Pharmacological characterization of RP 62203, a novel 5‐hydroxytryptamine 5‐HT<sub>2</sub> receptor antagonist

Doble, Adam; Girdlestone, D.; Piot, O.; Allam, D.; Betschart, J.; Boireau, A.; Dupuy, Aubry E.; Guérémy, C.; Ménager, Jean; Zundel, J.L.; Blanchard, Jean‐Charles

doi:10.1111/j.1476-5381.1992.tb14206.x

Cited by 47 publications

(17 citation statements)

References 58 publications

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“…But this does not negate the potential importance of the 5-HT2 site in mediating inhibitory effects since m-chlorophenylpiperazine, other agonists at the 5-HT2c site and withdrawal from ethanol treatment may mediate their anxiogenic-like behaviours in animals (mouse light/dark test, rat social interaction) and anxiogenic effects in man at this site (see Kennett et al, 1989;Lal et al, 1993). Evidence to support a greater involvement of the 5-HT2c than the 5-HT2A receptor comes from the present findings in (Doble et al, 1992). Such interactions, particularly at the 5-HTlA and 5-HT3 receptors which can mediate changes in behaviour in response to aversive situations, are worthy of further investigation (see Costall et al, 1990;Treit, 1991).…”

Section: Discussionsupporting

confidence: 58%

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Costall

Naylor

1995

British J Pharmacology

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1 The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2 The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test.3 The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4 Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5 Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6 The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7 In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

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Section: Discussionsupporting

confidence: 58%

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Costall

Naylor

1995

British J Pharmacology

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“…The tritiated form of this ligand has been used both in in vitro and in vivo binding experiments (Rinaldi-Carmona et al 1993) but not as radioligand for autoradiographical visualization. Another recently available antagonist, RP62203, relatively selective for 5-HT 2A receptors (Doble et al 1992) has been used in its tritiated form for the autoradiographical visualization of these receptors in rat brain (Malgouris et al 1993b). In addition to labelling 5-HT 2A receptors the radioligand labels other serotonin receptor sites wich are especially prominent in choroid plexus.…”

Section: Discussionmentioning

confidence: 99%

Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907

López-Giménez

Mengod

Palacios

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

181

113

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“…Assays were conducted in duplicate. [ 3H I Mesulergine was used at a concentration of 2 nM, which approximates its KD at 5-HT 2A and 5-HT2~sites (Hoyer, 1988;Van Wijngaarden et al, 1990;present results to label 5-HT 2A sites (Doble et al, 1992;Malgouris et al, 1993a,b). Assays were carried out by incubating 100 ‚ag of membrane protein in a total volume of 250 ‚al containing 50 mM HEPES-Tris, pH 7.4, with the indicated additions.…”

Section: Radioligand Binding Assaysmentioning

confidence: 99%

“…5-HT2A sites in caudate were measured by using (70-100-fold) for 5-HT2A sites versus 5-HT2~sites (Malgouris et al, 1 993a) and its relatively low affinity for dopamine D2 receptors and tetrabenazine sites (Doble et al, 1992;Malgouris et al, 1993b). The Bmax for 5-HT2A sites was 165.4 ±9.7 fmol/mg of protein (Table 1), which is consistent with data from studies using [ 3H]ketanserin Hrdina and Vu, 1993 picts competition data with mianserin in the presence of 100 nM spiperone.…”

Section: Density Of 5-ht2a and 5-ht2~sites In Caudatementioning

confidence: 99%

The Serotonin 5‐HT_2C Receptor Is a Prominent Serotonin Receptor in Basal Ganglia: Evidence from Functional Studies on Serotonin‐Mediated Phosphoinositide Hydrolysis

Wolf

Schutz

1997

Journal of Neurochemistry

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Serotonin (5-hydroxytryptamine; 5-HT) and 5-HT2receptors belong to the class of phosphoinositide-specific phospholipase C (PLC)-linked receptors. Conditions were established for measuring 5-HT2A-linked and 5-HT2~-linkedPLC activity in membranes prepared from previously frozen rat frontal cortex and caudate. In the presence of Ca 2~(300 nM) and GTPyS (1 ftM), 5-HT increased PLC activity in caudate membranes. Pharmacological analysis using the selective 5-HT 2A antagonist, spiperone, and the nonselective 5-HT2AI2C antagonist, mianserin, demonstrated that over half of the 5-HT-stimulated PLC activity was due to stimulation of 5-HT2~receptors as opposed to 5-HT2A receptors. Radioligand binding assays with [ 3H]RP62203 and [3H]-mesulergine were used to quantify 5-HT 2A and 5-HT2s ites, respectively, in caudate. From these data, the Bmax for caudate 5-HT2A sites and 5-HT2~sites was 165.4 ii 9.7 fmol/mg of protein and 49.7 ±3.3 fmol/mg of protein, respectively. In contrast to that in caudate, PLC activity in frontal cortex was stimulated by 5-HT in a manner that was inhibited by the 5-HT2A-selective antagonists, spiperone and ketanserin. Taken together, the results indicate that 5-HT2A-and 5-HT2~-linkedPLC activity can be discerned in brain regions possessing both receptor subtypes using membranes prepared from previously frozen tissue. More importantly, significant 5-HT2~-mediated phosphoinositide hydrolysis was observed in caudate, despite the relatively low density of 5-HT2~sites. The significance of these observations with respect to the physiological function of 5-HT2~receptors is discussed. Key Words: Serotonin receptor-Phospholipase C-Phosphoinositide hydrolysis-Brain-Rat.

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Pharmacological characterization of RP 62203, a novel 5‐hydroxytryptamine 5‐HT₂ receptor antagonist

Cited by 47 publications

References 58 publications

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907

The Serotonin 5‐HT_2C Receptor Is a Prominent Serotonin Receptor in Basal Ganglia: Evidence from Functional Studies on Serotonin‐Mediated Phosphoinositide Hydrolysis

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Pharmacological characterization of RP 62203, a novel 5‐hydroxytryptamine 5‐HT2 receptor antagonist

Cited by 47 publications

References 58 publications

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907

The Serotonin 5‐HT2C Receptor Is a Prominent Serotonin Receptor in Basal Ganglia: Evidence from Functional Studies on Serotonin‐Mediated Phosphoinositide Hydrolysis

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Pharmacological characterization of RP 62203, a novel 5‐hydroxytryptamine 5‐HT₂ receptor antagonist

The Serotonin 5‐HT_2C Receptor Is a Prominent Serotonin Receptor in Basal Ganglia: Evidence from Functional Studies on Serotonin‐Mediated Phosphoinositide Hydrolysis