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

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Abstract

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-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.

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Acknowledgements

This study was supported by Bristol-Myers Squibb Company (Princeton, NJ, USA) and Otsuka Pharmaceutical (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb Company.

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Correspondence to Arlene D. Stark.

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Stark, A.D., Jordan, S., Allers, K.A. et al. Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology 190, 373–382 (2007). https://doi.org/10.1007/s00213-006-0621-y

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  • DOI: https://doi.org/10.1007/s00213-006-0621-y

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