Aripiprazole, a novel antipsychotic drug, inhibits quinpriole-evoked GTPase activity but does not up-regulate dopamine D 2 receptor following repeated treatment in the rat striatum

Abstract

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [ 3H]spiperone binding with a 100-fold higher affinity than [ 3H]SCH23390 binding, and inhibited the quinpriole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D 2 receptor binding and mRNA level in rat striata were examined by a [ 3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in B max of [ 3H]spiperone binding at 1 mg/kg and in the level of dopamine D 2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the B max of [ 3H]spiperone binding non-significantly, and had no effect on the level of dopamine D 2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D 2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D 2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability of aripiprazole to act without side effects including tardive dyskinesia.