Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the 'atypical' antipsychotics, clozapine and risperidone.
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 dose50 (ED50) 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 (ED50 = 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 (ED50 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.
Schreiber
R
R
Department of Psychopharmacology, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
Brocco
M
M
Millan
M J
MJ
D000662:Amphetamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D003024:Clozapine / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D018967:Risperidone; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000662:Amphetamines; D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D007555:Isoxazoles; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C079049:volinanserin; D003024:Clozapine; D018967:Risperidone; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine