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 D-2 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 H-1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED(50) = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H-1, D-2, alpha(1) and alpha(2) receptors became occupied (ED(50) = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H-1 and alpha(1) receptors at low doses (ED(50)= 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D-2, alpha(2), cholinergic muscarinic and 5-HT1A receptors at higher doses (ED(50)= 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D-2 and alpha(1), receptors at low doses (ED(50) = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED(50) = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED(50)-values in various brain areas, e.g. D-2 receptors in striatum and mesolimbic areas. The ED(50)-values for the ex vivo measured occupancy of 5-HT2 and D-2 receptors were in good agreement with ED(50)-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D-2 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 D-2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D-2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs, low (25%) D-2 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 D-2 receptors underlies the beneficial effects on the negative symptoms of schizophrenia and reduces incidence of EPS. At dosages inducing 25% D-2 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 H-1 receptors. At 25% D-2 receptor occupancy, clozapine (3.1 mg/kg) resulted in 65% occupancy of 5-HT2 receptors, but also in more than 80% occupancy of alpha(1) receptors and full occupancy of H-1 receptors. At 25% D-2 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 D-2 receptor occupancy; the gradual increase in D-2 receptor occupancy with increasing dosages provides a wider therapeutic window before EPS-inducing high D-2 receptor occupancy is reached.