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

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]GTPγS 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-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-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-HT_2A-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-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.