BLOCKADE OF THE DISCRIMINATIVE STIMULUS EFFECTS OF DOI BY MDL-100,907 AND THE ATYPICAL ANTIPSYCHOTICS, CLOZAPINE AND RISPERIDONE

被引:122
作者
SCHREIBER, R
BROCCO, M
MILLAN, MJ
机构
[1] Department of Psychopharmacology, Institute de Recherches Servier, Centre de Recherches de Croissy, 78920 Croissy-sur-Seine, 125, Chemin de Ronde
关键词
ANTIPSYCHOTIC; DOI ((2,5-DIMETHOXY-4-IODOHENYL)-2-AMINOPROPAN) DRUG DISCRIMINATION; MDL 100,907; 5-HT2A RECEPTOR;
D O I
10.1016/0014-2999(94)90643-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose(50) (ED(50)) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidine-methanol) very potently (ED(50) = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED(50) values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.
引用
收藏
页码:99 / 102
页数:4
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