Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties

Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D2 receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD2 receptor function and affinity, and of in vivo models of dopamine rat D2 receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD2 receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D2 receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.