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)

The effects of the selective 5-HT1A agonists 8-OH-DPAT and flesinoxan and the selective 5-HT2 antagonists ritanserin and ketanserin on immobility time in rats bred for predisposition to catalepsy have been studied. Treatment with 8-OH-DPAT as well as flesinoxan caused a marked dose-dependent decrease in immobility time. Ritanserin and ketanserin did not affect immobility time at any dose tested. It was suggested that 5HT1A rather than 5-HT2 serotonin receptors are involved in the catalepsy and that an hereditary predisposition to catalepsy may be the result of an inherited alteration in 5-HT1A receptors.
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PMID:Effect of selective 5-HT1A agonists and 5-HT2 antagonists on inherited catalepsy in rats. 784

The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.
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PMID:Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist. 796 8

Intracellular recordings were made from neurons of the nucleus prepositus hypoglossi in slices of guinea pig medulla. 5-HT (serotonin) caused a hyperpolarization followed by a late depolarization. The hyperpolarization was mediated by 5-HT1A receptor activation and could be selectively blocked by pindobind-5HT1A (PBD). 5-HT then caused a depolarization only. A selective 5-HT2 agonist, (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), also caused a depolarization. Ketanserin and spiperone, 5-HT2 antagonists, blocked the depolarization due to both 5-HT and DOI. Focal electrical stimulation caused an IPSP mediated by 5-HT acting upon 5-HT1A receptors and a slow EPSP (s-EPSP). PBD blocked the IPSP, leaving an isolated s-EPSP. Both spiperone and ketanserin antagonized the s-EPSP, while DOI occluded it. The s-EPSP was from 2 to 10 mV in amplitude and 35-50 sec in duration, and showed voltage dependence consistent with a decrease in potassium conductance. Both the IPSP and the s-EPSP were presynaptically inhibited by the 5-HT1D agonist sumatriptan. These data indicate that the s-EPSP is mediated by 5-HT acting upon 5-HT2 receptors. This represents strong support for the role of 5-HT as an excitatory neurotransmitter in the CNS. Further, it demonstrates that synaptic release of 5-HT can mediate opposing effects on the membrane potential of a single cell.
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PMID:A slow excitatory postsynaptic potential mediated by 5-HT2 receptors in nucleus prepositus hypoglossi. 815 79

The clinical discoveries that drugs that stimulate 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly, have antidepressant properties has stimulated interest in defining the role of the 5-HT receptor system in the clinical effects of antidepressant drugs. Two approaches are reviewed in this paper that address the neurochemical mediation of the therapeutic effects of antidepressant drugs from the standpoint of animal behavior. The first approach utilizes a behavioral response in rats, the forced swimming test, that correlates well with predicting antidepressant drugs in humans. Studies are reviewed that examined serotonergic compounds in the forced swimming test, from the standpoint of identifying better serotonergic mechanisms involved in the antidepressant response. Both 5-HT uptake inhibitors and 5-HT1A receptor agonists produce effects in the forced swimming test that are similar to those of other classes of antidepressant drugs. In contrast, agonists at other 5-HT receptors or 5-HT receptor antagonists do not produce antidepressant-like behavioral effects. Evidence for an important role of 5-HT1A receptors in the antidepressant response is supported by findings that antagonists of 5HT1A receptors prevent the ability of 5-HT1A receptor agonists to reduce immobility in the forced swimming test. The results of studies interfering with 5-HT neurotransmission, either by inhibition of 5-HT synthesis or by the destruction of 5-HT neurons, favor the idea that the effects of 5-HT1A receptor agonists are produced by the stimulation of postsynaptic 5-HT1A receptors. The second approach for studying the behavioral effects of antidepressant drugs employs drug discrimination studies, conducted using a discriminated taste aversion procedure, to provide a method for studying the discriminative stimulus effects of the antidepressant 5-HT uptake inhibitor sertraline. Rats were trained to discriminate the effects of sertraline (10 mg/kg) from saline. Other 5-HT uptake inhibitors, such as fluoxetine, fluvoxamine and paroxetine, substituted for the sertraline stimulus. High doses of norepinephrine uptake inhibitors, such as desipramine or maprotiline, were required to produce similar effects. These two behavioral approaches promise to be useful for defining the important pharmacological effects associated with the behavioral effects of antidepressant drugs.
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PMID:Antidepressant-like behavioral effects of serotonin receptor agonists. 817 Jun 24

We have recently shown that the stereotyped behaviour induced by the uncompetitive NMDA receptor antagonist dizocilpine (MK-801) can be attenuated or blocked by partial agonists at 5-HT receptors of the 5HT1A subtype, indicating that 5-HT (5-hydroxytryptamine, serotonin) is involved in the stereotyped behaviour produced by dizocilpine. In the present experiment, a selective, silent 5-HT1A receptor antagonist, (+)-WAY 100135 (N-tert-butyl 3-4(2-methoxyphenyl) piperazin 1-yl-2-phenylpropanamide dihydrochloride), was used to further study the role of 5-HT activation in dizocilpine-induced behaviours. At a dose of 10 mg/kg, (+)-WAY 100135 significantly reduced the intensity of head weaving induced by dizocilpine, but this effect was lost by increasing the dose to 20 mg/kg. At this higher dose, (+)-WAY 100135 induced marked but short-lasting increases in skeletal muscle tone and hindlimb abduction, resembling components of the '5-HT behavioural syndrome', which would explain its biphasic effects on dizocilpine induced behaviours. The data substantiate that, in addition to the well known activation of dopaminergic transmission, activation of the 5-HT system might be involved in the behavioural effects of NMDA receptor antagonists such as dizocilpine.
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PMID:Effects of the novel 5-HT1A receptor antagonist, (+)-WAY 100135, on stereotyped behaviour induced by the NMDA receptor antagonist dizocilpine in rats. 822 42

Microdialysis was used to characterize the effect of serotonergic input on cholinergic interneurons in the nucleus accumbens (NAC) of freely moving rats. Local infusion of 5-hydroxytryptamine (5-HT) or the serotonin reuptake blocker fluoxetine significantly decreased extracellular acetylcholine (ACh) in the NAC. This decrease in ACh was blocked by the 5-HT1 (and beta-adrenergic) antagonist propranolol. To test suggests that 5-HT inhibits ACh interneurons via one of the 5-HT1 receptor types. The 5HT1A agonist 8-OH-DPAT given systemically again decreased extracellular levels of ACh, and the effect was dose-dependent. The 5-HT1A effect was probably exerted in the NAC, because local infusion of 8-OH-DPAT mimicked systemic injections. These microdialysis results are similar to in vitro studies which suggest an inhibitory impact of 5-HT on ACh release in basal ganglia slices and homogenates. The decrease in extracellular ACh as measured in vivo is apparently mediated, at least in part, through a 5-HT1A receptor in the accumbens. Given the role of the NAC in behavior reinforcement, this 5-HT-ACh interaction may be involved in serotonergic treatment of depression.
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PMID:In vivo modulation of acetylcholine in the nucleus accumbens of freely moving rats: I. Inhibition by serotonin. 837 97

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Saline-key responding occurred following administration of the D1 agonist SKF-38393, the D1 antagonist SCH-23390, the alpha 2 receptor agonist clonidine, the alpha 1 antagonist prazosin, a nonselective beta-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D2/D3 agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3-1.0 mg/kg), whereas much lower doses (0.003-1.0 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT3 antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT1A and DA D1 and D2 receptors.
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PMID:The discriminative stimulus effects of methamphetamine in pigeons. 852 78

Activation of 5HT1A receptors produces many different physiologic responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170-186) antibody was produced that showed both high titer for peptide binding and immunocytochemical staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from our studies of Macaca fascicularis brains are presented. We observed two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also observed in the nucleus locus coeruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1-4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addition to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clinical implications of 5-HT1A cellular localization are briefly discussed.
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PMID:Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. 871 28

The increase in extracellular 5-hydroxytryptamine (5-HT) in rat hypothalamus following administration of fluoxetine, a 5-HT-uptake inhibitor, was enhanced by the injection of LY206130(1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-prop ano l maleate), a 5HT1A receptor antagonist, or by L-5-hydroxytryptophan (L-5-HTP), the 5-HT precursor. Elevation of serum corticosterone, measured as a functional output of hypothalamic 5-HT pathways, was greater in rats treated with fluoxetine plus LY206130 or with fluoxetine plus L-5-HTP than in rats treated with the agents alone. Synergism between effects of fluoxetine and L-5HTP has often been reported, but this is the first report of an increased functional effect when a 5-HT1A receptor antagonist is combined with a 5-HT uptake inhibitor to augment the increase in extracellular 5-HT.
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PMID:Serum corticosterone increases reflect enhanced uptake inhibitor-induced elevation of extracellular 5-hydroxytryptamine in rat hypothalamus. 872 99

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared to the relatively resistant Fischer F344 rat, is related to a hyporesponsive hypothalamopituitary adrenal axis to inflammatory and other stress mediators. Since 5-HT and the 5HT1A receptor are important stimulators of this axis, we have investigated the levels of 5-HT1A receptor binding sites and encoding mRNA, 5-HT and 5-hydroxyindole acetic acid in various brain regions of Lewis, Harlan Sprague Dawley and Fischer F344 rats. Lewis rats expressed significantly less hippocampal and frontal cortical 5-HT1A receptor binding sites and mRNA than Harlan Sprague-Dawley and Fischer F344 rats. Adrenalectomy increased the number of 5HT1A receptor binding sites and mRNA expression in the hippocampus of all three strains. The levels of hippocampal 5-HT in Fischer F344 rats were significantly greater than levels detected in the same regions for the other two strains. Hypothalamic 5-HT and 5-hydroxyindole acetic acid levels in Harlan Sprague-Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindole acetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the the activity and responsiveness of the hypthalamopituitary-adrenal axis. We have published these data in an earlier report.
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PMID:Hippocampal 5-HT1A receptor binding site densities, 5-HT1A receptor messenger ribonucleic acid abundance and serotonin levels parallel the activity of the hypothalamo-pituitary-adrenal axis in rats. 878 33


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