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)

Experimental lesions followed by binding of [3H]4-trans-2-carboxy-5,7-dichloro-4-phenylamino-carbonylamino-1,2 ,3,4- tetrahydroquinoline ([3H]L-689,560, a novel ligand that binds to the glycine modulatory site), [3H]glycine and [3H]glutamate (N-methyl-D-aspartate (NMDA) sensitive) to cryostat sections and quantitative autoradiography were used to investigate the cellular localization of the NMDA receptor complex in the neocortex of the rat. The lesions were produced by intrastriatal injections of either volkensin (2 and 6 ng) or ricin (10 ng): both are suicide transport agents but only the former is retrogradely transported in the CNS. The binding of [3H]L-689,560 was significantly reduced in rats receiving 2 or 6 ng volkensin in deep cortical layers of Fr1/Fr2 ipsilateral to the striatal lesion. Similar reductions were also seen in [3H]glycine and [3H]glutamate binding, but only in rats receiving 6 ng volkensin. Quantitative histological analysis had previously revealed a loss of large infragranular pyramidal neurones with sparing of both interneurones and supragranular pyramidal neurones. There were no significant reductions in binding of any ligand in the superficial layers. In cortical areas Par1/Par2, [3H]L-689,560 was also significantly reduced in deep layers but only in rats receiving 6 ng volkensin. Binding was also reduced in the superficial layers by contrast to Fr1/Fr2. [3H]Glycine and [3H]glutamate binding were unaffected in this area. Binding of [3H]L-689,560 was unaffected in any area following intrastriatal ricin injection. The present study indicates that the NMDA receptor complex is present on pyramidal cells forming the corticofugal pathways. This is discussed in terms of the 5-HT1A receptor which is enriched on these cells.
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PMID:NMDA receptors assessed by autoradiography with [3H]L-689,560 are present but not enriched on corticofugal-projecting pyramidal neurones. 136 17

PD 118717 (7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]-propoxy]-2H-1- benzopyran-2-one sulfate) proved to be a dopamine (DA) D-2 autoreceptor agonist in biochemical and electrophysiological studies in rats and to exhibit an antipsychotic-like profile in behavioral tests in rodents and monkeys. In vitro binding studies indicated that PD 118717 bound selectively to DA D-2 vs. D-1 receptors and exhibited agonist binding properties (biphasic inhibitory curves and GTP shift) similar to DA. It also had significant affinity for serotonin-(5-HT)1A but not 5-HT1B and 5-HT2 receptors. PD 118717 was active in antagonizing the tau-butyrolactone-induced accumulation of dopa in rat striatum and mesolimbic regions. PD 118717 also depressed the firing of DA neurons in substantia nigra pars compacta of rats. In both of the latter tests the effects of PD 118717 were reversed by haloperidol. PD 118717 decreased brain DA metabolism, decreased DA utilization, decreased accumulation of dopa after inhibition of L-aromatic amino acid decarboxylase, stimulated serum corticosterone and inhibited stimulated serum prolactin levels. PD 118717 did not alter striatal acetylcholine levels; nor did it induce locomotor stimulation or stereotypy in normal animals, suggesting a lack of postsynaptic DA stimulation of normosensitive DA receptors. In tests designed to reveal even weak postsynaptic DA agonist effects, PD 118717 stimulated locomotor activity in 6-hydroxydopamine-lesioned animals and relatively higher doses induced a low degree of stereotyped behavior when combined with the DA D-1 agonist SKF 38393. PD 118717 decreased the accumulation of 5-hydroxytryptophan in brain, an effect probably due to an agonist action at 5-HT1A receptors. PD 118717 decreased spontaneous locomotor activity in rodents, antagonized amphetamine-stimulated hyperactivity in mice and inhibited Sidman avoidance in monkeys, effects seen with antipsychotic agents. Unlike DA antagonist antipsychotics, PD 118717 did not induce extrapyramidal dysfunction in monkeys. PD 118717 displayed behavioral activity after p.o. dosing and its effects did not show tolerance on repeated dosing. In conclusion, PD 118717 has the profile of a DA autoreceptor agonist in neurochemical and neurophysiological tests and produces effects suggestive of antipsychotic efficacy without neurological side effect liability in preclinical behavioral tests.
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PMID:Pharmacological characterization of PD 118717, a putative piperazinyl benzopyranone dopamine autoreceptor agonist. 136 70

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.
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PMID:Synthesis and biological characterization of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents. 136 78

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake? 136 65

The effects of pretreatment with the potent and selective 5-HT1A receptor ligand, MDL 73005EF, on the cardiovascular responses to administration of the 5-HT1A receptor agonists, 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), flesinoxan and 5-methylurapidil were studied in conscious spontaneously hypertensive rats (SHR) and compared with those of putative 5-HT1A receptor antagonists. MDL 7300EF (0.1-3 mg/kg) induced a dose-dependent but transient decrease in mean arterial pressure (MAP). Pretreatment with doses of 1 or 3 mg/kg MDL 73005EF significantly inhibited the hypotensive and bradycardiac effects of 8-OH-DPAT (0.03-1 mg/kg). Pretreatment with 1 mg/kg MDL 73005EF similarly reduced the hypotensive actions of flesinoxan (0.3-1 mg/kg) and 5-methylurapidil (0.1 mg/kg). In contrast, MDL 73005EF did not significantly affect the decrease in blood pressure induced by administration of 0.01 mg/kg clonidine, 0.3 mg/kg hydralazine or 0.2 mg/kg nifedipine. The effect of 8-OH-DPAT (0.1 mg/kg) on MAP was also reduced by pretreatment with 1 mg/kg BMY 7378, buspirone or pindolol, but not NAN 190 or spiperone. BMY 7378, NAN 190, pindolol and spiperone induced a significant decrease in blood pressure. To rule out the possibility that the reduced baseline may have influenced responses to 8-OH-DPAT, we showed that pretreatment with the vasodilator, hydralazine (0.3 mg/kg), had no effect on the MAP response to 8-OH-DPAT although it significantly reduced MAP. We conclude that MDL 73005EF acts as a mixed agonist/antagonist at 5-HT1A receptors since it caused a decrease in blood pressure, but also reduced the cardiovascular responses to the 5-HT1A receptor agonists, 8-OH-DPAT, flesinoxan and 5-methylurapidil.
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PMID:Cardiovascular effects of the 5-HT1A receptor ligand, MDL 73005EF, in conscious spontaneously hypertensive rats. 136 61

The effects of 5-HT1A-receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and gepirone, a 5-HT1A/5-HT2-receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and a 5-HT2-receptor agonist (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/)DOI) on the 5-HT1C-receptor-mediated exploratory hypoactivity in rats, induced by m-trifluoromethylphenylpiperazine (TFMPP) or m-chlorophenylpiperazine (m-CPP), were studied in the open field test. (+/-)DOI attenuated the effects of TFMPP and abolished those of m-CPP (not dose-dependently). 5-MeODMT showed a weak antagonistic action only at one, intermediate dose. The effects of TFMPP or m-CPP were not changed by 8-OH-DPAT or gepirone. At the same time, 8-OH-DPAT, gepirone, 5-MeODMT and (+/-)DOI themselves practically did not change the exploratory activity of rats. The obtained results permit an assumption that a functional interaction exists between 5-HT1C- and 5-HT2-receptors, but not between 5-HT1C- and 5-HT1A-ones.
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PMID:Modulation of the 5-HT1C receptor-mediated behavior by 5-HT2, but not 5-HT1A, receptor activation. 136 16

Specific serotonin binding (5-HT1, 5-HT1A, and 5-HT2 subtypes) and membrane anisotropy were measured at 2 h intervals over a 24 h period in the hippocampus and cortex of Wistar WU rats, housed under a 12 h light-dark cycle, with lights on at 07.00. All experiments were performed both in March and December. In the hippocampus significant circadian rhythms could be ascertained for 5-HT1 binding sites in March and December while for 5-HT1A (subtype of 5-HT1) binding sites the circadian rhythm was only significant in March. The membrane anisotropy also showed significant variations only in March. Circadian rhythms were also found in the cortex for 5-HT1 (December) and 5-HT2 (March and December) binding sites as well as for the membrane anisotropy (December). A correlation was found between membrane anisotropy and 5-HT1 and 5-HT2 binding sites in hippocampus and cortex, respectively. A circadian rhythmicity was also observed for serotonin release as measured by in vivo voltammetry in both brain areas. The results obtained on the diurnal variations of serotonin receptor subtypes and serotonin release and the probable inverse relationship of these two parameters may be relevant in understanding the coupling of pre- and postsynaptic activity.
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PMID:Circadian and seasonal rhythms of 5-HT receptor subtypes, membrane anisotropy and 5-HT release in hippocampus and cortex of the rat. 136 61

8-OH-DPAT, a selective 5-HT1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.
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PMID:Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after repeated administration on a conditioned avoidance response (CAR) in the rat. 136 47

Adenylate cyclase activity was measured in platelet membranes from 10 healthy controls, 12 depressed patients, and the same patients after treatment with clomipramine (CMI) followed by lithium carbonate (Li) supplementation, in an attempt to determine whether any evidence for an effect on the serotonergic system could be obtained in peripheral cells. There were no differences in basal, NaF-, PGE1-, or forskolin-stimulated activity either between the control subjects and depressed patients or between activities in the patients measured before treatment, after CMI, and after CMI+Li. The degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT, an effect putatively mediated by a 5-HT1A-like receptor, was not different in the depressed patients compared to controls or affected by CMI treatment, but was significantly reduced after Li supplementation.
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PMID:Platelet adenylate cyclase activity in depression and after clomipramine and lithium treatment: relation to serotonergic function. 136 62

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats. 136 53


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