Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography.

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H1, D2, alpha 1 and alpha 2 receptors became occupied (ED50 = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H1 and alpha 1 receptors at low doses (ED50 = 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, alpha 2, cholinergic muscarinic and 5-HT1A receptors at higher doses (ED50 = 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D2 and alpha 1 receptors at low doses (ED50 = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol.(ABSTRACT TRUNCATED AT 400 WORDS)