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 = 0.067mg/kg). Nearly full occupancy (80%) was achieved before H₁, D₂, α₁ andα₂ receptors became occupied (ED₅₀ = 0.45, 0.66, 0.75and3.7mg/kg, respectively). Clozapine displayed occupancy of H₁ andα₁ receptors at low doses (ED₅₀ = 0.15and0.58mg/kg, respectively) and of 5-HT₂, 5-HT_1C, D₂, α₂, cholinergic muscarinic and 5-HT_1A receptors at higher dosesED₅₀ = 1.3, 1.8, 9.0, 9.5, 11and15mg/kg, respectively). Haloperidol occupied D₂ andα₁ receptors at low doses (ED₅₀ = 0.13and0.42mg/kg, respectively) and 5-HT₂ receptors at a higher dose (ED₅₀ = 2.6mg/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. It was also suggested that a strong 5-HT₂ receptor blockade preceding a low occupancy of D₂ receptors underlies the beneficial effects on the negative symptoms of schizophrenia and reduces incidence of EPS. At dosages inducing 25% D₂ receptor occupancy in the caudate-putamen, risperidone (0.11 mg/kg) showed 60% occupancy of 5-HT₂ receptors and less than 25% occupancy of the other receptors including H₁ receptors. At 25% D₂ receptor occupancy, clozapine (3.1 mg/kg) resulted in 65% occupancy of 5-HT₂ receptors, but also in more than 80% occupancy ofα₁ receptors and full occupancy of H₁ receptors. At 25% D₂ receptor occupancy, haloperidol (0.048 mg/kg) virtually did not interfere with other receptors. Our study provides evidence that risperidone shows an in vivo receptor occupancy profile in the rat brain that is compatible with the one that is apparently required for beneficial clinical effects, i.e. predominant 5-HT₂ receptor occupancy concomitant with low D₂ receptor occupancy; the gradual increase in D₂ receptor occupancy with increasing dosages provides a wider therapeutic window before EPS-inducing high D₂ receptor occupancy is reached.