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 effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066 B and RU 24969, the 5-HT1A/1B antagonist (+/-)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43694, the unselective 5-HT receptor antagonist methiothepin, and carbidopa + L-5-hydroxytryptophan (L-5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethyl-phenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%-220% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo. 132 93

The effects of various manipulations of brain 5-HT mechanisms on the behavioural responses induced by the selective NK-3 tachykinin agonist senktide in rodents were assessed. Senktide elicited wet dog shakes in the rat which were attenuated by the 5-HT1C/2 antagonist mianserin and the selective 5-HT2 antagonist altanserin. Senktide-induced forepaw treading was stereospecifically attenuated by the 5-HT1A + B antagonist (-)-alprenolol. Senktide also elicited chewing mouth movements and yawning, which were unaffected by mianserin, altanserin, (+)- or (-)-alprenolol, or the selective 5-HT3 antagonist ICS 205-930, but attenuated by the muscarinic antagonist scopolamine. Penile grooming elicited by senktide was attenuated by mianserin, but was unaffected by the other antagonists. Senktide-induced wet dog shakes were enhanced by the 5-HT reuptake inhibitors citalopram and fluoxetine, suppressed by the monoamine oxidase (MAO)-B inhibitor pargyline, but unaffected by the MAO-A inhibitor clorgyline. Forepaw treading was potentiated by citalopram and clorgyline, but not significantly altered by fluoxetine or pargyline. Depletion of 5-HT by p-chlorophenylalanine (PCPA) in the rat attenuated senktide-induced wet dog shakes and forepaw treading. Neither PCPA nor 5,7-dihydroxytryptamine affected senktide-induced behaviours in the mouse, but the degree of brain 5-HT depletion caused by these treatments in mice was relatively small. These findings indicate that stimulation of NK-3 tachykinin receptors by senktide results in a complex behavioural syndrome which is mediated by multiple 5-HT receptors, and dependent upon intact stores of endogenous 5-HT. Independent stimulation of brain cholinergic mechanisms by senktide is also confirmed.
 ...
PMID:Pharmacological characterization of the behavioural syndrome induced by the NK-3 tachykinin agonist senktide in rodents: evidence for mediation by endogenous 5-HT. 169 59

The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT1A receptor mediated lower lip retraction (LLR), 5-HT1C receptor mediated penile erections (PE) or 5-HT2 receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT1A and 5-HT2 receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT1C receptor mediated behaviour remained unchanged. The ED50 for the 5-HT1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1 mg/kg/day) pretreated rats. The number of 5-HT2 receptor mediated (+/-)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED50 for 8-OH-DPAT induced LLR (ED50 values were 0.06 and 0.14 mg/kg, respectively, in placebo--and tranylcypromine--pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT1C and 5-HT2 receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed.
 ...
PMID:Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists, antagonists or anti-depressants. 183 64

There have been few studies investigating the effect of treatments that alter serotonergic neurotransmission on the density of serotonin1A (5-hydroxytryptamine1A [5-HT1A]) receptors, even though lesioning serotonergic neurons has been reported to enhance certain responses thought to be due to activation of 5-HT1A receptors and repeated treatment of rats with different types of antidepressants can diminish 5-HT1A-mediated responses. Consequently, the binding of 3H-8-hydroxy-2-(di-n-propylamino)-tetralin (DPAT) to 5-HT1A receptors in serotonergic cell body and terminal field areas of rat brain was measured by quantitative autoradiography following either the lesioning of serotonergic neurons with 5,7-dihydroxytryptamine (5,7-DHT), or after chronic administration of monoamine oxidase inhibitors (MAOIs) (clorgyline, phenelzine, or tranylcypromine) or inhibitors of 5-HT uptake (citalopram or sertraline). Treatment of rats with 5,7-DHT did not cause any significant increase in binding of 3H-DPAT to 5-HT1A receptors in any area of the brain examined. There was no significant reduction in the binding of 3H-DPAT in terminal field areas of serotonergic innervation in rats treated with 5,7-DHT except in the CA2/CA3 region of the hippocampus (33% to 35% reduction). In the dorsal and median raphe nuclei, the specific binding of 3H-DPAT was reduced by treatment of rats with 5,7-DHT. In lesioned rats, the binding of 3H-cyanoimipramine (3H-CN-IMI) to uptake sites for serotonin was essentially eliminated in all terminal field areas examined, as well as in the dorsal and median raphe nuclei. Repeated administration of clorgyline, phenelzine, tranylcypromine, citalopram, or sertraline produced an attenuation of the hypothermic response of rats to acute subcutaneous injection of the 5-HT1A-receptor-agonist DPAT. In spite of this change in 5-HT1A responsivity, these treatments caused in the same animals no consistent change in the binding of 3H-DPAT in either serotonergic cell body or terminal field areas. Of the five drugs studied that diminished DPAT-induced hypothermia, only phenelzine and clorgyline significantly reduced the binding of 3H-DPAT, and even then in only a few of the 12 areas of brain measured. As a result of treatment of rats with tranylcypromine there was a significant increase in the binding of 3H-DPAT in the CA2/CA3 region of the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:A quantitative autoradiographic study of serotonin1A receptor regulation. Effect of 5,7-dihydroxytryptamine and antidepressant treatments. 202 79

The anatomical distribution of [3H]norharman binding sites was determined by quantitative autoradiography in rat brain slices. They are enriched in hypothalamic, thalamic, accumbens and amygdaloid nuclei as well as in hippocampal, neocortical and olfactory-related structures. The distribution pattern differs from that of other previously described receptors or binding sites (e.g. monoamine oxidase, benzodiazepine, tryptamine, 5-hydroxytryptamine receptors (5-HT1A, 5-HT1B, 5-HT1C, 5HT2], which suggests that a unique class of [3H]norharman binding sites exists in the rat brain. The findings are consistent with previous experiments which showed high affinity binding sites for [3H]norharman in rat brain membranes (KD 1.552 nM; autoradiography KD 5.5 nM). A correspondence in the displacing activity of drugs was found for both methods (crude membrane fraction: harman much greater than tryptamine much greater than 5-hydroxytryptamine greater than N-methyl-beta-carboline-3-carboxamide (FG 7142) = diazepam; autoradiography: harman much greater than tryptamine much greater than FG 7142 greater than 5-hydroxytryptamine greater than diazepam). Provided that the binding sites represent functional receptors, the present anatomical findings may explain the biological effects of norharman, e. g. pro-conflict behaviour (limbic-hypothalamic structures), tonic-clonic convulsions (limbic-cortical structures) and alterations of locomotor activity (accumbens nucleus).
 ...
PMID:Quantitative autoradiography of [3H]norharman [( 3H]beta-carboline) binding sites in the rat brain. 215 25

Obsessive-compulsive disorder (OCD) is emerging very clearly as a serotonin specific illness. The evidence for this comes from a variety of clinical sources. Firstly the efficacy of 5-HT uptake inhibitors, especially clomipramine, is consistent and strong. Secondly clomipramine has not merely been found to be effective against placebo in 9 placebo controlled studies, it is also found to be more effective in some studies than reference tricyclic antidepressants and monoamine oxidase inhibitors. In other studies tricyclic antidepressants do not appear to be better than placebo. The lack of efficacy of general antidepressants, neuroleptics and benzodiazepines supports the specificity of the serotonin effect. Thirdly the evidence of the efficacy of clomipramine in OCD without concomitant depression reported by Montgomery 1980 and supported by other studies suggests that 5-HT uptake inhibitors have a specifically anti-obsessional effect. The lack of response of depressive symptoms in OCD to other antidepressants suggests that these depressive symptoms are integral to OCD and will only respond when the OCD is treated. Many of the studies found efficacy for 5-HT uptake inhibitors compared with placebo despite both groups being treated with concomitant behaviour therapy. This argues either for behaviour therapy being relatively ineffective or for there being a synergistic effect with the 5-HT uptake inhibitor which is more likely. Results from studies with selective serotonergic probes with a worsening of OCD symptoms in response to the 5-HT1A agonist, m-chlorophenyl piperazine, add support to the serotonergic hypothesis of OCD but further investigation is needed.
 ...
PMID:[Biological treatments in obsessive-compulsive disorder]. 220 92

Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5-HT2 antagonist methysergide and the 5-HT neurotoxin 5,7-dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m-trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.
 ...
PMID:Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behavior. 274 11

Hypo- and hyperthermic responses resulting from the activation of putative 5-HT1A and 5-HT2 receptors, respectively, were examined after the chronic treatment of rats with monoamine oxidase inhibitors. The treatment of rats for 4 or 7 days with nialamide (40 mg/kg, twice daily) resulted in a suppression of the hypothermic effect of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05-0.25 mg/kg, SC). The decrease in body temperature elicited by a low dose of 5-methoxy-N, N-dimethyltryptamine (5MeODMT, 1 mg/kg) also was diminished in rats treated chronically with nialamide. The administration of a high dose of 5MeODMT (5 mg/kg) resulted in a hyperthermic response, which was also attenuated after the repeated administration of nialamide. The repeated administration of clorgyline (a selective inhibitor of type A MAO) or deprenyl (a selective inhibitor of type B MAO) failed to alter the hypothermic effect of 8-OH-DPAT. However, in animals treated chronically with both clorgyline and deprenyl, a suppressed response to 8-OH-DPAT was observed. In view of the concept that the hypo- and hyperthermic responses to 5-HT agonists are mediated by 5-HT1A and 5-HT2 receptor subtypes, respectively, it is concluded that the responsiveness of these 5-HT receptor subtypes involved in thermoregulatory responses is decreased following chronic treatment of rats with monoamine oxidase inhibitors. It appears that inhibition of both type A and B MAO is necessary for this desensitization process.
 ...
PMID:Suppression of the hypo- and hyperthermic responses to 5-HT agonists following the repeated administration of monoamine oxidase inhibitors. 294 56

The effect of chronic administration of various monoamine oxidase (MAO) inhibitors on the ability of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to inhibit forskolin-stimulated adenylate cyclase activity was studied. Groups of 12 rats were given either saline, (E)-beta-fluoromethylene-m-tyrosine (MDL 72394 0.25 mg/kg p.o.), clorgyline (1 mg/kg p.o.), selegiline (1 mg/kg p.o.) or tranylcypromine (5 mg/kg p.o.) once a day for 21 days. Biochemical determinations were made 72 h after the final dose. MDL 72394 and tranylcypromine produced a nonselective inhibition of MAO but clorgyline and selegiline selectively inhibited MAO A and MAO B respectively. All treatments that inhibited MAO A also increased tissue levels of 5-HT. Chronic treatment with MDL 72394, clorgyline or tranylcypromine reduced the ability of 8-OH-DPAT to inhibit forskolin-stimulated adenylate cyclase activity. These data suggest that chronic nonselective and chronic MAO A inhibition causes a down-regulation of the 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase activity.
 ...
PMID:Chronic MAO A and MAO B inhibition decreases the 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase. 323 80

The synthesis of a tritiated derivative of the 5-HT1A photoaffinity probe 8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin ([3H]8-methoxy-3'-NAP-amino-PAT) allowed the use of this probe for attempting the irreversible labeling of specific binding sites in rat brain membranes. Sodium dodecyl-sulfate-polyacrylamide gel electrophoresis of proteins solubilized from hippocampal microsomal membranes that had been incubated with 20 nM [3H]8-methoxy-3'-NAP-amino-PAT under UV light revealed a marked incorporation of 3H label into a 63-kilodalton protein termed PI. As expected of a possible correspondence between PI and 5-HT1A receptor binding sites, 3H labeling by the photoaffinity probe could be prevented by selective 5-HT1A ligands such as 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, buspirone, and gepirone and by N-ethylmaleimide, but not by the 5-HT2 antagonist ketanserin, noradrenaline- and dopamine-related drugs, monoamine oxidase inhibitors, and chlorimipramine. Furthermore, the regional and subcellular distributions of PI were identical to those of specific 5-HT1A binding sites. These results indicated that the binding subunit of the 5-HT1A receptor is a 63-kilodalton protein with a functionally important sulfhydryl group(s).
 ...
PMID:Identification of the 5-HT1A receptor binding subunit in rat brain membranes using the photoaffinity probe [3H]8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin. 359 78


1 2 3 4 5 6 7 Next >>