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 mechanisms of the antinociceptive effect of desipramine (DMI) are only partly known. It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N-methyl-D-aspartic acid (NMDA) receptor complex. In this study, the modulatory effect of DMI on the biting and scratching behaviour induced by intrathecal (i.th.) administration of NMDA (0.25 nmol) was investigated. Desipramine was administered acutely, either intrathecally (0.7-35 micrograms) or intraperitoneally (i.p., 10 mg/kg), or chronically in the drinking water (0.15 g/l) for 3 weeks. The NMDA-induced behaviour was significantly reduced both after acute and chronic administration of DMI. Several studies have shown a functional upregulation of the 5-HT1A receptor after chronic treatment with DMI. The activation of this receptor using the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), leads to a reduction in NMDA-induced behaviour. Using the 5-HT1A antagonist NAN-190 (10 micrograms, i.th.), the effect of chronic administration of DMI on the NMDA-induced behaviour was reversed. However, NAN-190 also increased NMDA-induced behaviour in the control group, suggesting that a tonic inhibition of this behaviour, mediated by the 5-HT1A receptor, may exist. These findings indicate that DMI may reduce glutaminergic transmission at the spinal NMDA receptor. As this receptor is central in spinal nociceptive transmission, this could be one mechanism for the antinociceptive effect of DMI.
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PMID:Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice. 833 22

The pharmacological properties of SDZ 216-525, methyl 4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1-p iperazinyl)1H- indole-2-carboxylate, a new selective and potent 5-HT1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative 5-HT1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216-525 showed high affinity and selectivity for 5-HT1A sites (pKD = 9.2) as compared to 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3 sites (pKD = 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for alpha 1, alpha 2, beta 1 and beta 2 adrenoceptors, and dopamine D2 receptors was at least 50-100 times lower than for 5-HT1A sites. The effects of SDZ 216-525, MDL 73005 and NAN 190 on 5-HT1 receptor-linked second messengers were characterised in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT1A), rat substantia nigra (5-HT1B) and calf substantia nigra (5-HT1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT1C). SDZ 216-525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2-[N-dipropyl-amino]-tetralin) on 5-HT1A receptors (pKB = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models (pKB values < 6.9).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SDZ 216-525, a selective and potent 5-HT1A receptor antagonist. 838 69

We tested the hypothesis that the rat bowel and pancreas contain 5-HT1A receptors. 3H-8-hydroxy-2-(di-n-propylamino)tetralin (3H-8-OH-DPAT) was used as a radioligand. Binding of 3H-8-OH-DPAT to membranes derived from the myenteric plexus and the pancreas was investigated by rapid filtration. Alternatively, radioautography was employed to locate 3H-8-OH-DPAT binding sites in frozen sections of unfixed bowel or pancreas. An excess of 5-HT (10 microM) was used to define nonspecific binding. Saturable, high affinity binding of 3H-8-OH-DPAT to enteric (Kd = 2.8 +/- 1.1 nM; Bmax = 83.8 +/- 4.3 fmol/mg protein) and pancreatic (Kd = 6.6 +/- 1.3 nM; Bmax = 44 +/- 2.2 fmol/mg protein) membranes was found. The binding of 3H-8-OH-DPAT to enteric and pancreatic membranes was inhibited by 8-OH-DPAT, NAN-190, and spiperone. In contrast, the binding of 3H-8-OH-DPAT to enteric and pancreatic membranes was not inhibited by 5-carboxyamidotryptamine, or by a variety of compounds known to bind to other subtypes of 5-HT receptor. Digoxigenin-labeled oligonucleotides were found to detect mRNA encoding the 5-HT1A receptor in a subset of neurons in myenteric and submucosal ganglia. In contrast, 5-HT1A mRNA was not found in the pancreas. Radioautography revealed that the highest density of 3H-8-OH-DPAT binding sites was found in the stomach. These sites were especially numerous in the lamina propria adjacent to gastric glands, and in myenteric ganglia. Pancreatic 5-HT1A receptors were located on nerves, lymphoid tissue (especially the capsule of nodes), and on cells scattered in the pancreatic parenchyma. The concentration of 3H-8-OH-DPAT binding sites in the rat bowel and pancreas was less than that of 3H-5-HT binding sites; however, the distribution of 3H-8-OH-DPAT binding sites was similar to that of sites that bind 3H-5-HT. It is concluded that the rat gut and its extension in the pancreas contains 5-HT1A receptors. Many, if not all, of the nerve cells and processes that express 5-HT1A receptors express 5-HT1P receptors as well. The function of these receptors in the physiology of the entero-pancreatic innervation remains to be determined.
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PMID:Detection of the 5-HT1A receptor and 5-HT1A receptor mRNA in the rat bowel and pancreas: comparison with 5-HT1P receptors. 842 44

Exposure to HBO causes hypothermia, bradycardia, head weaving, resting tremor, piloerection, and straub tail in rats. These physiological and behavioral responses can also be evoked by selective activation of serotonin1A (5-HT1A) receptors. The purpose of the current study was to determine if hypothermia caused by HBO is due to increased activation of 5-HT1A receptors. The levels of brain biogenic amines were measured in brain regions of Sprague-Dawley (SD) rats exposed to HBO. Exposure to HBO caused an increase in the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (92%, p < 0.05) and occipital-temporal cortex (116%, p < 0.05), but not in other brain regions. Exposure to HBO did not change the levels of tryptophan, serotonin (5-HT), other biogenic amines, or their metabolites. It is hypothesized that the Fawn Hood (FH) rat, which is reported to be resistant to hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), has an abnormality of 5-HT1A receptor activity. Although the FH rat was more resistant to hypothermia induced by HBO than the SD rat, we were not able to confirm that this rat was resistant to hypothermia induced by 8-OH-DPAT. The 5-HT receptor antagonists, 1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol (Pindolol), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), and methysergide, did not block hypothermia induced by HBO in SD rats. A series of control experiments were used to confirm that the antagonists blocked hypothermia induced by serotonin agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypothermia induced by hyperbaric oxygen is not blocked by serotonin antagonists. 844 68

Serotonin-1A (5-HT1A) binding sites were previously localized in several regions of the ventral medulla associated with neural regulation of the cardiovascular system. Some of these binding sites were associated with serotonergic neurons of the ventral medulla. The purpose of these studies was to assess and characterize hypotensive responses to a 5-HT1A agonist, (8-hydroxy-dipropylaminotetraline, 8-OH-DPAT), administered to the ventral medulla of the rat, to correlate the responsive ventral medullary sites with the distribution of 3H-8-OH-DPAT binding sites, and to assess the role of serotonergic systems in mediating the hypotensive responses. Ventral medullary application of 8-OH-DPAT caused dose-related reductions in mean arterial pressure and heart rate which were mediated by the autonomic nervous system. The hypotensive response to 8-OH-DPAT was attenuated by pretreatment with the 5-HT1A antagonists, spiperone or NAN-190. Microinjections of 8-OH-DPAT into ventral medullary structures revealed that 8-OH-DPAT responsive sites included the raphe pallidus, the parapyramidal region, and the rostral ventrolateral medulla. The role of serotonergic terminals in mediating the responses of 8-OH-DPAT was evaluated in animals pretreated with the serotonin nerve toxin, 5,7-dihydroxytryptamine (5,7-DHT). Cardiovascular responses to ventral medullary application of 8-OH-DPAT were unaffected by the selective depletion of serotonin. Thus, whereas the hypotensive responses elicited by 8-OH-DPAT in the raphe pallidus and parapyramidal region may involve serotonergic neurons, other non-serotonergic sites (e.g. the rostral ventrolateral medulla) can mediate the hypotensive actions of 8-OH-DPAT.
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PMID:Hypotensive effects of 5-HT1A receptor activation: ventral medullary sites and mechanisms of action in the rat. 845 Jan 76

In this study, we examined the localization of the 5-hydroxytryptamine (5-HT)1A receptors mediating hypothermia in the rat, evaluated the pharmacological specificity of this response and examined the influence of a series of novel 5-HT1A receptor ligands upon core temperature. Administered s.c., 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), an agonist at both pre- and postsynaptic 5-HT1A receptors, elicited pronounced hypothermia. In contrast, BMY 7378, which shows low efficacy at postsynaptic 5-HT1A receptors but high efficacy at presynaptic 5-HT1A receptors, elicited only mild hypothermia. Similarly, 8-OH-DPAT was more efficacious than BMY 7378 in eliciting corticosterone secretion, a response mediated by postsynaptic 5-HT1A receptors, whereas BMY 7378 was as efficacious as 8-OH-DPAT in inhibiting striatal accumulation of 5-hydroxytryptophan, a response mediated by presynaptic 5-HT1A receptors. These data suggest, by analogy, that postsynaptic 5-HT1A receptors mediate hypothermia, an interpretation supported by the observation that destruction of central 5-HT neurons with 5,7-dihydroxytryptamine failed to reduce 8-OH-DPAT-induced hypothermia (DIH). Agonists at 5-HT1B, 5-HT1C, 5-HT2 and/or 5-HT3 receptors did not elicit hypothermia, and drugs releasing 5-HT elicited hyperthermia. In contrast, DIH was fully mimicked by the novel 5-HT1A receptors agonists, eltoprazine, WY 48,723, MDL 72832, tandospirone, S 14671, S 14506 and WY 50,324, whereas the novel partial agonist, zalospirone, was less efficacious. DIH was blocked by (-)-alprenolol, (+/-)-pindolol and the novel beta-blocker, (-)-tertatolol, which also has high affinity for 5-HT1A receptors; in distinction, betaxolol and ICI 118,551, antagonists at beta-1 and beta-2 adrenoceptors, respectively, were inactive. Spiperone, NAN-190 and BMY 7378 also inhibited DIH whereas ritanserin, SCH 39166, raclopride and prazosin, antagonists at 5-HT2 receptors, D1 and D2 dopamine receptors and alpha-1 adrenoceptors, respectively, were inactive. The novel 5-HT1A antagonists, WAY 100,135, MDL 73005 EF and (very potently) SDZ 216-525 all blocked DIH. Potency for induction of hypothermia and inhibition of DIH correlated well with affinity for 5-HT1A binding sites. In conclusion, hypothermia is a highly specific and sensitive response to activation of postsynaptic 5-HT1A receptors. Furthermore, DIH is inhibited by their selective blockade. At postsynaptic 5-HT1A receptors mediating hypothermia, eltoprazine, WY 48,723, MDL 72832 and tandospirone are agonists, zalospirone is a partial agonist and (-)-tertatolol, WAY 100,135, MDL 73005 EF and SDZ 216-525 are antagonists.
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PMID:Induction of hypothermia as a model of 5-hydroxytryptamine1A receptor-mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists. 845 Apr 71

The primary mammalian circadian clock, located in the suprachiasmatic nuclei (SCN), receives a major input from the raphe nuclei. The role of this input is largely unknown, and is the focus of this research. The SCN clock survives in vitro, where it produces a 24-hr rhythm in spontaneous neuronal activity that is sustained for at least three cycles. The sensitivity of the SCN clock to drugs can therefore be tested in vitro by determining whether various compounds alter the phase of this rhythm. We have previously shown that the nonspecific serotonin (5-HT) agonist quipazine resets the SCN clock in vitro, inducing phase advances in the daytime and phase delays at night. These results suggest that the 5-HT-ergic input from the raphe nuclei can modulate the phase of the SCN circadian clock. In this study we began by using autoradiography to determine that the SCN contain abundant 5-HT1A and 5-HT1B receptors, very few 5-HT1C and 5-HT2 receptors, and no 5-HT3 receptors. Next we investigated the ability of 5-HT-ergic agonists and antagonists to reset the clock in vitro, in order to determine what type or types of 5-HT receptor(s) are functionally linked to the SCN clock. We began by providing further evidence of 5-HT-ergic effects in the SCN. We found that 5-HT mimicked the effects of quipazine, whereas the nonspecific 5-HT antagonist metergoline blocked these effects, in both the day and night. Next we found that the 5-HT1A agonist 8-OH-DPAT, and to a lesser extent the 5-HT1A-1B agonist RU 24969, mimicked the effects of quipazine during the subjective daytime, whereas the 5-HT1A antagonist NAN-190 blocked quipazine's effects. None of the other specific agonists or antagonists we tried induced similar effects. This suggests that quipazine acts on 5-HT1A receptors in the daytime to advance the SCN clock. None of the specific agents we tried were able either to mimic or to block the actions of 5-HT or quipazine at circadian time 15. Thus, we were unable to determine the type of 5-HT receptor involved in nighttime phase delays by quipazine or 5-HT. However, since the dose-response curves for quipazine during the day and night are virtually identical, we hypothesize that the nighttime 5-HT receptor is a 5-HT1-like receptor.
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PMID:Serotonin and the mammalian circadian system: I. In vitro phase shifts by serotonergic agonists and antagonists. 849 Feb 7

The antidepressant-like effect of 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a selective 5-HT1A receptor agonist, was studied in the forced swimming wheel test in reserpine-treated mice. 8-OH-DPAT and the antidepressant imipramine, dose-dependently increased the number of turns of a water wheel made by mice. This effect of imipramine (30 mg/kg, i.p.) was enhanced by reserpine treatment 24 hr before the test. The effect of 8-OH-DPAT (0.3 mg/kg, i.p.) was also enhanced in reserpine-treated mice. This enhanced effect of 8-OH-DPAT was blocked by pretreatment with the 5-HT1A receptor antagonists, (-)-propranolol (3 mg/kg, i.p.) and NAN-190 (1 mg/kg, i.p.), but was not blocked by a beta-blocker, (-)-atenolol (3 mg/kg, i.p.). 8-OH-DPAT did not affect locomotor activity in the reserpinized mice and did not affect the reduction of monoamine content induced by reserpine. These results suggest that the effect of 8-OH-DPAT in increasing the number of turns of the wheel made by mice was exerted through a 5-HT1A receptor and that this effect did not reflect only changes in the locomotor activity of the mice.
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PMID:Role of 5-HT1A receptors in the forced swimming wheel test in reserpine-treated mice. 849 37

Rats were trained to discriminate 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, 1.25 mg/kg i.p.), a selective and nonselective 5-hydroxytryptamine1A (5-HT, serotonin) receptor agonist, respectively, from saline in a two-lever procedure. The selective 5-HT1A receptor agonist ipsapirone substituted completely for 8-OH-DPAT (ED50, 1.52 mg/kg) and 5-OMe-DMT substituted partially for 8-OH-DPAT, whereas 8-OH-DPAT (ED50, 0.07 mg/kg) and ipsapirone (ED50, 4.15 mg/kg) substituted completely for 5-OMe-DMT. These results suggest that the discriminative stimulus properties of both 8-OH-DPAT and 5-OMe-DMT are 5-HT1A receptor mediated, although 5-OMe-DMT may involve an additional interaction with other 5-HT receptor subtypes. 5-OMe-DMT substituted for 8-OH-DPAT after application in the lateral ventricle (ED50, 3.0 micrograms/rat) and the dorsal raphe nucleus (DRN, 1.1 micrograms/rat). After application in the DRN (ED50 range, 1.4-5.0 micrograms/rat) and the median raphe nucleus (2.3 micrograms/rat), and after bilateral application into the CA-4 region of the dorsal hippocampus (4.1 micrograms/rat), 8-OH-DPAT also produced responding on the 8-OH-DPAT lever. Ipsapirone also substituted for 8-OH-DPAT after application into the DRN and the hippocampus (ED50S, 38 and 62 micrograms/rat, respectively). The 5-HT1A mixed agonist-antagonist (1-(2-methoxyphenyl) 4-[4-(2-pthalimido)butyl]piperazine, i.p. NAN-190) attenuated the discriminative stimulus effects of 8-OH-DPAT injected i.p. (0.1 mg/kg), into the DRN (10 micrograms) or into the hippocampus (2 x 10 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies on the neuronal circuits involved in the discriminative stimulus effects of 5-hydroxytryptamine1A receptor agonists in the rat. 849 7

Serotonin (5-HT) is generally considered to serve a facilitatory role in the regulation of adrenocortical secretion. Numerous studies have shown that administration of 5-HT1A receptor agonists increases plasma corticosterone (CS) concentrations in rats; however, the mechanism has not been established. Rats were prepared with a cannula implanted above the lateral cerebral ventricle, or bilateral cannulae above the hypothalamic paraventricular nuclei (PVN), the site of the perikarya of corticotropin-releasing factor (CRF)-secreting neurons regulating adrenocortical secretion. In sodium pentobarbital-anesthetized rats, intracerebroventricular and intra-PVN administration of 5-HT resulted in a multi-component dose-response curve in plasma CS, whereas administration of 5-HT in conscious animals resulted in low-dose inhibition and higher dose elevation of plasma CS levels. Under pentobarbital anesthesia, central administration of the selective 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone decreased plasma CS levels, relative to saline-treated control rats, at all doses tested (0.001-20 nmol). In conscious rats, administration of 8-OH-DPAT decreased adrenocortical secretion at lower doses and significantly increased plasma CS concentrations at higher doses. Ipsapirone produced similar but less pronounced effects. In contrast, intraperitoneal injection of 8-OH-DPAT (2 mumol/kg) increased plasma CS concentrations, but this was not prevented by prior intracerebroventricular administration of the 5-HT1A antagonist, NAN-190 (5 nmol). Pentobarbital anesthesia completely blocked the plasma CS response to peripheral administration of 8-OH-DPAT. In view of the adrenocortical activating effects of hypotensive stimuli, we speculate that the well-documented hemodynamic changes following 5-HT1A receptor stimulation may be responsible for the adrenocortical responses observed. Our data demonstrate that low doses of 5-HT1A agonists delivered directly into the CNS decrease adrenocortical secretion. Since intra-PVN injections of 8-OH-DPAT to pentobarbital-anesthetized rats also decreased hypothalamo-pituitary-adrenocortical activity, it appears that a component of the inhibitory effect of 5-HT1A receptor activation is mediated by a direct effect at the level of the PVN, and presumably involves CRF-secreting neurons.
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PMID:Central 5-HT1A receptors inhibit adrenocortical secretion. 851 Aug 3


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