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BACKGROUND: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors. MATERIALS AND METHODS: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties. RESULTS: Aripiprazole produced increases in [(35)S]GTPgammaS binding to rat hippocampal membranes. Its potency (pEC(50) = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT(1A)-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT(1A)-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT(1A) receptors (K (i) = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT(2A) receptors (K (i) = 3.4 nM), moderate affinity to 5-HT(2C) (K (i) = 15 nM) and 5-HT(7) (K (i) = 39 nM) receptors, and low affinity to 5-HT(6) receptors (K (i) = 214 nM) and 5-HT transporter (K (i) = 98 nM). In addition, aripiprazole potently blocked 5-HT(2A)-receptor-mediated increases in intracellular Ca(2+) levels in a rat pituitary cell line (IC(50) = 11 nM). DISCUSSION: These results support a partial agonist activity for aripiprazole at 5-HT(1A) receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

Original publication

DOI

10.1007/s00213-006-0621-y

Type

Journal article

Journal

Psychopharmacology (Berl)

Publication Date

02/2007

Volume

190

Pages

373 - 382

Keywords

Animals, Antipsychotic Agents, Aripiprazole, CHO Cells, Calcium, Cell Line, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Drug Interactions, Electrophysiology, Hippocampus, Humans, Male, Neurons, Piperazines, Quinolones, Radioligand Assay, Raphe Nuclei, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT2A, Serotonin 5-HT1 Receptor Agonists, Serotonin 5-HT1 Receptor Antagonists, Serotonin 5-HT2 Receptor Agonists, Serotonin 5-HT2 Receptor Antagonists, Serotonin Antagonists, Serotonin Plasma Membrane Transport Proteins, Serotonin Receptor Agonists