title: In vitro receptor binding and in vivo receptor occupancy in rat and guinea pig brain: risperidone compared with antipsychotics hitherto used.
abstract: Risperidone was compared with antipsychotics hitherto used for in vitro receptor binding using animal brain or cloned (human) receptors and in vivo receptor occupancy in rat and guinea pig brain following acute treatment. Both in vitro and in vivo, risperidone, 9-OH-risperidone, SM-9018, clozapine and clocapramine showed higher affinity for 5-HT2A- than for D2-receptors, whereas mosapramine, haloperidol, bromperidol and nemonapride had a slight to strong preference for D2- compared to 5-HT2A-receptors. In vivo, risperidone showed the highest potency for 5-HT2A-receptor occupancy; To obtain the same extent of D2-receptor occupancy, a 19-times higher dosage was required. 9-OH-Risperidone, the principal active metabolite of risperidone, showed a receptor occupancy profile comparable to that of risperidone. No regional selectivity for D2-receptor occupancy in mesolimbic vs nigrostriatal areas was detected for any of the compounds. Risperidone differed from the other compounds by the remarkably shallow slope of its D2-receptor dose-occupancy curve. A greater predominance of 5-HT2A-receptor vs D2-receptor occupancy and a more gradual occupancy of D2-receptors differentiate risperidone from the other compounds. Both properties probably assist in preventing an extensive blockade of D2-receptors, the cause for extrapyramidal symptoms (EPS). The predominant 5-HT2A-receptor occupancy most likely underlies risperidone's beneficial effects on the negative symptoms of schizophrenia and an adequately low D2-receptor occupancy adds to the treatment of positive symptoms with a low liability of EPS.
authors.affiliation: Janssen Research Foundation, Department of Biochemical Pharmacology, Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Schotte
authors.forename: P
authors.initials: P
authors.lastname: Bonaventure
authors.forename: P F
authors.initials: PF
authors.lastname: Janssen
authors.forename: J E
authors.initials: JE
authors.lastname: Leysen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018967:Risperidone / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D006220:Haloperidol; D018967:Risperidone