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)

(-)-LY293284, (-)-4R-6-acetyl-4-(di-n-propylamino)1,3,4,5- tetrahydrobenz[c,d]indole, is a conformationally restricted tryptamine derivative with an acetyl group serving as a protophilic substitution for the hydroxyl in serotonin (5-HT). In ligand displacement studies, LY293284 had a Ki of 0.07 nM for the 5-HT1A receptor but no affinity for other monoaminergic receptors within 3 orders of magnitude. LY293284 was evaluated in in vivo models, which have been used as markers for presynaptic and postsynaptic 5-HT1A receptor activity. LY293284 decreased hypothalamic 5-hydroxyindoleacetic acid levels (ED50, 2.9 micrograms/kg s.c.) and dorsal raphe serotonergic neuron firing rate (ED50, 0.08 micrograms/kg s.c.), which are accepted indices of presynaptic activity. LY293284 also induced a reduction in body temperature in rats (ED50, 3.6 micrograms/kg s.c.), which was blocked by pretreatment with (+/-)-pindolol. Hypothermic responses of rats to 5-HT1A agonists have had both pre- and postsynaptic characteristics in previous studies. The ED50 values for 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in these tests were 15 to 45 times higher than those observed for LY293284. In models for postsynaptic activity, the ED50 for LY293284 for elevating serum corticosterone levels was 9.7 micrograms/kg s.c. and the minimum effective doses to induce lower lip retraction and flat posture were 3 micrograms/kg s.c. For comparison, the same indices obtained for 8-OH-DPAT were 222.4 and 100 micrograms/kg, respectively. The 5-HT syndrome responses induced by LY293284 were also attenuated by pretreatment with (+/-)-pindolol. LY293284 was 10 times more potent than 8-OH-DPAT in a drug discrimination test that used pigeons trained to identify 8-OH-DPAT. In sexual behavior tests with male rats, LY293284 induced a maximal reduction in ejaculatory latency at 0.01 micrograms/kg s.c., which was approximately 10 times higher potency than 8-OH-DPAT. In the pigeon conflict model for anxiolytic activity, LY293284 was 100 times more potent than 8-OH-DPAT in increasing punished responding. In the rat forced swim model for antidepressant-like activity, LY293284 was 30 and 35 times more potent than 8-OH-DPAT in decreasing immobility time and defecation rate. These studies have demonstrated that LY293284 is a highly selective and extremely potent 5-HT1A receptor agonist and represents a useful pharmacological tool for studying 5-HT1A receptor-mediated effects.
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PMID:Pharmacological characterization of LY293284: A 5-HT1A receptor agonist with high potency and selectivity. 752 57

The effects of intracerebroventricular administration of the 5-hydroxytryptamine (5-HT)1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 pmol) on adrenocortical and neurochemical responses to stress were examined in conscious male rats. The following stress paradigms were used: acoustic stimulation (105 dB for 2 min); footshock (0.2 mA, five shocks over 5 min); conditioned fear (animals placed in a footshock chamber for 5 min, 24 h after footshock); restraint (5 min); intraperitoneal (i.p.) injection of recombinant human interleukin-1 alpha (rHu-IL-1 alpha, 20 micrograms/kg); and injection of cocaine hydrochloride (20 mg/kg, i.p.). As previously shown, 8-OH-DPAT was able to attenuate the adrenocortical response to acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration. Cocaine decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios and norepinephrine (NE) concentration in the prefrontal cortex, hypothalamus, and brainstem in all experiments, and 8-OH-DPAT reversed the changes in DOPAC/DA ratio without affecting 5-HIAA/5-HT ratios or NE content. 8-OH-DPAT alone had no effect on these parameters, although it decreased NE content in the prefrontal cortex in several experiments, and in the brainstem in one experiment. Significant decreases in NE content were observed in some brain regions following some of the stressors, but these changes were not generally affected by 8-OH-DPAT. Increases in the 5-HIAA/5-HT and DOPAC/DA ratios were also observed in some brain sites following some stressors, but these changes were not affected by 8-OH-DPAT except in the case of the increased 5-HIAA/5-HT ratio in the prefrontal cortex following the conditioned fear response. These results indicate that although 8-OH-DPAT is able to decrease plasma corticosterone responses following acoustic stress, conditioned fear, rHu-IL-1 alpha, and cocaine administration, these effects do not appear to be related to an action of the 5-HT1A agonist on biogenic amine metabolism. This observation indicates that the predominant effect of 8-OH-DPAT on adrenocortical responses is mediated at postsynaptic sites not involved in the regulation of cerebral biogenic amine metabolism.
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PMID:Effects of the serotonin1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin on neurochemical responses to stress. 753 Feb 93

Mature (3-4 months) and aged (18-19 months) Sprague-Dawley (SD) rats were treated with 5-HT receptor agonists and drug-induced behaviours monitored. The 5-HT2/1C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), induced wet dog shakes and back muscle contractions which were significantly increased in aged, compared to mature, rats, suggesting an age-related enhancement of 5-HT2 receptor function. In contrast, the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) induced forepaw treading, flat body posture, hypothermia and hyperactivity which were not significantly different in aged compared to mature rats. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and frontal cortex were measured using high performance liquid chromatography with electrochemical detection. There were no age-related changes in hippocampal 5-HT or 5-HIAA. However both 5-HT and 5-HIAA were increased in the frontal cortex of aged SD rats. 8-OH-DPAT reduced 5-HIAA in both regions examined in mature rats, an effect which was attenuated in the aged rats, suggesting an age-related reduction in presynaptic 5-HT1A receptor function. DOI did not induce any changes in 5-HT or 5-HIAA in either of the regions examined. Radioligand binding studies with [3H] ketanserin showed there to be no significant age-related changes in cortical 5-HT2 receptor density or affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Age-related behavioural, neurochemical and radioligand binding changes in the central 5-HT system of Sprague-Dawley rats. 753 51

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3- pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent (Ki = 51 nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT1A,1D,2A and 2C receptors at a concentration of 10 microM. 680C91 had no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of L-[ring-2-14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C91, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.
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PMID:The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat. 753 65

Effects of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.04, 0.25, or 1.0 mg/kg), on hypothalamic serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and their ratio were determined in adult male rats and in diestrous, proestrous, and estrous female rats. Consistent with its action at the somatodendritic 5-HT1A autoreceptor, 8-OH-DPAT decreased the 5-HIAA/5-HT ratio, but the decrease was least evident in proestrous females and in males. Similar to hypothalamic tissue, there was also a decline in the 5-HIAA/5-HT ratio in the hippocampus after treatment with 0.25 mg/kg 8-OH-DPAT. When ovariectomized rats were treated with oil or estradiol benzoate followed 48 h later by oil or progesterone, 0.25 mg/kg 8-OH-DPAT produced a decrease in the hypothalamic 5-HIAA/5-HT ratio in every group except those rats treated with progesterone without estrogen priming. Treatment with estradiol benzoate increased hypothalamic 5-HIAA, and both progesterone and 8-OH-DPAT reduced the metabolite to the level of the ovariectomized control. These results suggest that both estrogen and progesterone contribute to an estrous cycle modulation of the 5-HT1A somatodendritic autoreceptor.
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PMID:Gender and estrous cycle effects of the 5-HT1A agonist, 8-OH-DPAT, on hypothalamic serotonin. 754 20

This laboratory previously demonstrated that in utero ethanol exposure markedly impairs the development of the serotonergic system in rat brain. Developmental abnormalities could be detected as early as G15 in the brainstem and G19 in the cortex. Because of the importance of fetal serotonin (5-HT) and 5-HT1A receptors for the normal development of 5-HT containing neurons, we initiated studies to determine whether administration of a 5-HT1A agonist, buspirone, to pregnant rats could overcome the adverse effects of in utero ethanol exposure on the developing serotonergic system in offspring. Female, Sprague-Dawley rats were given daily subcutaneous injections of buspirone (4.5 mg/kg) from gestational day 13 (G13) to G20. 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content were determined in the cortex and cortical regions. These experiments demonstrated that the ethanol-associated abnormalities in the development of the serotonergic system can be partially overcome by in utero exposure to buspirone. Specifically, whereas untreated ethanol rats had a deficiency of 5-HT and/or 5-HIAA in whole cortex on PN5, and in the motor cortex on PN19 and 35, no significant differences were detected in these regions of the age-matched offspring of buspirone-treated, ethanol-fed rats. In contrast, the 5-HT and 5-HIAA deficiency in the somatosensory cortex of 19-day-old offspring of ethanol-fed rats was not corrected by in utero buspirone treatment. These results suggest that the abnormal development of cortical projections of serotonergic neurons may be due in part to the low fetal 5-HT content in ethanol-exposed rats and may potentially be overcome by in utero treatment with a 5-HT1A agonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of pregnant alcohol-consuming rats with buspirone: effects on serotonin and 5-hydroxyindoleacetic acid content in offspring. 768 Aug 41

The characteristics of the serotonin (5-HT) output in the dorsal and median raphe nuclei of the rat were studies using in vivo microdialysis. The basal output of 5-HT increased after KCl was added to the perfusion fluid. In contrast, neither the omission of calcium ions nor the addition of 0.5 microM tetrodotoxin affected dialysate 5-HT or 5-hydroxyindoleacetic acid (5-HIAA). Reserpine did not decrease the output of 5-HT and 5-HIAA 24 h later and p-chloroamphetamine increased 5-HT in both vehicle- and reserpine-treated rats severalfold. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at 1 or 10 microM, perfused into the raphe did not change the outputs of 5-HT or 5-HIAA. Higher doses (0.1, 1, and 10 mM) increased extracellular 5-HT in the raphe, probably via an inhibition of uptake. In animals bearing two probes (raphe nuclei and ventral hippocampus), only the 10 mM dose of 8-OH-DPAT perfused into the raphe decreased the hippocampal output of 5-HT and 5-HIAA. The systemic injection of 0.1 mg/kg 8-OH-DPAT decreased dialysate 5-HT and 5-HIAA in the raphe and hippocampus. These results suggest that extracellular 5-HT in raphe nuclei originates from a cytoplasmic pool and is not dependent on either nerve impulse of 5-HT neurons or local activation of 5-HT1A receptors.
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PMID:In vivo brain dialysis study of the somatodendritic release of serotonin in the Raphe nuclei of the rat: effects of 8-hydroxy-2-(di-n-propylamino)tetralin. 768

The effects of conditioned fear stress (CFS), an animal model of anxiety, on brain dopamine (DA) and serotonin (5-HT) metabolism and behavior were investigated in rats. CFS (exposure to an environment paired previously with footshock) after single footshock stress increased plasma corticosterone levels and defecation, and induced freezing behavior. It also increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the medial prefrontal cortex (mPFC), paraventricular nucleus of the hypothalamus (PVH) and lateral hypothalamus, increased homovanillic acid (HVA) levels in the mPFC and amygdala, and increased 5-hydroxyindoleacetic acid (5-HIAA) level in the mPFC. Rats exposed to the stress for 10 days displayed enhanced freezing induced by CFS compared to rats given only one footshock session, according to the augmentation of fear. CFS after repeated footshock increased DOPAC levels in all seven brain regions and HVA levels in the mPFC, nucleus accumbens, amygdala and hippocampus. It also increased 5-HIAA levels in the mPFC and PVH. Thus, it was deduced that CFS after repeated footshock activated DA and 5-HT metabolism not only in the mPFC but also in other various brain regions, whereas increased metabolism of both DA and 5-HT was marked in the mPFC after CFS following a single footshock. In behavioral pharmacological experiments, the effects of various serotonergic agents and diazepam on CFS-induced freezing behavior were examined. The benzodiazepine diazepam (1mg/kg) and the selective 5-HT1A agonist ipsapirone (0.5-10mg/kg) significantly reduced freezing. The augmentation of 5-HT activity by the 5-HT precursor (L-5-HTP) and the selective 5-HT reuptake inhibitor (citalopram) also attenuated freezing. The 5-HT synthesis inhibitor PCPA failed to change freezing. In conclusion, these results suggest that the anxiolytic effect of ipsapirone results from the activation of postsynaptic 5-HT1A receptors and the facilitation of 5-HT neurotransmission decreases anxiety. This model may be useful for detecting the anxiolytic potential for drugs and examining the relationship of 5-HT to anxiety.
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PMID:[Effects of conditioned fear stress on monoaminergic systems in the rat brain]. 768 27

In the present paper, the effect of different stressors on extracellular 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the frontal cortex and the N. raphe dorsalis (NRD) of the rat were studied. The following stressful procedures were used: Immobilization, 10 min, cold, 20 min, and forced exercise in a rotating wheel, 2h. These procedures were compared with a handling procedure, 10 min. The extracellular 5-HIAA concentration was followed by in vivo voltammetry with carbon multifibre electrodes in the awake animal. Handling had no significant effect on extracellular 5-HIAA concentrations neither in the frontal cortex nor the NRD, whereas immobilization and cold evoked significant increases in both brain areas. During and after forced exercise a significant increase was measurable only in the frontal cortex, while extracellular 5-HIAA concentrations were unchanged in the NRD. Since it is very likely that the modulation of the activity of the central serotoninergic system under stressful conditions is closely connected with changes in behaviour and temperature regulation, we compared our findings on extracellular 5-HIAA levels during stress with the effect of the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), a substance known to reduce body temperature. The i.p. injection of a low dose decrease significantly both, the extracellular 5-HIAA concentration in the NRD and body temperature. Our results suggest that the serotoninergic activation in the frontal cortex may prove to be a general response to stress which could function perhaps as a part of the central coping mechanism, whereas serotonin (5-HT) in the NRD may modulate specific regulatory responses such as body temperature.
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PMID:Stress-induced changes of extracellular 5-hydroxyindoleacetic acid concentrations followed in the nucleus raphe dorsalis and the frontal cortex of the rat. 768 45

The two diphenylbutylpiperazinepyridinyl derivatives, FG5865 and FG5893, have a unique receptor binding profile in that they show very high and essentially equipotent affinities for both 5-HT1A and 5-HT2 receptors. The present report describes the acute effects of FG5865 and FG5893 on presynaptic 5-hydroxytryptamine (5-HT) neuronal function in the rat CNS, using established ex vivo and in vivo neurochemical techniques. Post-mortem measurements of tissue levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and of the formation of 5-hydroxytryptophan (5-HTP; after inhibition of aromatic amino acid decarboxylase by NSD 1015) showed that FG5865 (0.1-20 mg/kg, s.c.) and FG5893 (0.1-20 mg/kg, s.c.) dose dependently decreased the synthesis and the metabolism/turnover of 5-HT--this to an extent comparable to the reference 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Reserpine (5 mg/kg, s.c.) pretreatment did not prevent the FG5893-induced decrease of 5-HT synthesis rate. In contrast, about 25-50 times higher doses of FG5865 were required to produce a comparable decrease in brain 5-HT synthesis in reserpinized vs. non-pretreated rats. In in vivo microdialysis experiments, both FG5865 (0.1-3.0 mg/kg, s.c.) and FG5893 (0.03-1.0 mg/kg, s.c.) caused a marked and dose-dependent decrease of 5-HT release in the ventral hippocampus. Pretreatment with the 5-HT1A receptor antagonist, (+/-)-pindolol (8 mg/kg, s.c.), abolished the FG5865 (0.3 mg/kg, s.c.)-induced reduction of 5-HT release, and (-)-pindolol (8 mg/kg, s.c.) similarly reversed the FG5893 (0.3 mg/kg, s.c.)-induced decrease. Local infusion of FG5865 into the ventral hippocampus (10 microM, 20-min pulse) resulted in a rapid and transient elevation of the 5-HT output, an effect that was independent of extracellular Ca2+. FG5893, on the other hand, did not affect the 5-HT release upon local administration. The results demonstrate that FG5865 and FG5893 potently affect a range of neurochemical indices of rat brain 5-HT neuronal activity in vivo, in a way consistent with indirect (FG5865) and direct (FG5865 and FG5893) stimulation of the 5-HT1A autoreceptors in the raphe nuclei.
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PMID:5-HT1A autoreceptor-mediated effects of the amperozide congeners, FG5865 and FG5893, on rat brain 5-hydroxytryptamine neurochemistry in vivo. 769 22


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