| Research Abstract |
In vivo occupation of dopamine D-1, D-2and serotonin(5-HT)2 receptors by typical and atypical antipsychotic drugs(APDs)was examined using Nethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline(EEDQ), a protein alkylating reagent which nonselectively and irreversibly inactivates these receptor binding sites. APDs were classified into typical or atypical based on their capacity to induce extrapyramidal side effect(EPS)in man and/or catalepsy in laboratory rodents. Pretreatment of rats with five different classes of typical APDs(haloperidol, 0.25-3 m, /kg ; chlorpromazine, 5-10 mg/k-g ; cisflupenthixol, I mc, /k-g ; zoiepine, 5 mg/kg and nemonapride, 0.5-2 mg/kg potently reversed the EEDQ(8 mg/kg)-induced D-2 receptor inactivation in rat striatum. In contrast, some atypical APDs or its candidates(clozapine, 530 mg/kg ; fluperlapine, 10 mg/ka- risperidone, 0.25 - 3 mg/kg ; setoperone, 0.025 - 0.25 mg/kg ; an-d ORG 5222, 0.25 mg/kg)showed considerable occupation of 5-HT2 receptors in cerebral cortex with smaller or negligible occupation of D-2 and D-1 receptors in striatum. Pretreatment with the other atypical APDs(sulpiride, 30 mgfk-, ; and amperozide, I mg/kg)had no effect on the EEDQ-induced inactivation of these three receptors, although high dose of sulpiride(60 mglkg)and amperozide(5 mg/kg)exhibited slight but significant reversal of D-2 and 5-HT2 receptor inactivation, respectively. It was concluded that a certain group of atypical APDs is characterized by high occupancy of 5-HT2 receptor with lower or minimal occupancy of D-2 and DI receptors in vivo. These pharmacological characteristics of atypical APDs may be relevant in their low capacity to induce EPS and the reported benefical effect on negative symptoms of schizophrenia.
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