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)

Drugs with different intrinsic activity at 5-HT1A receptors and antagonists at 5-HT2A/2C and 5-HT3 receptors were studied for their ability to increase the rates of punished operant responding in rats. Like chlordiazepoxide (5 and 10 mg/kg) and diazepam (1.25 and 2.5 mg/kg), 0.125 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and 5 and 10 mg/kg ipsapirone, a partial agonist at these receptors, increased the rates of punished responding, whereas (S)-WAY 100135, a 5-HT1A receptor antagonist, had no effect at doses from 1 to 10 mg/kg. 8-OH-DPAT and ipsapirone, like benzodiazepines, significantly reduced unpunished responding. The 5-HT2A/2C receptor antagonists ritanserin (2 mg/kg), mianserin (8 mg/kg), and mesulergine (0.1 mg/kg) significantly increased the rates of punished responding, whereas 0.5-2 mg/kg ketanserin, that has higher affinity for 5-HT2A than 5-HT2C receptors, had no effect. Antagonists, at 5-HT3 receptors such as ondansetron (0.001-0.1 mg/kg) and tropisetron (0.001-0.1 mg/kg), had no effect on punished or unpunished responding. The results show that agents acting as full or partial agonists at 5-HT1A receptors and blockers of postsynaptic 5-HT2C receptors have anxiolytic-like effects in a model of punished operant responding, whereas antagonists at 5-HT1A and 5-HT3 receptors have no such effect.
 ...
PMID:5-HT1A receptor full and partial agonists and 5-HT2C (but not 5-HT3) receptor antagonists increase rates of punished responding in rats. 858 3

Various models of rodent agonistic behavior are described, which differentiate between offensive and defensive/flight models. Particular attention is given to one male and one female paradigm for offensive aggression, i.e. resident/intruder or territorial aggression (RI) and maternal aggression (MA). After an overview of the serotonin (5-HT) system in the CNS, a description is given of the ligands available. Subsequently, the effects of various drugs affecting serotonergic transmission in the RI- and MA-paradigms are described. The 5-HT1A receptor agonists busipirone, ipsapirone, and 8-OH-DPAT decreased aggression in RI and MA, but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific antiaggressive profile. Nonselective 5-HT1 receptor agonists, such as RU24969, eltoprazine, and TFMPP reduced aggression quite specifically, did not decrease social interest or exploration, and sometimes even increased these behaviors. In RI and MA, the behavioral effects of these drugs were roughly similar. In contrast, MA was more sensitive to treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression nonspecifically at the highest dose only. DOI, a 5-HT2A/2C# receptor agonist, decreased aggressive behavior and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by "wet dog shaking" characteristic of 5-HT2 receptor stimulation. The nonspecific 5-HT receptor agonist (and 5-HT2 receptor antagonist) quipazine also induced "wet dog shaking" at doses which suppressed aggression, social interest, and exploration but increased inactive behaviors (sitting and lying). The discussion delineates a specific role for 5-HT1B receptor-subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs, and this fact underlines the consistent role of 5-HT in different forms of aggression.
 ...
PMID:Serotonin receptors and animal models of aggressive behavior. 861 5

Effects of 5-HT receptor agonists (8-OH-DPAT, DOI and mCPP) on the binding parameters of corticosteroid receptors in the hippocampus of adult rats were studied. Glucocorticoid (GR) and mineralocorticoid (MR) receptors were examined by an in vitro [3H]corticosterone binding in cytosol, using the selective GR agonist RU 28362 to discriminate between MR and GR. Treatment with 8-OH-DPAT and mCPP given for 7 but not 1 days increased the density of MR. None of the compounds under investigation influenced the density of GR or the affinity of MR and GR in the rat hippocampus. Our results suggest that, in contrast to the postnatal period, the 5-HT1A and/or 5-HT2C, but not 5-HT2A, receptor is mainly involved in the regulation of MR in adult rats.
 ...
PMID:Role of the serotoninergic system in the regulation of glucocorticoid and mineralocorticoid receptors in the rat hippocampus. 861 8

We characterized the role of endogenous serotonin (5-HT) in regulating in vivo acetylcholine (ACh) output in frontal cortex of freely moving rats using the microdialysis technique. Systemic (0.63, 1.25 and 2.5 mg/kg, i.p.) or local (20 and 40 microM, reverse dialysis) administration of the 5-HT releaser and uptake inhibitor, d-norfenfluramine, dose-dependently enhanced frontal cortex ACh output. The d-norfenfluramine-induced increase in cortical ACh release was tetrodotoxin sensitive and completely prevented by a 7-day chemical degeneration of the serotonergic afferents to the frontal cortex. Investigating the 5-HT receptors that might mediate the d-norfenfluramine cholinergic effect, we found that the 5-HT4 (GR 125487) and 5-HT2A/2C (ritanserin) receptor antagonists, at doses effective in other in vivo tests, did not prevent the increase in cortical ACh output induced by the maximal effective does of d-norfenfluramine. However, the 5-HT1A/1B receptor antagonists (-)-pindolol (8 mg/kg, s.c.) or (-)-propanolol (8.8 mg/kg, i.p.) antagonized the increasing effect of d-norfenfluramine although the selective 5-HT1A receptor antagonist WAY-100635 (1 and 2 mg/kg, s.c.) did not. In accordance with an involvement of the 5-HT1B receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT1B agonist, CP-93,129, given locally (2, 4 and 8 micrograms/side) does-dependently raised cortical ACh release. In conclusion, the overall regulatory control exerted by endogenous 5-HT in vivo is to facilitate frontal cortex ACh release through 5-HT1B receptors located in the frontal cortex. The 5-HT1B receptors may act indirectly to facilitate ACh release probably by inhibiting cortical inhibitory inputs onto the cholinergic neurons.
 ...
PMID:Endogenous serotonin facilitates in vivo acetylcholine release in rat frontal cortex through 5-HT 1B receptors. 862 64

A conflict procedure in pigeons was used to characterize the antipunishment effects of the putative mixed 5-hydroxytryptamine (5-HT)1A agonist/5-HT2A/2C antagonists WY 50,324, CGS 18102A, LEK 8804 and FG 5974 and to further investigate interactions between the antipunishment effects of the 5-HT1A agonists buspirone and 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] administered in combination with the mixed 5-HT2A/2C antagonist ritanserin and the alpha 1 antagonist prazosin. The 5-HT1A agonists, buspirone and 8-OH-DPAT, which lack affinity for 5-HT2A/2C receptors, produced dose-related increases in punished responding. Of the compounds with a mixed binding profile, only WY 50,324 showed effects that were comparable to those observed after 8-OH-DPAT, whereas FG 5974 and CGS 18102A exhibited limited effects on punished responding, and LEK 8804 was ineffective. Administration of a relatively low, behaviorally active dose of ritanserin (0.16 mg/kg) significantly enhanced the potency of 8-OH-DPAT and buspirone to increase punished responding from 8 to 50-fold without altering their effects on unpunished responding. Importantly, ritanserin failed to increase the number of doses of 8-OH-DPAT that significantly increased punished responding. In contrast, prazosin (2.5 mg/kg) significantly enhanced the potency and increased the number of doses of buspirone exerting significant effects on punished responding, but did not alter the effects of 8-OH-DPAT. Taken together, the results neither explain the suggested greater efficacy in producing anxiolytic effects of compounds with putative mixed 5-HT1A agonist and 5-HT2A/2C antagonist properties, nor confirm a proposed interaction between alpha1 adrenoreceptors and 5-HT1A agonists in preclinical tests of anxiolytic activity.
 ...
PMID:Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT2A/2C antagonist anxiolytics. I. Antipunishment effects in the pigeon. 863 1

Hormonal responses to challenge with the 5-HT2A/2C probe d-fenfluramine and hormonal and thermal responses to challenge with the 5-HT1A probe ipsapirone were correlated with self-report and historical assessments of aggression in a pilot sample of eight male personality-disordered individuals. Prolactin responses to d-fenfluramine and cortisol responses to ipsapirone challenge were inversely correlated with self-reported assaultiveness. Thermal responses to ipsapirone were inversely correlated with a historical assessment of aggression. Since none of these physiological indices of 5-HT system function were intercorrelated, it is possible that simultaneous assessment of these 5-HT indices may yield a more comprehensive assessment of the relationship between central 5-HT system function and aggressive behavior in humans.
 ...
PMID:Physiological responses to d-fenfluramine and ipsapirone challenge correlate with indices of aggression in males with personality disorder. 867 71

Previous results from our laboratory indicate that serotonin (5-HT) potentiates pain produced by other inflammatory mediators. To characterize the receptor subtype(s) mediating this synergistic effect of 5-HT, selective 5-HT agonists were injected, alone or with noradrenaline (NA) or prostaglandin E2 (PGE2), into the plantar surface of the paws of rats. The behavioural response (favouring, elevation and licking the paw) was recorded using the rating scale developed to quantify formalin-induced pain. The 5-HT1A and 5-HT3 agonists, 8-OH-DPAT and 2-methyl-5-HT, respectively, produced only transient responses by themselves and did not interact with PGE2 or NA. The 5-HT2 agonists, alpha-methyl-5-HT and DOI, also produced transient responses alone, but induced lifting and licking of the injected paw lasting more than 30 min when combined with PGE2 or NA. The lifting and licking response produced by 5-HT plus PGE2 was not altered by intraplantar pretreatment with the 5-HT1A and 5-HT3 antagonists, BMY 7378 and tropisetron, but was attenuated by the 5-HT2A/2C antagonist ketanserin. The pain response produced by alpha-methyl-5-HT plus PGE2 was blocked by pretreatment with the 5-HT2A/2C antagonists ketanserin and ritanserin, and the 5-HT2A antagonist spiperone (MPE50 values 1.4, 7.7 and 0.06 nmol, respectively). The second phase of the response to intraplantar formalin was also attenuated by ketanserin, ritanserin and spiperone (MPE50 values 11.3, 21.8 and 0.23 nmol, respectively). These data imply that 5-HT2A antagonists may be effective peripherally acting analgesics or analgesic adjuncts in pain associated with 5-HT release from platelets, such acute injury and, perhaps, some chronic pain states.
 ...
PMID:Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators. 868 2

In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.
 ...
PMID:Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium. 869 81

Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoal kanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]-8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, 1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-am inopropane (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [125I]DOI and [3H]ketanserin binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED50 of 61 nmol/kg and had Kj values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these new analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT2 receptors.
 ...
PMID:Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. 870 29

1. The decerebrate cat preparation with an intact spinal cord is characterized by a high degree of excitability in extensor motoneuron pools, which is eliminated by acute spinalization. Subtype-specific agonists for serotonin (5-HT) were investigated in terms of their effectiveness in restoring the extensor excitability following spinalization. 2. Our hypothesis was that 5-HT2 receptors have the primary role in enhancement of extensor reflex excitability, whereas 5-HT1A and 5-HT1B/D receptors are relatively unimportant. Reflex excitability was assessed from the tonic levels of force and electromyographic (EMG) output from the ankle extensors medial gastrocnemius (MG) and soleus (SOL), and from the reflex forces in both these muscles generated by ramp-and-hold stretches of MG. 3. Before spinal transection, MG and SOL usually exhibited a small amount of tonic background EMG activity and force output. Ramp-and-hold stretch of MG generated a large-amplitude reflex response. Spinal transection at the level of T10 virtually abolished tonic background activity in both extensors and greatly attenuated the MG stretch reflex. Ventral topical application of the selective 5-HT2A/2C agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane hydrochloride (DOI) restored the amplitude of the MG stretch reflex in a dose-dependent fashion. However, a considerable portion of the DOI-mediated restoration of MG stretch reflex force was due to elevation of tonic background force levels above previous intact cord levels. 4. The DOI-induced increase in extensor tonic background excitability and facilitation of MG stretch reflex were reversed by ventral topical administration of the selective 5-HT2 antagonist ketanserin. No increase in extensor excitability was observed in spinalized preparations after administration of either the 5-HT1A agonist (+-)-8-hydroxy-dipropylaminotetralin hydrobromide or the 5-HT1B/1D agonist 7-trifluoromethyl-4-(4 methyl-1-piperazinyl)-pyrrolo[1,2- a]quinoxaline maleate. These data strongly suggest that the DOI-induced facilitation of extensor stretch reflex and tonic activity in spinalized preparations is mediated through an action on spinal 5-HT2 receptors. 5. One important difference between the actions of DOI in spinalized versus intact states was that the DOI-induced tonic and reflex forces in the spinalized state were subject to irregular oscillations. In contrast, DOI did not noticeably affect the smoothness of reflex force generation in the intact state. This discrepancy was probably due to the effects of clasp knife inhibition from muscular free nerve endings, which have potent reflex actions in the spinalized but not intact states. Thus DOI elevated excitability levels but did not alter the effects of spinalization on stretch reflex patterns.
 ...
PMID:Restoration of extensor excitability in the acute spinal cat by the 5-HT2 agonist DOI. 871 39


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