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)

Ipsapirone, a new anxiolytic drug with a high affinity to 5-HT1A receptors, given in a dose of 10 mg/kg ip markedly accelerated noradrenaline disappearance after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (250 mg/kg ip) in the cortex, hippocampus and hypothalamus of male Wistar rats. It also increased disappearance of dopamine and the level of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum. At the same time, the level of 5-hydroxyindoleacetic acid was decreased in the cortex, striatum, hypothalamus, but not changed in the hippocampus. 8-OH-DPAT, a selective agonist of 5-HT1A receptors, used in a dose of 5 mg/kg sc was less effective, having accelerated noradrenaline disappearance in the cortex and hypothalamus, and having increased only the level of homovanillic acid in the striatum. The effect of ipsapirone on catecholamine turnover might be secondary in relation to inhibition of the serotonin neurons. A direct interaction between ipsapirone and its metabolite 1-PP with alpha 1- and alpha 2-adrenoceptors is very likely, too.
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PMID:Ipsapirone, a new anxiolytic drug, stimulates catecholamine turnover in various regions of the rat brain. 198 Mar 61

The affinities of several 5-hydroxy-indole derivatives for serotonin-1 (5-HT1) binding site subtypes, labeled with 2 nM [3H]5-HT, were assessed by quantitative autoradiography on rat brain sections. The results obtained with known ligands, namely 5-hydroxytryptamine (5-HT), 5-methoxytryptamine (5-Me-OT), 5-methoxy-N,N- dimethyl-tryptamine (5-Me-ODMT), 5-hydroxy-N,N-dimethyl-tryptamine (bufotenine) and 8-hydroxy-2-[di-N-propylamino]tetralin (8-OH-DPAT) demonstrate the reliability and the advantages of this technique for pharmacological studies. Novel serotonin derivatives were synthesized by carboxymethylation of the hydroxyl group. One of those new ligands, serotonin-O-carboxy-methyl- glycyl-tyrosinamide (S-CM-GTNH2), inhibited 2 nM [3H]5-HT binding to the substantia nigra with an IC50 of 22.4 nM, a value which is 22 times lower than that found in the dentate gyrus and choroid plexus. This demonstrates the preferential affinity of S-CM-GTNH2 for 5-HT1B versus 5-HT1A and 5-HT1C binding sites. S-CM-GTNH2 contains a tyrosine residue, which may be useful for the synthesis of a radioactive iodinated molecule and for the preparation of 'long-lasting ligands' linked through peptide bonds with a protein. These derivatives could be of great interest for ultrastructural and behavioral studies relevant to 5-HT1B sites.
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PMID:A new 5-hydroxy-indole derivative with preferential affinity for 5-HT1B binding sites. 206 May 97

Effects of lithium, carbamazepine, zotepine, and clonazepam were examined on the behaviour mediated by 5-HT1A receptor and at 5-HT1A binding sites in rats. Forepaw treading, one component of 5-HT behavioural syndrome following subcutaneous injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), was not altered by reserpine, p-chlorophenylalanine, or alpha-methyl-p-tyrosine; in reserpine-treated rats, it was antagonized only by spiperone or by (-)-propranolol. These results indicate that 8-OH-DPAT-induced forepaw treading is produced by the direct stimulation of 5-HT1A receptor postsynaptically and also that this behaviour is not mediated by monoaminergic neurons. Lithium, carbamazepine, and zotepine inhibited forepaw treading in untreated rats; only lithium and clonazepam inhibited it in reserpine-treated rats. After 14 days treatment, only lithium enhanced it while its enhancement was abolished by reserpine. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that zotepine possessed weak affinity for 5-HT1A receptor; others lacked affinity. These results from acute experiments suggest that all drugs tested have inhibitory effects on the 5-HT1A receptor function. These effects, however, were not mediated by 5-HT1A receptor. And it is also suggested that the 5-HT1A receptor function after chronic lithium treatment might be enhanced by monoaminergic systems transsynaptically.
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PMID:[Behavioural effects of 8-OH-DPAT, a 5-HT1A agonist in rats and effects on the behaviour of antimanic drugs]. 289 36

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.
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PMID:Chronic MAO A and MAO B inhibition decreases the 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase. 323 80

Organotypic cultures of fetal mouse spinal cord-ganglion explants (2-4 weeks in vitro) contain forskolin-stimulated adenylate cyclase (AC) activity that is inhibited by levorphanol and other opioid agonists in a dose-dependent manner. Inhibition by levorphanol no longer occurs if sodium is omitted from the incubation and the levorphanol inhibition is blocked by the opioid antagonist, naloxone. These findings together with the ineffectiveness of dextrorphan indicate that the opioid inhibition of forskolin-stimulated AC is receptor mediated. Both the delta- and kappa-receptor subtypes appear to be involved since the selective delta-opioid agonist, [D-Pen2, D-Pen5]enkephalin, and the selective kappa-opioid agonist, t-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide (U-50,488H) are both effective at nanomolar concentrations. In contrast, the selective mu-opioid agonist, Tyr-D-Ala-Gly-N-MePhe-Gly-ol, has no significant effect even at micromolar concentrations. Both cord and ganglion components of the explants contain opioid-sensitive AC. Forskolin-stimulated AC of the explants is also inhibited by serotonin and carbachol. The serotonin effect appears to be mediated by 5-HT1A receptors, based on relative agonist and antagonist selectivity. Chronic exposure of cultures to morphine results in enhanced basal and forskolin-stimulated AC as well as attenuation of opioid-inhibition of AC assayed in the presence of forskolin; treatment of explants with pertussis toxin causes similar changes in the AC system. The inhibitory effect of serotonin is also attenuated by the pertussis toxin treatment. Basal AC activity of the explants (assayed without forskolin present) is stimulated to a small but significant extent by opioids and by serotonin. The opioid stimulatory effect is markedly enhanced following either morphine or pertussis toxin treatment of the explants. The attenuation of opioid- and serotonin-inhibition of AC produced by chronic exposure to pertussis toxin and the attenuation of opioid inhibition produced by exposure to morphine are consonant with the attenuation of opioid and monoaminergic depression of sensory evoked dorsal horn network responses after similar chronic treatments. It is proposed that the inhibitory effects of opioids and serotonin on these neurons are mediated by receptors that are negatively coupled via a pertussis toxin sensitive Gi protein to AC. Furthermore, alterations of AC with chronic morphine treatment may be involved in the development of physiologic tolerance to opioids.
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PMID:Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. 337 Apr 65

Spinal serotonin1 (5-HT1)(labelled by [3H]5-HT), 5-HT1A (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT)), mu- (labelled by [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol ([3H]DAGO) and [3H]naloxone) and delta-opiate (labelled by [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr [( 3H]DSTLE] receptor binding sites were studied in adult rats using quantitative autoradiography after either neonatal treatment with capsaicin or unilateral cervical dorsal rhizotomy. Both treatments produced a significant loss of 5-HT (-20 to -30%) and opiate (-30 to -45%) binding sites within the superficial layers of the dorsal horn, suggesting they are partly located presynaptically on primary afferent fibres. Thus, 5-HT, as well as opiates, might generate analgesia by acting--at least partly--on primary afferent nociceptive fibres at the spinal level.
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PMID:Autoradiographic evidence of serotonin1 binding sites on primary afferent fibres in the dorsal horn of the rat spinal cord. 344 2

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.
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PMID:Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. 378 Aug 61

In this study, we examined and characterized the action of the stereoisomers of 2-amino-4-methyl-delta 2-5-phenyl-oxazoline (4-methylaminorex, 4-MAX) on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10) in anesthetized male rats. This was accomplished using the technique of extracellular single unit recording. The intravenous (i.v.) administration of the stereoisomers of 4-MAX (0.1-6.4 mg/kg) produced a dose-dependent suppression of the basal firing rate of A10 DA cells with the following rank order of potency: trans 4S,5S > cis 4R,5S approximately cis 4S,5R >> trans 4S,5S 4-MAX. The rank order of potency of the isomers of 4-MAX to suppress the firing of A9 DA cells was trans 4S,5S = cis 4R,5S = cis 4S,5R >> trans 4R,5R. The trans 4S,5S isomer was 5-fold more potent in suppressing DA cell firing in the A10 compared to the A9 area. The suppressant action of the isomers on A9 and A10 DA cells was reversed by the i.v. administration of haloperidol and the D2/D3 receptor antagonists (-)-sulpiride and (-)-eticlopride but not by the D1 receptor antagonists SCH 23390 and SCH 39166. In addition, the suppressant action of the trans 4S,5S isomer on A10 DA cells was not antagonized or reversed by the i.v. administration of the receptor antagonists granisetron (5-HT3), ritanserin (5-HT2A,C), idazoxan (alpha 2), phentolamine (peripheral alpha 1), (+/-)-pindolol (5-HT1A,B beta) or prazosin (alpha 1). The pretreatment of animals with either alpha-methyl-p-tyrosine (AMPT) or reserpine, but not p-chlorophenylalanine (PCPA), (+/-)-fluoxetine or tomoxetine, significantly attenuated the suppression of A10 DA cell firing produced by trans 4S,5S 4-MAX. Overall, our results suggest that the suppressant action of 4-MAX on midbrain DA cell firing may be mediated by the release of DA, which subsequently interacts with D2/D3 receptors.
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PMID:Comparison of the action of the stereoisomers of the psychostimulant 4-methylaminorex (4-MAX) on midbrain dopamine cells in the rat: an extracellular single unit study. 748 94

The inhibition of serotonin (5-HT) release produced by antidepressants varying in relative selectivity for blocking uptake of 5-HT and noradrenaline (NA) was compared. Release was measured by microdialysis in anesthetized rats with nerve terminal 5-HT uptake inhibited by local infusion of citalopram (1 microM) through a dialysis probe in hippocampus. With 5-HT uptake first blocked in hippocampus, systemic injection of uptake inhibitors produced decreases in dialysate 5-HT, presumably due to autoreceptor stimulation in the raphe. The largest decreases (about 60-70%) in 5-HT were produced by the selective 5-HT uptake inhibitors sertraline, paroxetine and citalopram. Nonselective blockers caused less suppression of release. Thus, the maximum decrease in 5-HT was 35% after clomipramine, a less selective 5-HT uptake inhibitor, and < or = 30% after the nonselective 5-HT/NA uptake blockers imipramine and amitriptyline, 5-HT was not decreased after maprotiline, a selective NA uptake blocker. Pretreatment with (+)WAY100135 to block 5-HT1A autoreceptors, abolished the inhibition of 5-HT release produced by systemic sertraline, clomipramine and imipramine. One explanation for the difference between selective and nonselective inhibitors with respect to central 5-HT release, is the excitatory effect of (alpha 1) adrenergic receptor stimulation on 5-HT neuronal discharge. However, pretreatment with alpha-methyl-p-tyrosine to deplete NA, did not influence the inhibition of 5-HT release produced by imipramine.
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PMID:Differential inhibition of serotonin release by 5-HT and NA reuptake blockers after systemic administration. 762 67

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or alpha-methyl-p-tyrosine, but not by 5-HT depletion with p-chlorophenylalanine. These data suggest that lithium enhances 5-HT1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT1A receptor down-regulation and unaltered 5-HT1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.
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PMID:Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems. 787 Oct 12


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