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)

The non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), induces in rats a characteristic behavioural syndrome with ataxia, stereotypies and hyperlocomotion. At least part of this behavioural syndrome is thought to be related to interactions between glutamatergic and dopaminergic neurotransmission. Based on recent biochemical evidence that serotonin (5-HT) might also be involved in the effects of MK-801 several 5-HT receptor ligands were tested for effects on MK-801-induced behaviours. The 5-HT1A receptor ligands, ipsapirone and NAN-190, which are known to display antagonist-like properties in functional models of postsynaptic 5-HT1A receptor activity attenuated or blocked the hyperlocomotion and head weaving observed after administration of MK-801, whereas the 5-HT2 receptor antagonist, ritanserin, was ineffective in this respect. The dopamine receptor antagonist, haloperidol, and the alpha 1-adrenoceptor antagonist, prazosin, also attenuated behaviours induced by MK-801. In contrast to its effects on stereotypies induced by MK-801, ipsapirone potentiated rather than attenuated the stereotyped behaviour induced by the dopamine receptor agonist, apomorphine, indicating that antagonism of MK-801-induced stereotypies by ipsapirone may not be related to the dopaminergic system. The data indicate that, in addition to catecholaminergic systems, serotonergic neurotransmission is significantly involved in the mechanisms by which MK-801 alters behaviour in rats.
 ...
PMID:The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. 135 90

The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia, locomotion, stereotypies) in amygdala-kindled rats, whereas the amphetamine-like behavioral alterations of the syndrome (locomotion, stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats, behavioral effects were scored using a ranked intensity scale, and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats, 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats, especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801, indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone, a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore, these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist, prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists, which could relate to the recent finding of increased function of NMDA receptors following kindling.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors. 167 88

In studying the role of serotonin (5-HT) in the mechanism of action of benzodiazepine (BDZ)-induced wet-dog shakes (WDS), only certain 1,4-substituted BDZ agonists were found to induce WDS at doses up to 60 mg/kg in the rat with the rank order of potency at peak dose effect clonazepam greater than nitrazepam = flunitrazepam much greater than nimetazepam = lorazepam. BDZs evoking WDS at lowest doses contained an R7 nitro group on the A ring. Non-BDZ agonists (CL 218,872), inverse agonists (beta-CCE), peripheral type receptor agonists (Ro 5-4864), and BDZ antagonists (Ro 15-1788) did not induce shaking behavior. Several 5-HT1 and 5-HT2 agonists and antagonists were tested as blockers, but only putative 5-HT1A agonists reduced WDS, 8-OH-DPAT and ipsapirone but not PAPP and 5-MeO-DMT having a significant effect. The effect of 8-OH-DPAT was dose dependent, with an ID50 of 0.86 mg/kg, but it was not reversed by 5-HT or adrenergic antagonists at the doses studied. Intracisternal 5,7-dihydroxytryptamine lesions did not alter frequency, latency, or time course of BDZ-induced WDS. BDZ-evoked WDS were enhanced by Ro 15-1788 (which inhibited ataxia) but were unaffected by the various types of BDZ agonists. Several BDZ agonists induced both WDS and ataxia, but ataxia was not blocked by serotonergic drugs. No significant correlation with ataxia, BDZ radioligand binding, antipentylenetetrazol activity, or other BDZ property was found. BDZ-evoked WDS may relate to the unique predominance of BDZ II and 5-HT1A receptors in the hippocampus, an important site for WDS, but 5-HT1A agonists appear to modulate WDS by opposing pharmacologic actions rather than by direct receptor antagonism. These data indicate a species difference in the shakes induced by BDZs in rats (5-HT2 independent) and in mice (5-HT2 related).
 ...
PMID:Benzodiazepine-induced shaking behavior in the rat: structure-activity and relation to serotonin and benzodiazepine receptors. 254 77

The serotonin syndrome has increasingly been recognised in patients who have received combined serotonergic drugs. This syndrome is characterised by a constellation of symptoms (confusion, fever, shivering, diaphoresis, ataxia, hyperelflexia, myoclonus or diarrhoea) in the setting of the recent addition of a serotonergic agent. The most common drug combinations causing the serotonin syndrome are monoamine oxidase inhibitors (MAOIs) and serotonin selective reuptake inhibitors (SSRIs), MAOIs and tricyclic antidepressants, MAOIs and tryptophan, and MAOIs and pethidine (meperidine). This syndrome is caused by excess serotonin (5-hydroxytryptamine; 5-HT) availability in the CNS at the 5-HT1A-receptor. There may also be some interaction with dopamine and 5-HT2-receptors. This syndrome probably has a low incidence, even among patients taking these drug combinations, and there is likely to be some other as yet unidentified inciting factor causing some patients to develop a full serotonin syndrome. Because fatalities and severe complications have accompanied the serotonin syndrome, the previously described drug combinations should be used cautiously or not at all. The serotonin syndrome is usually mild and, if managed with drug withdrawal and supportive therapy, generally improves within hours. Patients who develop hyperthermia should be treated aggressively with external cooling and paralysis. Methysergide and cyproheptadine appear to be useful adjuncts in treating the serotonin syndrome.
 ...
PMID:The serotonin syndrome. Implicated drugs, pathophysiology and management. 757 68

In this study, we examined whether activation of 5-HT1A receptors elicits antinociception in response to acute noxious chemical, thermal and mechanical stimuli in mice. In the writhing test, both agonists (e.g., 8-OH-DPAT, S 14671 and WY 50,324) and partial agonists (e.g., buspirone and gepirone) elicited a pronounced antinociception. However, antagonists (e.g., (-)-alprenolol and WAY 100,135) also induced antinociception and, at lower (inactive) doses, failed to modify the action of agonists. In addition, the separation between doses required for induction of antinociception as compared to those required for induction of ataxia (in the rotarod test) was variable and low for both agonists (median: 1.9) and partial agonists (median: 1.3), although it was somewhat greater for antagonists (> or = 3.3). In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT1A antagonists which, themselves, were inactive in this paradigm. The 5-HT1C/2 antagonist, ritanserin, the 5-HT3 antagonist, ondansetron, the dopamine D2 receptor antagonist, raclopride, and the alpha 1-adrenoceptor antagonist, prazosin, were also ineffective in modifying the antinociception evoked by 5-HT1A agonists and partial agonists in the hot-plate test. In contrast, their actions were strongly attenuated by the alpha 2-adrenoceptor antagonist, idazoxan. In the tail-flick tests to noxious heat and noxious pressure, 5-HT1A receptor agonists, partial agonists and antagonists generally failed to induce antinociception. Moreover, modulation of stimulus intensity (from very weak to very intense) did not reveal any influence upon the latency to respond. In conclusion, in the writhing test, the data provide no evidence for a specific antinociceptive effect of the activation of 5-HT1A receptors. Further, in the hot-plate test, for those 5-HT1A agonists and partial agonists which induce antinociception, alpha 2-adrenoceptors rather than 5-HT1A receptors are implicated in their actions. Finally, in reflexive tests, irrespective of stimulus quality or intensity, 5-HT1A agonists and partial agonists do not mediate antinociception. These data suggest that the activation of 5-HT1A receptors does not, under these conditions of acute noxious stimulation, elicit antinociception.
 ...
PMID:Serotonin and pain: evidence that activation of 5-HT1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice. 797 Aug 39

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0-32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1-3.2 mg/kg p.o.; 0.1-32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1-18 mg/kg, p.o.; 0.1-1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group. Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.
 ...
PMID:Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination. 810 30

We propose a serotonergic hypothesis for cerebellar ataxia. The levorotatory form of 5 hydroxytryptophan has been shown to be partially active in subtypes of cerebellar ataxia, including cerebellar cortical atrophy (CCA). Buspirone, a 5-HT1A agonist usable in human medicine, has been studied in a group of 14 patients with cerebellar cortical atrophy. Patients were given Buspirone for 2 months. The evaluation of cerebellar ataxia was made by a semi-quantitative scale, 10 fully quantitative measures and measurements of the sway path and sway area of the center of gravity at posturography. The primary endpoints were the modifications of the ataxia scores. At 2 months, the decrease of the ataxia scores was significant, both in the intention-to-treat (14 cases) and target (11 cases) populations. In the target population, secondary endpoints like the time measurements for pronouncing a standard sentence, the time for drawing a ladder and posturographic parameters were significantly improved; the mean global ataxia score was improved by 37.4%. These preliminary data might confirm a link between cerebellar ataxia and the metabolism of serotonin.
 ...
PMID:[Effect of buspirone, a serotonergic 5-HT-1A agonist in cerebellar ataxia: a pilot study. Preliminary communication]. 878 1

In mice injected with formalin into the hindpaw, the 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, equipotently inhibited the early phase (EP) and late phase (LP) of licking. At higher doses, they provoked ataxia and inhibited the writhing elicited by intra-abdominal acetic acid. The antagonists, (-)-alprenolol, (-)-tertatolol, WAY-100,135 and S 15931 were more potent against the LP than the EP. They also inhibited writhing, and only at very high doses did they elicit ataxia. In rats, 8-OH-DPAT and flesinoxan increased the current required to elicit vocalisation upon electrical stimulation of the tail. The action of 8-OH-DPAT was blocked by WAY-100,135, which, like other antagonists, was inactive alone. Interestingly, a low dose of 8-OH-DPAT partially inhibited the antinociceptive action of the mu-opioid agonist, morphine, the action of which was dose-dependently facilitated by (-)-alprenolol and S 15931. Administered s.c., 8-OH-DPAT elicited spontaneous tail-flicks (STFs) in rats: these were abolished by WAY-100,135, (-)-tertatolol, (-)-alprenolol and S 15931. STFs were also eliminated by s.c. or i.t. administration of the alpha 2-adrenergic receptor agonist, clonidine, the GABAA agonist, muscimol or the GABAB agonist, baclofen. The mu-opioid, morphine, blocked STFs only at high doses and the kappa-opioid agonists, U 50,488 and U 69,593, even at supra-ataxic doses, were inactive. Antagonists at neurokinin (NK)1 (RP 67580), NK2 (SR 48,968) and bradykinin (BK)2 (Hoe 140) receptors, as well as aspirin, did not block STFs, though indomethacin was effective. Antagonists at the glycine B site coupled to the NMDA receptor, L 687,414, L 701,324 and (+)-HA966, blocked STFs. Furthermore, (+)-HA 966 and the competitive NMDA receptor antagonist, CPP, were active upon i.t. administration. STFs were also blocked by s.c. or i.t. administration of the AMPA antagonists, YM 900 and NBQX. In conclusion, the influence of 5-HT1A ligands upon nociception is dependent upon the algesiometric paradigm. Intriguingly, modulation of 5-HT1A receptor-mediated STFs reveals parallels to neuropathic pain.
 ...
PMID:Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. 878 80

We have previously proposed a serotonergic hypothesis for cerebellar ataxia and mentioned that the levorotatory form of 5-hydroxytryptophan, a serotonin precursor, is partially active in subtypes of cerebellar ataxia, including cerebellar cortical atrophy (CCA). It has been demonstrated that 5-HT1A serotonergic receptors play an important role in the control of Purkinje cells discharges and in the inhibition of the release of glutamate by cerebellar glutamatergic terminals. To test further the serotonergic hypothesis of cerebellar ataxia, we administered buspirone, a 5-HT1A agonist usable in human medicine, in a randomized double blind drug placebo trial for 4 months. Nineteen patients with CCA were included; nine patients were given placebo and 10 Buspirone, at the mean dose of 0.69 mg/kg. The evaluation of ataxia was based on a static and a kinetic ataxia scale, fully quantitative measures and the evaluation of the sway path and area at posturography. At 4 months, a significant effect of buspirone was observed for drug induced gains of the kinetic score, two items of the static score, and the maximum duration of standing upright with feet together. These results indicate that a novel chemical therapeutic approach is possible for cerebellar ataxia; moreover, they support the existence of a link between cerebellar ataxia and disturbances of the serotonergic cerebellar system, especially a serotonergic deficit.
 ...
PMID:Buspirone, a serotonergic 5-HT1A agonist, is active in cerebellar ataxia. A new fact in favor of the serotonergic theory of ataxia. 919 69

The present study was conducted to investigate the effects of two noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, GYKI 52466 and GYKI 53405 (the racemate of talampanel) on the generation of spike-wave discharges (SWD) parallel with the vigilance and behavioral changes in the genetic absence epilepsy model of WAG/Rij rats. Intraperitoneal (i.p.) administration of GYKI 52466 (1-[4-aminophenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine; 3, 10 and 30 mg/kg, i.p.), the prototypic compound of the 2,3-benzodiazepine family, caused a fast dose-dependent increase in the number and cumulative duration of SWD. These changes were accompanied by dose-dependent increase in duration of light slow wave sleep (SWS1) and passive awake, vigilance states associated with the presence of SWD. In addition a short, transient behavioral activation occurred that was followed by strong ataxia and immobility, decrease of active wakefulness and increase in deep slow wave sleep. GYKI 53405 (7-acetyl-5-(4-aminophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-b][2,3]benzodiazepine, the racemate of talampanel, 16 mg/kg, i.p.) failed to affect any measure of SWD and vigilance. When used as a pretreatment, GYKI 52466 (10 mg/kg) slightly attenuated SWD-promoting effects of the 5-HT1A receptor agonist 8-OH-DPAT, it decreased cumulative duration and average time of paroxysms. In conclusion, AMPA receptors play moderate role in regulation of epileptic activity, and some of these effects are connected to their effects on vigilance in this model.
 ...
PMID:Effect of two noncompetitive AMPA receptor antagonists GYKI 52466 and GYKI 53405 on vigilance, behavior and spike-wave discharges in a genetic rat model of absence epilepsy. 1514 61


1 2 Next >>