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)

One of the proposed mechanisms of action for the anxiolytic effects of the benzodiazepines is via a decrease in central serotonergic neurotransmission. The aim of this study was to combine in vivo microdialysis in the rat with behaviour on the elevated X-maze to determine changes in 5-HT release in the ventral hippocampus with concomitant measurement of behaviour. Twenty minutes exposure to the elevated X-maze resulted in an increase in extracellular 5-HT in the ventral hippocampus with no change in extracellular 5-HIAA. Restricting the rat to either the open or the closed arms produced an increase in extracellular 5-HT, however the increase in 5-HT when restricted to the open arms was not significantly greater than that on the closed arms. Forty minutes pretreatment with diazepam (2.5 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over 5 min and 20 min exposures of the rats to the X-maze. Diazepam had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the .5-HT1A receptor partial agonist ipsapirone (1 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus but did not produce behaviour different from vehicle controls after 5 or 20 min periods on the X-maze.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. 128 16

Rats treated chronically (14 days) with the 5-HT2 receptor antagonist ritanserin, show decreased 5-HT2 receptor numbers in the frontal cortex. The present experiments were designed to investigate the effects of acute and chronic ritanserin treatment on the autoregulatory control of the release of 5-HT and its metabolite 5-HIAA in vivo in rats using intracerebral dialysis. Neither acute nor chronic ritanserin treatment altered basal extracellular levels of 5-HT or 5-HIAA, suggesting that 5-HT2 receptors do not directly influence 5-HT release. In the control animals, systemic stimulation of somatodendritic 5-HT1A receptors with the 5-HT1A receptor agonist 8-OH-DPAT, inhibited the release of 5-HT presumably via inhibitory feedback autoregulation; an effect also seen in animals treated acutely with ritanserin. However, in the animals treated chronically with ritanserin, administration of 8-OH-DPAT produced an initial increase in extracellular 5-HT which declined gradually to the end of the experiment. These results suggest that chronic, but not acute, 5-HT2 receptor antagonist treatment attenuates the 5-HT1A receptor-mediated autoregulation of 5-HT release. The underlying mechanisms have yet to be ascertained.
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PMID:Chronic 5-HT2 receptor antagonist treatment alters 5-HT1A autoregulatory control of 5-HT release in rat brain in vivo. 170 42

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.
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PMID:Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine. 182 32

In this paper we present the neurochemical profile of eltoprazine, a drug that specifically inhibits offensive aggression. Eltoprazine interacts selectively with serotonin (5-HT) receptor subtypes (Ki-values for 5-HT1A, 5-HT1B and 5-HT1C receptors are 40, 52 and 81 nM respectively). Affinity for other neurotransmitter receptors is much lower (Ki-values greater than 400 nM) than for 5-HT1 receptors. The selective interaction with 5-HT1 receptor subtypes is confirmed by in vitro autoradiographic studies using radiolabelled eltoprazine. The overall distribution of [3H]eltoprazine bears a strong resemblance to the localization of 5-HT1 binding sites labelled by [3H]5-HT, although some differences are observed. Eltoprazine (1 microM) inhibits the forskolin stimulated c-AMP production in hippocampus slices of the rat, indicating an agonistic action on the 5-HT1A receptor. The K+ stimulated release of 5-HT from rat cortex slices is inhibited by eltoprazine (pD2 = 7.8). The maximal response, however, was clearly less than that of the full agonist 5-HT, indicating partial agonistic activity on the 5-HT1B receptor (alpha = 0.5). Eltoprazine has a weak antagonistic action (IC50 = 7 microM) on the 5-HT1C receptor as revealed by inhibition of the 5-HT-induced accumulation of inositol phosphates in the choroid plexus of the pig. In vivo, eltoprazine reduces 5-HIAA levels in the striatum, without affecting the 5-HT levels. Eltoprazine also reduces the 5-HT synthesis rate as shown by 5-HTP accumulation after decarboxylase inhibition. These data indicate that eltoprazine acts as a 5-HT agonist in vivo in a dose range that affects aggressive behaviour (0.3-3 mg/kg p.o.). Taken together from a variety of neurochemical studies there is strong evidence both in vitro and in vivo that the pharmacological actions of eltoprazine can be attributed to an interaction with the 5-HT system, most probably via a (partial) agonistic action on 5-HT1A and 5-HT1B receptors.
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PMID:Neurochemical profile of eltoprazine. 198 26

Administration of 60 micrograms/kg s.c. of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a dose previously shown to cause hyperphagia in satiated rats (but not to cause the 5-HT behavioural syndrome) decreased 5-HIAA and 5-HIAA/5-HT ratio in several brain regions, the most marked effects being in pons + medulla oblongata, a region containing 5-HT cell bodies and ascending 5-HT axons. Micro-infusion of 8-OH-DPAT (250 and 500 ng) into the dorsal or medial raphe nuclei significantly increased food intake and feeding duration but did not produce the 5-HT behavioural syndrome. Results suggest that 8-OH-DPAT induced hyperphagia is mediated via a agonist action on somatodendritic 5-HT autoreceptors.
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PMID:Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors. 243 Aug 15

The 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone or TVXQ 7821 (ipsapirone) but not the 5-HT1B agonist RU 24969, attenuated the hyperphagic response to 8-OH-DPAT administered on the next day. Attenuation was still apparent on the fifth day after either 8-OH-DPAT or buspirone but not on the tenth day after 8-OH-DPAT administration. The ability of 8-OH-DPAT to reduce raphe 5-HIAA levels was also impaired by previous 8-OH-DPAT treatment. However, the 8-OH-DPAT or 5-methoxy-N,N-dimethyltryptamine-induced 5-HT syndromes were unaltered. The results indicate that a single pretreatment with 5-HT1A agonists rapidly desensitises 5-HT1A presynaptic receptor-mediated responses. This effect may mediate the antidepressant-like action of the drugs in an animal model of depression.
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PMID:Single administration of 5-HT1A agonists decreases 5-HT1A presynaptic, but not postsynaptic receptor-mediated responses: relationship to antidepressant-like action. 244 2

Ipsapirone (TVX Q 7821), a compound with a high affinity for the 5-HT1A receptor-subtype, decreased by itself 5-HIAA level and reduced 5-HIAA accumulation after probenecid administration in the rat hypothalamus. The reduced 5-HIAA level and 5-HIAA/5-HT ratio after the 5-HT1A selective agonist 8-OH-DPAT was not antagonized by pretreatment with ipsapirone.
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PMID:Effects of ipsapirone on the level of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in some regions of the rat brain. 247 37

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.
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PMID:Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine. 252 83

Rat pups were injected intracisternally (i.c.) or intraperitoneally (i.p.) with 5,7-dihydroxytryptamine (5,7-DHT) or saline and challenged 2 and 14 weeks later with the 5-HT precursor 5-hydroxytryptophan (5-HTP), which evokes behavioral supersensitivity in adult rats, 5,7-DHT induced transient postinjection convulsions in rats injected i.c. but not i.p. Rats with either type of 5,7-DHT lesions displayed supersensitive behavioral responses to 5-HTP. However, rats lesioned by i.p. injections exhibited significantly greater shaking behavior (+1445%) in response to 5-HTP than their i.c. counterparts, who instead showed more forepaw myoclonus (+250%) and head weaving (+270%), the core features of the 5-HT syndrome. Differences in 5-HT syndrome behaviors were already present 2 weeks after lesioning, whereas the difference in shaking behavior was not. After 14 weeks, 5-HT was selectively depleted (-43 to -92%) in hippocampus, spinal cord, and frontal cortex, and differences between i.c. and i.p. 5,7-DHT routes were insignificant except in frontal cortex. Brainstem 5-HT concentrations were significantly increased (+35%) after i.p. 5,7-DHT injections in contrast to reduction (-89%) after i.c. 5,7-DHT; 5-hydroxyindole acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) ratios were decreased (-20%) with either route. These data suggest that brainstem 5-HT hyperinnervation following i.p. 5,7-DHT injection modifies the functional consequences of injury in abating the 5-HT syndrome, but does not result in complete recovery since shaking behavior is enhanced. Loss of presynaptically mediated autoregulation or receptor dysregulation may play a major role in behavioral supersensitivity induced by 5-HTP in rats with 5,7-DHT lesions. To the extent that the 5-HT syndrome is mediated by 5-HT1A receptors and shaking behavior by 5-HT2 sites, differential responses to injury of 5-HT1A and 5-HT2 receptors may contribute to these behavioral differences.
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PMID:Brainstem serotonergic hyperinnervation modifies behavioral supersensitivity to 5-hydroxytryptophan in the rat. 258 10

Although suicide was traditionally considered an extreme response to stress, with the most frequent stress being depressive illness, severity of depression does not distinguish those who commit suicide from non-suicide attempters. A biological role involving the serotonergic system, possibly associated with a genetic risk factor, has been postulated. Low levels of 5-HT and 5-HIAA have been found in post-mortem examinations of brain-stem tissues of suicide victims (levels in cortical tissue were generally normal). An increased number of 5-HT2 receptors was found in the pre-frontal cortex of suicide victims, such upregulation having been demonstrated in induced 5-HT deficiency states; 5-HT1A receptors were also increased. Receptor populations may be altered by chronic psychotropic medication; e.g. 5-HT2 downregulation occurs following administration of antidepressants. There is some indication that the adrenergic system may be involved as well, but this will require further study. Antidepressant drugs may be effective in preventing suicide in patients with non-depressive syndromes who exhibit suicidal behaviour.
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PMID:Evidence for the 5-HT hypothesis of suicide. A review of post-mortem studies. 269 42


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