ARIPIPRAZOLE, A NOVEL ANTIPSYCHOTIC DRUG, INHIBITS QUINPIROLE-EVOKED GTPASE ACTIVITY BUT DOES NOT UP-REGULATE DOPAMINE D-2 RECEPTOR FOLLOWING REPEATED TREATMENT IN THE RAT STRIATUM

Aripiprazole, a quinolinone derivative, is a new dopaminergic agent wh ich has been recently developed and demonstrated to be clinically usef ul as an antipsychotic drug with reduced extrapyramidal motor side eff ects. Here, we found that aripiprazole competed [H-3]spiperone binding with a 100-fold higher affinity than [H-3]SCH23390 binding, and inhib ited the quinpirole-induced facilitation of high-affinity GTPase activ ity in rat striatal membranes. The effects of chronic administration o f aripiprazole and haloperidol on dopamine D-2 receptor binding and mR NA level in rat striata were examined by a [H-3]spiperone binding assa y and a ribonuclease protection assay. Haloperidol induced a significa nt rise in B-max of [H-3]spiperone binding at 1 mg/kg and in the level of dopamine D-2L receptor mRNA at 4 mg/kg. A high dose of aripiprazol e (100 mg/kg) only tended to increase the B-max of [H-3]spiperone bind ing non-significantly, and had no effect on the level of dopamine D-2L receptor mRNA. These results indicated that aripiprazole had an antag onistic activity to dopamine D-2 receptors with a high affinity, but t hat 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 wit hout side effects including tardive dyskinesia.