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)

YM992, (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. YM922 showed the same high affinity as fluoxetine against the 5-HT reuptake site (Ki = 21 nM) and a similar affinity to that of crazodone against the 5-HT2A receptor (Ki = 86 nM). In other receptor binding studies, an affinity for the adrenergic alpha 1 receptor (Ki = 200 nM) and 5-HT2C receptor (Ki = 680 nM) was observed. In a monoamine uptake study, YM992 showed a selective 5-HT uptake inhibition (IC50 = 0.15 microM), but only very weakly inhibited both noradrenaline (NA) and dopamine (DA) uptake (IC50 = 3.1 microM (NA), > 10 microM (DA)). YM992 was also found to potently inhibit the aggregation of human platelets (IC50 = 1.9 microM), revealing antagonistic activity for the 5-HT2A receptor in vitro. Enhanced serotonergic neurotransmission, in particular that mediated by the 5-HT1A receptor, has recently been reported to be important in the long-term treatment of depressive disorders with antidepressants. In addition, some 5-HT1A receptor-mediated responses are known to be potentiated by co-administration of 5-HT2A receptor antagonists. Thus, YM992, having both selective 5-HT reuptake inhibition and 5-HT2A antagonistic activity, might show potent therapeutic activity as a novel antidepressant in comparison with conventional SSRIs.
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PMID:Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity. 902 10

Fast cyclic voltammetry (FCV) was used to measure electrically stimulated monoamine efflux in the rat ventral lateral geniculate nucleus (vLGN). The electrochemical characteristics of the released species resembled 5-HT but not dopamine or noradrenaline. Amine efflux was abolished by the sodium channel blocker tetrodotoxin (0.1 microM), Ro 4-1284 (1.0 microM), the fast-acting reserpine analogue, and removal of Ca2+ from the superfusate. Amine efflux was unaffected by the monoamine oxidase inhibitor clorgyline (0.1 microM). Of paroxetine (0.1 microM), desipramine (50 nM) and vanoxerine (0.5 microM), selective blockers of 5-HT, noradrenaline and dopamine uptake respectively, only paroxetine increased monoamine efflux (to 194 +/- 25%, mean +/- SEM) and prolonged the removal half-life (to 638 +/- 105%). The non-specific 5-HT1 antagonist methiothepin (0.2 microM) increased 5-HT efflux on long (20 pulses at 20 Hz) but not short trains (20 pulses at 100 Hz). When tested on pseudo-one-pulse stimulations (5 pulses, 100 Hz), the selective 5-HT1A agonist 8-OHDPAT (1.0 microM) had no effect. CP 93129 (0.3 microM), the selective 5-HT1B agonist, decreased 5-HT efflux to 37 +/- 4% of control and was antagonised by the 5-HT1B blocker isamoltane (0.5 microM) and by the 5-HT1D/B antagonist GR 127935 (50 nM). The preferential 5-HT1D agonist sumatriptan (0.5 microM) also decreased 5-HT efflux, to 55 +/- 6% and was antagonised by GR 127935 (50 nM) but not isamoltane (0.5 microM). These results suggest that 5-HT released in the vLGN can be measured by FCV. Furthermore, released 5-HT is taken up by the 5-HT transporter and may be under the influence of 5-HT1B and 5-HT1D autoreceptors.
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PMID:Serotonin efflux in the rat ventral lateral geniculate nucleus assessed by fast cyclic voltammetry is modulated by 5-HT1B and 5-HT1D autoreceptors. 902 11

In this study, we examined the influence of blockade of serotonin (5-HT)1A and/or 5-HT1B autoreceptors on the fluoxetine-induced increase in dialysate levels of 5-HT as compared with dopamine (DA) and noradrenaline (NAD) in single samples of the frontal cortex (FCx) of freely moving rats. Fluoxetine (10.0 mg/kg, s.c.) elicited a twofold increase in dialysate levels of 5-HT relative to baseline values. The selective 5-HT1A antagonist WAY 100,635 (0.16 mg/kg, s.c.) did not influence 5-HT release alone but doubled the influence of fluoxetine on basal levels. Similarly, the selective 5-HT 1B/1D antagonist GR 127,935 (2.5 mg/kg, s.c.) did not alter basal 5-HT levels alone and doubled the fluoxetine-induced increase in 5-HT levels. Combined administration of WAY 100,635 and GR 127,935 elicited an (at least) additive rise in the fluoxetine-induced increase in 5-HT levels to eightfold basal values, without modifying resting 5-HT levels. These changes were selective for 5-HT inasmuch as the parallel (twofold) increase in DA and NAD levels provoked by fluoxetine was not potentiated. The present data demonstrate that combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly and selectively potentiates the fluoxetine-induced increase in dialysate levels of 5-HT versus DA and NAD in the FCx of freely moving rats. These observations suggest that 5-HT 1A/1B antagonism may represent a novel strategy for the improvement in the therapeutic profile of 5-HT reuptake inhibitor antidepressant agents and that 5-HT may be primarily involved in such interactions.
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PMID:Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935. 904 62

Two state (agonist-antagonist) receptor systems may explain many discrepancies in receptor classification, but the role of transduction (G protein coupling) may be critical. We propose that in some instances synthetic agonists and antagonists may interact with the receptor in such a way as to modify coupling compared with endogenous agonists, and that the transduction system together with the local environment, may contribute more to the rank order of potency of agonists and antagonists than the receptor subtype as defined by structure. Allosteric interactions at ion channels and receptors require a modification of concepts of coupling. Imidazoline ligands have different efficacy in coupling alpha 2-adrenoceptors to G proteins, compared with adrenaline and noradrenaline, and do not show a marked sodium shift, implying that the sodium site, and by implication the arginine switch, is implicated in the differential coupling. The alpha 2-adrenoceptor labeled with a natural agonist does not show subtype selectivity whereas antagonist-labeled alpha 2-adrenoceptors show subtype selectivity. In the 5-HT1A receptor, palmitoylation (of receptor or G proteins) allows the expression of different agonist states. Thus transduction and G protein coupling must be taken into account in receptor classification, even if the primary classification may be structural.
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PMID:Transduction is a major factor influencing receptor characterization. 918 18

(R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045), a novel thiazole derivative, has high affinities for the human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D4.2 receptor, compared with human cloned dopamine D2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)2A receptor (Ki = 1.92 nM) and alpha-1 adrenoceptor (Ki = 1.40 nM) but weak affinities (IC50 values are approximately 1 microM) for six other neurotransmitter receptors (adenosine1, 5-HT1A, 5-HT1C, dopamine transporter, alpha2A and alpha2A) and negligible affinities (IC50 values are over 10(-5) M) for 42 other receptors, including neurotransmitters and hormones, ion channels and second messenger systems. Locomotor hyperactivity induced by methamphetamine (1 mg/kg i.p.) in mice was dose-dependently antagonized by NRA0045 (ED50 = 0.5 mg/kg i.p. and 1.9 mg/kg p.o., respectively). Methamphetamine (10 mg/kg i.p.)-induced stereotyped behavior in mice was dose-dependently antagonized by NRA0045, whereas NRA0045 did not exceed 50% inhibition even at the highest dose given (30 mg/kg i.p.). Catalepsy was dose-dependently and significantly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% induction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocortical dopaminergic neurons more selectively than behaviors associated with nigrostriatal dopaminergic neurons. In rats, tryptamine-induced clonic seizure, a 5-HT2 receptor-mediated behavior, was also dose-dependently inhibited by NRA0045 (ED50 = 1.7 mg/kg i.p.). Norepinephrine-induced lethality is regarded as being induced through the alpha-1 adrenoceptor. NRA0045 dose-dependently antagonized norepinephrine-induced lethality in rats (ED50 = 0.2 mg/kg i.p.). Thus NRA0045 may have a unique antipsychotic activity with regard to dopamine D4 and 5-HT2A receptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.
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PMID:In vitro and in vivo characterization of the dopamine D4 receptor, serotonin 5-HT2A receptor and alpha-1 adrenoceptor antagonist (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl]thiazole (NRA0045). 922 39

Milnacipran, a dual noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitor, increased extracellular levels of NA and 5-HT in hypothalamus of freely moving guinea pigs as measured by microdialysis. The basal levels of both monoamines, which were tetrodotoxin sensitive, were increased in a dose-dependent manner and to a similar extent after the intraperitoneal administration of milnacipran (10 and 40 mg/ kg i.p.). Levels of the NA metabolite 4-hydroxy-3-methoxyphenylglycol (MHPG) were decreased by milnacipran at 10 and 40 mg/kg i.p., whereas those of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) showed no effect. Subcutaneous injection of 5-HT1A and beta-adrenergic receptor antagonist (-)-pindolol alone, at 10 mg/kg, had no effect on the extracellular levels of NA or 5-HT. The concomitant administration of (-)-pindolol (10 mg/kg s.c.) with milnacipran (10 mg/kg i.p.) increased severalfold the effect of milnacipran on the extracellular levels of NA and 5-HT. These results indicate that milnacipran, by blocking the uptake of NA and 5-HT, increases virtually equipotently the extracellular levels of NA and 5-HT, confirming previous in vitro studies. In addition, the antagonism of 5-HT1A autoreceptors by (-)-pindolol potentiates the action of milnacipran on both NA and 5-HT systems, without modifying the ratio of these activities.
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PMID:Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea pig hypothalamus. 923 43

Norepinephrine (NE) is known to activate a number of immediate-early genes (IEGs) in the brain which may be involved in prolonged changes in neuronal function. To investigate the function of these genes it would be useful to have a model system in which they are induced in specific populations of cells in specific brain regions without systemic drug administration which can affect multiple sites. In the present paper we have shown that local infusions of NE or of the alpha2-adrenoceptor antagonist, atipamezole, in the mouse amygdala produces localized expression of fos. The expression of fos was blocked by a cocktail of an alpha1-(prazosin) and beta1-adrenoceptor (betaxolol) blocker but not by a selective 5-HT1A blocker (WAY100135). Prazosin and betaxolol did not have a nonspecific reducing action on fos expression. It is concluded that localized expression of fos after NE infusion in the mouse amygdala represents a model system for further studies of the role of IEG expression in central noradrenergic function.
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PMID:Activation of fos in mouse amygdala by local infusion of norepinephrine or atipamezole. 946 71

The mixed serotonin and noradrenaline reuptake inhibitor, duloxetine, (5.0 mg/kg, s.c.), increased levels of serotonin (220%), dopamine (180%) and noradrenaline (470%) in individual dialysates of frontal cortex of freely moving rats. Its influence on serotonin, but not dopamine or noradrenaline, levels was enhanced by the 5-HT1A receptor antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide 3HCl) (0.16 mg kg(-1), s.c). In the forced swimming test, although duloxetine was inactive alone, it dose dependently reduced immobility in the presence of WAY 100,635. Thus, blockade of 5-HT1A (auto)receptors selectively facilitates the influence of duloxetine on serotonin levels in the frontal cortex in rats and, in the forced swimming model, enhances its 'antidepressant' properties in parallel.
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PMID:WAY 100,635 enhances both the 'antidepressant' actions of duloxetine and its influence on dialysate levels of serotonin in frontal cortex. 954 35

1. A study was made of the effects of 5-carboxamidotryptamine (5-CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. Intravenous infusion of 5-CT at doses of 0.01, 0.1 and 1 mg kg(-1) min(-1) reduced the pressor effects obtained by electrical stimulation. The inhibitory effect of 5-CT was significantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-CT. 2. The inhibition induced by 0.01 microg kg(-1) min(-1) of 5-CT on sympathetically-induced pressor responses was partially blocked after i.v. treatment with methiothepin (10 microg kg(-1)), WAY-100,635 (100 microg kg(-1)) or GR127935T (250 microg kg(-1)), but was not affected by cyanopindolol (100 microg kg(-1)). 3. The selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT(1B/1D) receptor agonists sumatriptan and L-694,247 inhibited the pressor response, whereas the 5-HT1B receptor agonists CGS-12066B and CP-93,129 and the 5-HT2C receptor agonist m-CPP did not modify the pressor sympathetic responses. 4. The selective 5-HT1A receptor antagonist WAY-100,635 (100 microg kg(-1)) blocked the inhibition induced by 8-OH-DPAT and the selective 5-HT(1B/1D) receptor antagonist GR127935T (250 microg kg(-1)) abolished the inhibition induced either by L-694,247 or sumatriptan. 5. None of the 5-HT receptor agonists used in our experiments modified the pressor responses induced by exogenous noradrenaline (NA). 6. These results suggest that the presynaptic inhibitory action of 5-CT on the electrically-induced pressor response is mediated by both r-5-HT1D and 5-HT1A receptors.
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PMID:Characterization of prejunctional 5-HT1 receptors that mediate the inhibition of pressor effects elicited by sympathetic stimulation in the pithed rat. 955 6

Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
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PMID:Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain. 968 35


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