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)

Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)1C and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine. 5-HT antagonists selective for 5-HT2 vs. 5-HT1C receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine-appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT1A agonists, (+-)-8-hydroxy-2-(di-n-propylamino)tetralin and BMY 14802; the 5-HT1A/1B agonist, RU24969; the 5-HT1A partial agonist, NAN190; the 5-HT1C/2 antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT1C/2 agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the antidepressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT1C receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5-HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT1C receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. 140 90

We report the synthesis and pharmacological characterization of novel fluorescently labeled ligands with high affinity and specificity for D1 and D2 dopamine receptors. D1-selective antagonist probes have been synthesized using (R,S)-5-(4'-aminophenyl)-8-chloro-2,3,4,5-tetrahydro-3-methyl-[1H]-3- benzazepin-7-ol, the 4'-amino derivative of the high affinity D1-selective antagonist, SCH-23390, while D2-selective antagonist probes were synthesized using the high affinity, D2-selective agonist, N-(p-aminophenethyl)spiperone (NAPS). In addition, we have synthesized fluorescent probes using an amino-derivative of the high affinity, D2-selective agonist, 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT or N-0434). These ligands were coupled to the fluorescent moieties, fluorescein, rhodamine, coumarin, Texas red, Cascade blue, or Bodipy. This resulted in a wide variety of dopaminergic ligands which fluoresce at different wavelengths: Cascade blue and coumarin are blue fluorophores, fluorescein and Bodipy, are yellow-green, and Texas red and rhodamine are red. The interaction of these fluorescent ligands with dopamine and serotonin receptors was evaluated by examining their ability to compete for radioligand binding to D1 and D2 dopamine receptors and 5-HT1A, 5-HT1C and 5-HT2 serotonin receptors. We report here that these novel fluorescent ligands exhibit high affinity and, in general, selectivity for either D1 or D2 dopamine receptors. In addition, we demonstrate that the fluorescent derivatives of PPHT retain the full agonist efficacy exhibited by the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multiple fluorescent ligands for dopamine receptors. I. Pharmacological characterization and receptor selectivity. 167 66

In this study, we have identified and characterized 5-HT3-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT3 binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT3 receptor agonist 2-methylserotonin (2-Me-5HT), similar to the action of 5-HT, produced a current-dependent (10-80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT3 receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10-20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT3 antagonists, with a rank order of effectiveness as follows: ICS 205930 = (+/-)-zacopride greater than granisetron = ondansetron = LY 278584 greater than MDL 72222. Furthermore, the intravenous administration of (+/-)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT3 receptors antagonists, other receptor antagonists such as metergoline (5-HT1A,1B,1C.2), (+/-)-pindolol (5-HT1A,1B, beta), SCH 23390 (5-HT1C.2, D1), l-sulpiride (D2) or SR 95103 (GABAA) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT3-like receptors.
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PMID:5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study. 167 70

RDC4 is a guanine nucleotide-binding protein-coupled receptor clone originally isolated from a canine thyroid cDNA library by Libert and colleagues [Science (Washington D. C.) 244:569-572 (1989)]. We have isolated the corresponding genomic clone for RDC4, have expressed this clone in murine LM (tk-) fibroblasts, and have determined that it encodes a serotonin 5-hydroxytryptamine1D (5-HT1D) receptor. RDC4 is an intronless gene encoding a protein of 377 amino acids, which exhibits greatest sequence identity (43%) to the 5-HT1A receptor and lower overall homology to other serotonergic and catecholaminergic receptors. Membranes prepared from murine LM (tk-) fibroblasts stably transfected with this clone were shown to bind [3H]5-HT in a saturable manner and displayed an apparently homogeneous population of high affinity (Kd = 3.6 nM, Bmax = 275 fmol/mg of protein) [3H]5-HT binding sites. High affinity [3H] 5-HT binding was unchanged using assay conditions [1 microM (+/- )-pindolol and 1 microM (R)-(+/- )-SCH 23390) to pharmacologically mask 5-HT1A, 5-HT1B, and 5-HT1C receptors. Serotonergic ligands displaced specific [3H]5-HT binding with a rank order of potency expected of a 5-HT1D receptor subtype, 5-carboxyamidotryptamine greater than 5-HT greater than yohimbine greater than 8-hydroxy-2-(di-n-propylamino)tetralin greater than ketanserin = spiperone greater than zacopride. Further, transfected cells responded to addition of 5-HT by decreasing the level of forskolin-stimulated cAMP accumulation. These data indicate that the gene RDC4 encodes a functional 5-HT1D receptor.
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PMID:Expression and pharmacological characterization of a canine 5-hydroxytryptamine1D receptor subtype. 175 39

The serotonin (5-HT)1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine) , also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D1/D2) agonist, apomorphine, (0.01-0.63 mg/kg), LY 165,163 (0.16-10.0 mg/kg) dose-dependently elicited robust and sustained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT1A antagonist, (-)-alprenolol. It was also unaffected by the selective D1 antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetrahydro-1H-3-be nza zepine) (2.5 mg/kg) or the selective D2 antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D2 greater than D1) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D1 and D2 receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D1 or D2 agonists, the actions of which are completely blocked by D1 or D2 antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D1/D2 action rather than an activation of 5-HT1A sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The serotonin (5-HT)1A agonist, LY 165,163, induces contralateral rotation in unilateral substantia nigra-lesioned rats via dopamine receptors. 179 76

In the present experiments we have investigated the possible coupling of 5-hydroxytryptamine (HT)3 receptors to the metabolism of phosphatidylinositol (PI) in the rat fronto-cingulate and entorhinal cortices, two brain regions with relatively high density of this receptor subtype. 5-HT dose-dependently increases PI turnover (20-80% increase above basal stimulation), with an EC50 of 0.5 and 0.3 microM for fronto-cingulate and entorhinal cortices, respectively. This effect was blocked by the selective 5-HT3 antagonists, BRL 43694 (granisetron), GR 38032F (ondansetron) and ICS 205-930. The selective 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), mimicked the action of 5-HT and dose-dependently produced a significant increase in PI turnover (46-76% of the 5-HT response). The stimulatory action of 2-Me-5-HT and phenylbiguanide was blocked completely by granisetron, ondansetron and ICS 205-930 but not by other receptor antagonists such as (+/-)-pindolol (a beta, 5-HT1A and 5-HT1B receptor antagonist), methy-sergide (a 5-HT1 and 5-HT2 receptor antagonist), ritanserin (a 5-HT1C and 5-HT2 receptor antagonist), SR 95103 (gamma-aminobutyric acidA receptor antagonist), scopolamine (a muscarinic antagonist), (-)-eticlopride (a D2 receptor antagonist), SCH 23390 (a D1 5-HT2/1C receptor antagonist) and prazosin (an alpha-1 receptor antagonist). In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride. Thus, only the active enantiomer (S)-zacopride, but not the less active enantiomer (R)-zacopride, was effective in blocking the 2-Me-5-HT-induced effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of 5-hydroxytryptamine3 receptor agonists on phosphoinositides hydrolysis in the rat fronto-cingulate and entorhinal cortices. 184 25

A number of studies in the past have indicated that certain types of dopamine receptor-mediated behaviours can be reversed by serotonin agonists. We have recently described a behavior in neonatal rats induced by the selective D1 receptor agonist SKF 38393, which we termed vacillatory behavior. The current study was aimed at determining the effectiveness of several serotonin-specific agents at reversing this behavior. Behaviors measured on day 15 revealed that SKF 38393-mediated behavior was effectively blocked by SCH 23390 (a selective D1 antagonist), serotonin receptor agonists specific for the 5-HT1A receptor (buspirone and ipsapirone), and the serotonin uptake inhibitor clomipramine. However, the behavior was not reversed by diazepam. These data suggest that the serotonergic and dopaminergic neurotransmitter systems must be in a proper balance for appropriate decision-making behaviors to occur.
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PMID:Serotonergic agents restore appropriate decision-making in neonatal rats displaying dopamine D1 receptor-mediated vacillatory behavior. 236 8

The effects of 30 dopamine (DA) antagonists, including 4 as stereoisomeric pairs, on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied. SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists SCH 23390 and SKF 83566, and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by 3H-SCH 23390 in vitro. Pergolide-antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by 3H-spiperone in vitro. Pergolide-induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series. No interaction between D-1 and D-2 antagonists was observed in combination experiments with SCH 23390 and YM 09151-2 in both circling models. Among other reference neurotransmitter antagonists acting on alpha- and beta-adrenoceptors, histamine, serotonin and muscarinic receptors, only the alpha 1-adrenoceptor antagonist prazosin was effective in high doses. In contrast, the alpha 2- and beta-adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide. The 5-HT1A agonist 8-OHDPAT inhibited pergolide-induced circling only. It is concluded that these two behavioural models are selective in vivo measures of relative D-1 and D-2 receptor activity of DA antagonists.
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PMID:Inhibition of SKF 38393- and pergolide-induced circling in rats with unilateral 6-OHDA lesion is correlated to dopamine D-1 and D-2 receptor affinities in vitro. 294 56

The interaction of SCH 23390 with dopamine (DA) and serotonin (5-HT) systems has been examined in vivo and in vitro. Like selective 5-HT2 blockers, SCH 23390 inhibited in vivo [3H]spiperone binding in the rat frontal cortex (ID50: 1.5 mg/kg) without interacting at D2 sites. SCH 23390 was equipotent to cinanserin and methysergide. In vitro, SCH 23390 inhibited [3H]ketanserin binding to 5-HT2 sites (IC50 = 30 nM). Biochemical parameters linked to DA and 5-HT were not changed excepted in striatum where SCH 23390 increased HVA and DOPAC. In the L-5-HTP syndrome model, SCH 23390 clearly showed antagonism of 5-HT2 receptors. SCH 23390 had weak affinity for 5-HT1B (IC50 = 0.5 microM), 5-HT1A (IC50 = 2.6 microM) and alpha 1-adrenergic receptors (IC50 = 4.4 microM).
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PMID:Interaction of the D1 receptor antagonist SCH 23390 with the central 5-HT system: radioligand binding studies, measurements of biochemical parameters and effects on L-5-HTP syndrome. 329 Apr 70

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


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