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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2007-02

AUTHORS

Arlene D. Stark, Shaun Jordan, Kelly A. Allers, Robert L. Bertekap, Ruoyan Chen, Tanaz Mistry Kannan, Thaddeus F. Molski, Frank D. Yocca, Trevor Sharp, Tetsuro Kikuchi, Kevin D. Burris

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 [(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. More... »

PAGES

373-382

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00213-006-0621-y

DOI

http://dx.doi.org/10.1007/s00213-006-0621-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1009298887

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17242925


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