Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors : functional receptor-binding and in vivo electrophysiological studies

• Published in: Psychopharmacologia 2007-02, Vol.190 (3), p.373-382
• Main Authors: STARK, Arlene D, JORDAN, Shaun, BURRIS, Kevin D, ALLERS, Kelly A, BERTEKAP, Robert L, CHEN, Ruoyan, MISTRY KANNAN, Tanaz, MOLSKI, Thaddeus F, YOCCA, Frank D, SHARP, Trevor, KIKUCHI, Tetsuro
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Binding sites; Biological and medical sciences; Medical sciences; Membranes; Neuropharmacology; Pharmacology; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychotropic drugs; Rodents; Schizophrenia; T cell receptors
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-006-0621-y

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 [35S]GTPS binding to rat hippocampal membranes. Its potency (pEC50=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-HT1A-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-HT1A-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-HT1A 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-HT2A receptors (K i=3.4 nM), moderate affinity to 5-HT2C (K i=15 nM) and 5-HT7 (K i=39 nM) receptors, and low affinity to 5-HT6 receptors (K i=214 nM) and 5-HT transporter (K i=98 nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50=11 nM). Discussion These results support a partial agonist activity for aripiprazole at 5-HT1A 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. [PUBLICATION ABSTRACT]