IN-VITRO RECEPTOR-BINDING AND IN-VIVO RECEPTOR OCCUPANCY IN RAT AND GUINEA-PIG BRAIN - RISPERIDONE COMPARED WITH ANTIPSYCHOTICS HITHERTO USED

Risperidone was compared with antipsychotics hitherto used for in vitr o 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 D-2-receptors, whereas mosapramine, haloperidol, bromperidol and nemonapride had a slight to strong preference for D-2- compared t o 5-HT2A-receptors. In vivo, risperidone showed the highest potency fo r 5-HT2A-receptor occupancy; To obtain the same extent of D-2-receptor occupancy, a 19-times higher dosage was required. 9-OH-Risperidone, t he principal active metabolite of risperidone, showed a receptor occup ancy profile comparable to that of risperidone. No regional selectivit y for D-2-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 D-2-receptor dose-oc cupancy curve. A greater predominance of 5-HT2A-receptor vs D-2-recept or occupancy and a more gradual occupancy of D-2-receptors differentia te risperidone from the other compounds. Both properties probably assi st in preventing an extensive blockade of D-2-receptors, the cause for extrapyramidal symptoms (EPS). The predominant 5-HT2A-receptor occupa ncy most likely underlies risperidone's beneficial effects on the nega tive symptoms of schizophrenia and an adequately low D-2-receptor occu pancy adds to the treatment of positive symptoms with a low liability of EPS.