1. ¹Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA
2. ²Department of Psychiatry, University of California, San Francisco, CA, USA
3. ³Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA
4. ⁴Departments of Pharmacology, Psychiatry, Neurology, & Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Correspondence: Dr RB Mailman, Departments of Pharmacology, Psychiatry, Neurology, & Medicinal Chemistry, University of North Carolina School of Medicine, 7001C NC Neurosciences Hospital, CB #7160, Chapel Hill, NC 27599-7160, USA. Tel: +1 919 966 3205; Fax: +1 919 966 9604; E-mail: richard_mailman@med.unc.edu

Received 26 July 2005; Revised 1 December 2005; Accepted 21 February 2006; Published online 22 March 2006.

Abstract

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)S coupling). The current study examined the D_2L 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 D_2L receptor. These data are clear evidence that aripiprazole affects D_2L-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.