or carbachol-stimulated breakdown. It is concluded that IMR-32 and SK-N-MC neuroblastoma cells express muscarinic M1-type but not serotoninergic receptors coupled to phosphoinositide-specific phospholipase C. 8-OH-DPAT acts as a weak antagonist at these muscarinic receptors.
 ...
PMID:Antagonism by 8-hydroxy-2(di-n-propylamino)tetraline and other serotonin agonists of muscarinic M1-type receptors coupled to inositol phospholipid breakdown in human IMR-32 and SK-N-MC neuroblastoma cells. 182 86

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

The effects of hemicholinium-3 (HC-3) on spatial discrimination learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical "float" (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 micrograms/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 micrograms/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46-460 micrograms/kg/SC) and tetrahydroaminoacridine (THA) (2.2-10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046-1 mg/kg/SC), aceclidine (1-10 mg/kg/SC), oxotremorine (30-100 micrograms/kg/SC) and RS-86 (0.46, 1.0 microgram/kg/SC) were also effective. Pilocarpine (0.22-2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6-10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The alpha 2 agonist, clonidine (46, 100 micrograms/kg SC) and the antagonist idazoxan (32, 100 micrograms/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 micrograms/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 micrograms/kg) or by the benzodiazapine antagonist ZK-93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.
 ...
PMID:Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics. 252 45

The study of serotonin-4 (5-HT4) receptors in the central nervous system has been hindered by the lack of effective, selective antagonists. However, recently, several novel compounds have been synthesized and shown to act as antagonists at 5-HT4 receptors in smooth muscle and embryonic neurons in culture. In the present study, intracellular electrophysiological recordings were used to test the effects of three of these compounds: endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-6-methoxy- 2-oxo-1H-benzimidazole-1-carboxylate (DAU 6285), [1-[2-(methylsulfonylamino)ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate (GR 113808) and 2-diethylaminoethyl-(2-methoxy-4-amino-5-chloro) benzoate (SDZ 205-557) on the 5-HT4 reduction of the afterhyperpolarization seen in adult CA1 hippocampal neurons in brain slices. GR 113808, SDZ 205-557 and DAU 6285 all functioned as competitive antagonists at these 5-HT4 receptors. Although all three compounds tested acted as effective antagonists, they differed considerably in potency. When the potency of these antagonists at the 5-HT4 receptor that mediates the reduction of the afterhyperpolarization was compared with that observed for 5-HT4 receptors in biochemical and binding assays, an excellent correlation was observed. Among the antagonists tested, GR 113808 was the most potent (pA2 = GR 113808 > SDZ 205-507 > DAU 6285). It exhibited an apparent affinity for the 5-HT4 receptors in the low nanomolar range but did not antagonize 5-HT1A, beta-adrenergic or muscarinic receptor-mediated responses when applied at concentrations two orders of magnitude higher.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Antagonists of 5-HT4 receptor-mediated responses in adult hippocampal neurons. 796 22

The effect of serotonin [5-hydroxytryptamine (5-HT)] on pial venous tone of the pig was examined using in vitro tissue bath techniques. Isolated pial venous rings exhibited spontaneous rhythmic contractions (SRC) on mechanical stretching and/or applications of several vasoactive substances, including norepinephrine. On the other hand, KCl induced sustained active muscle tone (SAT) without SRC. The SRC induced by mechanical stretching were not affected by tetrodotoxin, nitro-L-arginine, alpha- and beta-adrenergic, histaminergic, and muscarinic receptor antagonists, indicating that the SRC in porcine pial veins are of myogenic origin. The SRC induced by stretching or applications of vasoactive substances and SAT induced by KCl were inhibited by 5-HT in a concentration-dependent manner. The inhibition was prevented by methysergide and methiothepin but not by ketanserin, propranolol, 3 alpha-tropanyl-1H-indole-3-carboxylic acid ester, hemoglobin, or nitro-L-arginine. The SRC and SAT were inhibited by 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-di-N-propylaminotetralin HBr (8-OHDPAT), 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), and 5-methoxytryptamine (5-MT), but not by sumatriptan, alpha-methylserotonin, or 2-methylserotonin. On the other hand, 5-CT, 8-OHDPAT, TFMPP, 5-MT, and sumatriptan constricted the porcine pial arteries exclusively. In 15% of pial venous preparations examined, 5-HT at low concentrations induced ketanserin-sensitive constrictions. These results indicate that the porcine pial venous smooth muscle contains multiple subtypes of 5-HT receptors. The 5-HT inhibition of SRC and SAT is predominant and is mediated by 5-HT1-like receptors, which, however, do not seem to correspond to 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, or 5-HT1F receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Serotonin relaxes porcine pial veins. 816 Aug 3

In this study we examined a possible contribution of serotonin (5-hydroxytryptamine, 5-HT) to spatial memory performance in the rat. Rats were trained to run in a radial maze in a manner that involved two kinds of memory function, i.e. working memory and reference memory. They received intrahippocampal microinjections of a 5-HT1A [8-hydroxy-2-(di-n-propylamino)tetralin or 8-OH-DPAT], or a 5-HT1B [3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one or CP-93,129] receptor agonist, and a muscarinic receptor antagonist (scopolamine). 8-OH-DPAT (5 micrograms/microliters), like injections of saline, induced no change in performance levels. In contrast, rats suffered an impairment in both reference and working memory following injection of scopolamine (10 micrograms/microliters). CP-93,129 induced a higher frequency of reference memory errors than of working memory errors at the intermediate (10 micrograms/microliters) and higher doses (16 micrograms/microliters). Thus, the stimulation of 5-HT1B receptors in the CA1 field of the dorsal hippocampus impairs the performance of rats in a spatial learning task.
 ...
PMID:Spatial memory deficits following stimulation of hippocampal 5-HT1B receptors in the rat. 857 7

NAN-190, a selective 5-HT1A receptor antagonist, had no effect on the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task with a three-panel runway setup, when injected bilaterlly at 0.32 or 1.0 micrograms/side into the dorsal hippocampus. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at 3.2 micrograms/side or the competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at 32 ng/side significantly increased the number of working memory errors. The increase in working memory errors induced by intrahippocampal scopolamine (3.2 micrograms/side) was reduced by concurrent infusion of 0.32 and 1.0 microgram/side NAN-190, an effect that reached significance only for the 1.0 microgram/side dose. In contrast, NAN-190 at 1.0 micrograms/side did not affect the increase in working memory errors when infused intrahippocampally together with 32 ng/side CPP. These results suggest that blockade of hippocampal 5-HT1A receptors does not affect impairment of working memory resulting from block of NMDA receptor-mediated neurotransmission, but that it can compensate deficiency of septohippocampal cholinergic activity involved in working memory performance of rats.
 ...
PMID:Blockade of 5-HT1A receptors compensates loss of hippocampal cholinergic neurotransmission involved in working memory of rats. 893 Mar 23

Central administration of galanin dose-dependently (minimum effective dose, M.E.D. = 1 nmol) blocked the hypothermia induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.5 mg/kg s.c.), in mice. This inhibitory effect was reversed by pretreatment with the galanin receptor antagonist galantide (0.3 nmol) and also by pretreatment with the ATP-sensitive potassium channel blockers glibenclamide (10 nmol) and gliquidone (10 nmol). The hypothermic response to 8-OH-DPAT was also blocked by the 5-HT1A receptor antagonist (N-(2,4(2-methoxyphenyl)-1-piperazinyl)ethyl-N-(2-pyridinyl)cyclohexane, (WAY 100,635, M.E.D. = 0.01 mg/kg s.c.), and the centrally acting muscarinic receptor antagonist scopolamine (M.E.D. = 10 mg/kg i.p.) but not the peripheral muscarinic receptor antagonist N-methylscopolamine. 8-OH-DPAT (0.5 mg/kg s.c.) also decreased cortical and hypothalamic 5-HT (5-hydroxytryptamine, serotonin) metabolism, an effect which was not blocked by pretreatment with galanin (0.3-3 nmol intracerebroventricular, i.c.v.). Neither did galanin (0.03-3 nmol/5 microliters i.c.v.) affect basal 5-HT metabolism in these brain regions. Furthermore, pretreatment in vitro of mouse cortical membranes with galanin (10 or 1000 nM) had no effect on 5-HT1A receptor affinity, Bmax or pharmacology determined using [3H]8-OH-DPAT. These results suggest that the inhibition of 8-OH-DPAT induced hypothermia by galanin is probably not mediated by an interaction with 5-HT1A receptors but more likely by blocking the indirect activation by 8-OH-DPAT of central cholinergic pathways involved in temperature regulation.
 ...
PMID:Effects of galanin on 8-OH-DPAT induced decrease in body temperature and brain 5-hydroxytryptamine metabolism in the mouse. 899 1

It is known that beta-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a beta-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its beta-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity.
 ...
PMID:The attenuating effect of carteolol hydrochloride, a beta-adrenoceptor antagonist, on neuroleptic-induced catalepsy in rats. 920 97

The effect of WAY 100635, a 5-HT1A receptor antagonist, on the impairment of spatial learning caused by intrahippocampal administration of scopolamine, a cholinergic muscarinic receptor antagonist, or 7-chloro-kynurenic acid, an antagonist at the glycine site associated with the NMDA receptor complex, was studied in a two-platform spatial discrimination task. Scopolamine (4 microg/microl) or 7-chloro-kynurenic acid (3 microg/microl), administered bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy with no effect on choice latency and errors of omission. Administered subcutaneously at 1 (but not at 0.3) mg/kg 30 min before each training session, WAY 100635 did not modify the acquisition of spatial learning, but prevented the impairment of choice accuracy caused by intrahippocampal scopolamine or 7-chloro-kynurenic acid. These findings suggest that blockade of 5-HT1A receptors can compensate the loss of cholinergic or NMDA-mediated excitatory input to pyramidal cells in the hippocampus. The mechanisms involved and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed.
 ...
PMID:WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7-chloro-kynurenic acid. 945 5


1 2 3 Next >>