Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

Aripiprazole is a unique atypical antipsychotic drug with an excellent side-effect profile presumed, in part, to be due to lack of typical D2 dopamine receptor antagonist properties. Whether aripiprazole is a typical D2 partial agonist, or a functionally selective D2 ligand, remains controversial (eg D2-mediated inhibition of adenylate cyclase is system dependent; aripiprazole antagonizes D2 receptor-mediated G-protein-coupled inwardly rectifying potassium channels and guanosine triphosphate nucleotide (GTP)γS coupling). The current study examined the D2L receptor binding properties of aripiprazole, as well as the effects of the drug on three downstream D2 receptor-mediated functional effectors: mitogen-activated protein kinase (MAPK) phosphorylation, potentiation of arachidonic acid (AA) release, and D2 receptor internalization. Unlike quinpirole (a full D2 agonist) or (−)3PPP (S(−)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, a D2 partial agonist), the apparent D2 affinity of aripiprazole was not decreased significantly by GTP. Moreover, full or partial agonists are expected to have Hill slopes <1.0, yet that of aripiprazole was significantly >1.0. Whereas aripiprazole partially activated both the MAPK and AA pathways, its potency vs MAPK phosphorylation was much lower relative to potencies in assays either of AA release or inhibition of cyclic adenosine 3′,5′-cyclic monophosphate accumulation. In addition, unlike typical agonists, neither aripiprazole nor (−)3PPP produced significant internalization of the D2L receptor. These data are clear evidence that aripiprazole affects D2L-mediated signaling pathways in a differential manner. The results are consistent with the hypothesis that aripiprazole is a functionally selective D2 ligand rather than a simple partial agonist. Such data may be useful in understanding the novel clinical actions of this drug.