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This G protein\u2010independent pathway may be important in mediating the antimanic effects of mood stabilizers and antipsychotics. The mood stabilizer lithium influences behavior and <jats:styled-content style=\"fixed-case\">Akt<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">GSK\u20103<\/jats:styled-content> signaling in mice and many antipsychotics have been shown to more potently antagonize the activity of the <jats:italic>\u03b2<\/jats:italic>\u2010arrestin\u20102 pathway relative to the G protein\u2010dependent pathway. Cariprazine, an antipsychotic with potent <jats:styled-content style=\"fixed-case\">D<jats:sub>3<\/jats:sub>R<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">D<jats:sub>2<\/jats:sub>R<\/jats:styled-content> partial agonist activity and preferential binding to <jats:styled-content style=\"fixed-case\">D<jats:sub>3<\/jats:sub>R<\/jats:styled-content>, was investigated for its effects on the mediators of <jats:styled-content style=\"fixed-case\">D<jats:sub>2<\/jats:sub>R<\/jats:styled-content> pathways in vitro and its efficacy in animal models of mania. Effects on G protein\u2010dependent activity were measured <jats:italic>via<\/jats:italic> inhibition of isoproterenol\u2010induced <jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> production; effects on <jats:styled-content style=\"fixed-case\">D<jats:sub>2<\/jats:sub>R<\/jats:styled-content>\/<jats:italic>\u03b2<\/jats:italic>\u2010arrestin 2 signaling were determined using bioluminescence resonance energy transfer (<jats:styled-content style=\"fixed-case\">BRET<\/jats:styled-content>). Cariprazine was tested in vivo for antimanic\u2010like activity, using the ouabain\u2010induced hyperactivity model in rats. Cariprazine was more potent than aripiprazole in inhibiting isoproterenol\u2010induced <jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> although both compounds showed similar maximum efficacy. In assays of <jats:styled-content style=\"fixed-case\">D<jats:sub>2<\/jats:sub>R<\/jats:styled-content>\/<jats:italic>\u03b2<\/jats:italic>\u2010arrestin 2\u2010dependent interactions, cariprazine showed very weak partial agonist activity, unless the levels of receptor kinase were increased; as an antagonist it showed similar potency to haloperidol and ~fivefold greater potency than aripiprazole. In an animal model of mania, cariprazine showed similar efficacy as lithium in attenuating the effects of ouabain\u2010induced hyperactivity. In summary, the differential effects of cariprazine on <jats:styled-content style=\"fixed-case\">D<jats:sub>2<\/jats:sub>R<\/jats:styled-content> G protein and <jats:italic>\u03b2<\/jats:italic>\u2010arrestin 2 mediators of signal transduction pathways could contribute to its potent antimanic\u2010like activity.<\/jats:p>","DOI":"10.1002\/prp2.73","type":"journal-article","created":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T08:35:18Z","timestamp":1417509318000},"source":"Crossref","is-referenced-by-count":26,"title":["Cariprazine exerts antimanic properties and interferes with dopamine D<sub>2<\/sub> receptor <i>\u03b2<\/i>\u2010arrestin interactions"],"prefix":"10.1002","volume":"3","author":[{"given":"Yonglin","family":"Gao","sequence":"first","affiliation":[{"name":"Departments of Cell Biology, Medicine and Neurobiology Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Peterson","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology, Medicine and Neurobiology Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Masri","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology, Medicine and Neurobiology Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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