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)

Evolutionary constant serotonin (5-HT) neuronal systems evolved along medial brain structures; yet, wide variations in functionality characterize serotonergic systems in mediating aggressive responses in species ranging from lobsters, ants, electric fish, and rodents to primates. So far, the attempts to correlate cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels with measures of aggression have revealed inverse, direct, or no correlations in different nonhuman primate species. It is difficult to harmonize the occasional correlations between CSF 5-HIAA and adaptive aggressive acts in nonhuman primates (a) with clinically diagnosed suicidal or impulsive individuals, and (b) with the biochemical, anatomical, and presumably functional differentiation of 5-HT pathways and receptor subtypes. Eltoprazine, a mixed 5-HT1A/B agonist, and meta-trifluoro-methylphenyl-piperazine HCl (TFMPP), a more selective 5-HT1B agonist, specifically decrease aggressive behavior in several animal species and situations in both sexes without detriment to other social, exploratory, or motoric activities. A definite role for 5-HT1A, 5-HT2, and 5-HT3 receptor subtypes in the mechanisms mediating aggressive behaviors has to await the development of selective agonists and antagonists, respectively.
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PMID:Brain 5-HT and inhibition of aggressive behavior in animals: 5-HIAA and receptor subtypes. 248 73

Serotonin 5-HT1A receptors in rat hippocampal membranes were solubilized by 10 mM 3-[3-(cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS) and chromatographed on various gels in an attempt to design a relevant protocol for their (partial) purification. In particular, an affinity gel made of the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) derivative 8-methoxy-2-[(N-propyl, N-butylamino)amino]tetralin (8-MeO-N-PBAT) coupled to Affigel 202 was specially developed for this purpose. First, studies of the effects of various compounds (detergents, lipids, reducing agents, sugars, etc.) on the specific binding of [3H]8-OH-DPAT and on the rate of heat-induced inactivation of solubilized 5-HT1A sites led to a buffer composed of 50 mM Tris-HCl, 50 microM dithiothreitol, 1 mM CHAPS, 10% glycerol, 0.1 mM MnCl2, and 50 micrograms/ml of cholesteryl hemisuccinate, pH 7.4, ensuring a high degree of stability of solubilized 5-HT1A sites, compatible with chromatographic analyses for 2-4 days at 4 degrees C. Adsorption and subsequent elution of [3H]8-OH-DPAT specific binding sites were found with several chromatographic gels, including wheat germ agglutinin-agarose, phenyl-Sepharose, hydroxylapatite-Ultrogel, diethylaminoethyl (DEAE)-Sepharose, and DEAE-Sephacel. Similarly, 8-MeO-N-PBAT-Affigel 202 allowed the adsorption and subsequent elution (by 1 mM 5-HT) of active 5-HT1A binding sites solubilized from rat hippocampal membranes. The two-step chromatography using 8-MeO-N-PBAT-Affigel 202 followed by wheat germ agglutinin-agarose gave a fraction enriched (by at least 400-fold) in 5-HT1A sites. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of this partially purified fraction revealed a major protein band with Mr close to 60,000.
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PMID:Chromatographic analyses of the serotonin 5-HT1A receptor solubilized from the rat hippocampus. 252 52

The present study assessed the functional integrity of the serotonin (5-HT) presynaptic receptor in the spinal cord of aged (18-20 months) rats. Previous research determined that exogenous 5-HT and 5-HT1B agonists, in adult (3 months) rats, activated the 5-HT presynaptic receptor resulting in a dose-dependent decrease in 3H-5-HT release from spinal cord slices. Contrastively, exogenous 5-HT and the selective 5-HT1B agonist 1-(m-chlorophenyl) piperazine HCl (mCPP) produced a dose-dependent increase in depolarization-evoked 3H-5-HT release from spinal cord of aged rats. The selective 5-HT1A agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT) increased 3H-5-HT release from aged rat spinal cord slices similar to results previously obtained from adult rat spinal cord slices. The inability of 5-HT and mCPP to inhibit 3H-5-HT release from spinal cord of aged rats indicates a functional change in the 5-HT presynaptic receptor in these animals. Possible mechanisms mediating this functional change are discussed.
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PMID:Functional change in the 5-HT presynaptic receptor in spinal cord of aged rats. 254 73

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.
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PMID:(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain. 279 4

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.
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PMID:Agonist activation of 5-HT1A receptors in the median raphe nucleus and female rat lordosis behavior. 770 14

The role of brain amines, possibly involved in psychological stress, was evaluated and we postulate that the 5-hydroxytryptamine 5-HT3 receptors in the central nervous system are involved in the gastric lesion formation by psychological stress. The stress was in a communication box paradigm, in which each nonshocked mouse (responder) was placed in a Plexiglas compartment adjacent to mice receiving electrical shocks (sender). The responder mice revealed rather depressed gastric secretion, but developed gastric lesions which are significantly attenuated by pretreatment of dl-p-chlorophenylalanine methyl ester:HCl (PCPA; 200-400 mg/kg p.o.), but not 6-hydroxydopamine (6-OH-DA; 60 micrograms/body i.c.v. or 80 mg/kg i.p. 1 hr after a 20-mg/kg i.p. dose of desipramine). Oral treatment with GR38032F (0.01-1 mg/kg), ICS205-930 (0.01-20 mg/kg), MDL72222 (0.01-1 mg/kg), metoclopramide (0.1-100 mg/kg), ketanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose-dependently attenuated the psychological stress lesion formation, and the activity was arranged in the order of their in vitro binding affinities for the 5-HT3, but not 5-HT1A or 5-HT2 receptors. In contrast, a peripherally acting 5-HT3 antagonist, M-840 ([[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5- yl]-methyl]trimethyl-ammonium iodide), dopamine acting compounds, haloperidol and FR64822 [N-(4-pyridylcarbamoyl)amino-1,2,3,6- tetrahydropyridine), and antisecretory drugs, atropine and famotidine, minimally affected the lesion formation.
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PMID:A mechanism of 5-HT3 receptor mediation is involved etiologically in the psychological stress lesion the stomach of the mouse. 796 2

SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors. 801 40

Pre-exposure to 5-hydroxytryptamine (5-HT) receptor agonists in conditioned taste aversion experiments was used to characterize the stimulus properties of fluoxetine. The taste aversion induced by fluoxetine (10 mg/kg) was completely prevented when mice were pre-exposed to fluoxetine or when they were pre-exposed to the preferential 5-HT1C receptor agonist MK 212. Pre-exposure to MK 212 also prevented the conditioned taste aversion induced by another serotonin uptake inhibitor, paroxetine. A partial attenuation of fluoxetine-induced conditioned taste aversion was seen after pre-exposure to a high dose of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1 mg/kg), but not to lower doses. No familiarization for the fluoxetine stimulus was obtained by pre-exposure to treatments with the mixed 5-HT1C/2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). With the reversed sequence, pre-exposure to fluoxetine prevented the conditioned taste aversion induced by MK 212 or 8-OH-DPAT and reduced that induced by DOI. It is concluded that the acute stimulus properties of fluoxetine mostly resemble those of a 5-HT1C receptor agonist. This supports the suggestion that the 5-HT1C receptor can play an important role in the therapeutic effect of 5-HT reuptake inhibitors.
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PMID:Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure. 801 51

The effects of chronic administration of desipramine, citalopram, and electroconvulsive shocks (ECS) on changes in rat motility after intraaccumbens (NAS) injections of selective serotonergic drugs were studied in intact and 5.7-DHT lesioned animals. It was shown that local injections of 8-OHDPAT and DOI-HCl depressed rat locomotor activity. Their effects appeared to be mediated postsynaptically, and could be antagonized by NAN-190 and ritanserin, respectively. Chronic but not acute pretreatment of rats with antidepressants (21 days long; the experiment was performed 24 h after the last dose) as well as repeated ECS (shocks were applied five times every second day), antagonized behavioral depression after 8-OHDPAT and DOI-HCl. The influence of antidepressant treatment was prevented by serotonergic lesions. Chronic administration of antidepressants and ECS did not equivocally affect the levels or metabolism of 5-HT, dopamine, and noradrenaline in the rat limbic forebrain. It is concluded that the present data indicate diminished activity of 5-HT systems related to the 5-HT1A and 5-HT2 receptors in the limbic nucleus, after chronic antidepressant treatment. This effect of drugs and ECS concerns nervous processes linked with the function of postsynaptically localized 5-HT receptor subtypes, and it probably depends on intact presynaptic 5-HT innervation.
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PMID:Antidepressant treatment and limbic serotonergic mechanisms regulating rat locomotor activity. 809 Jul 97

The purpose of the present study was to investigate the effect of microinjection of serotonin (5-HT) and selected 5-HT receptor subtype agonists and antagonists into the caudal nucleus raphe obscurus on gastrointestinal motor activity in urethane-chloralose anesthetized rats. Serotonin (0.6-18.0 nmol) dose-dependently increased intragastric pressure, and this effect was abolished by peripherally administered atropine (0.5-1.0 mg/kg, i.v.). Microinjection of a 5-HT1A receptor agonist, 8-hydroxy-N,N-dipropyl-2-amino-tetralin hydrobromide (0.06-12.0 nmol), a 5-HT1C/2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (4.5 and 18.0 nmol), as well as a 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide hydrochloride (0.6-18.0 nmol), also resulted in increases in intragastric pressure. The gastric excitatory effect of 5-HT (6.0 nmol) was markedly reduced by prior microinjection of a 5-HT1/2 receptor antagonist, methiothepin (200 nmol), into the same site, as well as by i.v. administration of a 5-HT2/1C antagonist, ketanserin (2.5 mg/kg). The effect of 5-HT (6.0 nmol) on intragastric pressure was completely blocked by i.v. administration of a mixture of the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazinehydrobromide++ + (3.5 mg/kg), ketanserin (2.5 mg/kg) and the 5-HT3 receptor antagonist 3-tropanyl-3,5-dichlorobenzoate (2.5 mg/kg). These results indicate that 5-HT activates gastric motor function in the caudal nucleus raphe obscurus via a vagally mediated pathway and that the activation of multiple 5-HT receptor subtypes is required for the gastric excitatory effect of 5-HT.
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PMID:Serotonin microinjected into the nucleus raphe obscurus increases intragastric pressure in the rat via a vagally mediated pathway. 809 47


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