pyrimidinones and zotepine

In vivo occupancy by typical or atypical antipsychotic drugs of dopamine D-1, D-2 and serotonin (5-HT)2 receptors in the membranes and slices of the rat brain was measured using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. In the membranes, the occupancy of D-1 receptors in the striatum by all tested drugs except cis-flupenthixol was minimal. Typical antipsychotic drugs such as chlorpromazine (10 mg/kg), haloperidol (1 mg/kg), cis-flupenthixol (1 mg/kg) and zotepine (5 mg/kg) occupied predominantly D-2 receptors in the striatum. Among atypical antipsychotic drugs, sulpiride (30 mg/kg) and amperozide (1 mg/kg) had no effect on the EEDQ-induced reduction in D-1, D-2 or 5-HT2 receptors, whereas clozapine (10 mg/kg), fluperlapine (10 mg/kg), risperidone (1 mg/kg), setoperone (0.25 mg/kg) and ORG 5222 (0.25 mg/kg) occupied mainly 5-HT2 receptors in the frontal cortex. In the slices, the occupancy by all tested drugs of D-1 receptors in the striatum, nucleus accumbens and substantia nigra was minimal with the exception of clozapine which showed about 30% occupancy in the substantia nigra. Typical antipsychotic drugs, chlorpomazine (10 mg/kg) and haloperidol (1 mg/kg) occupied predominantly D-2 receptors in the striatum and the nucleus accumbens. On the other hand, atypical antipsychotic drugs, clozapine (10 mg/kg) and risperidone (1 mg/kg), occupied mainly 5-HT2 receptors in the frontal cortex. These results suggest that there is a certain group of atypical antipsychotic drugs characterized by high occupancy of 5-HT2 receptors and low or minimum occupancy of D-2 receptors. These characteristics may be relevant to their weak potency in producing extrapyramidal side effects in man or catalepsy in rodents. Although we could find no clear regional differences in receptor occupancies by these antipsychotic drugs, further study are needed to elucidate this issue.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain; Chlorpromazine; Clozapine; Dibenzothiepins; Flupenthixol; Haloperidol; In Vitro Techniques; Isoxazoles; Male; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Serotonin; Risperidone