{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:32:56Z","timestamp":1781105576326,"version":"3.54.1"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"3","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,1,18]]},"abstract":"<jats:p>\n                    The D2\/AKT1\/GSK-3\u03b2 signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (\n                    <jats:italic>DRD2<\/jats:italic>\n                    rs1076560) and AKT1 (\n                    <jats:italic>AKT1<\/jats:italic>\n                    rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3\u03b2 proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of\n                    <jats:italic>DRD2<\/jats:italic>\n                    rs1076560 and the A allele of\n                    <jats:italic>AKT1<\/jats:italic>\n                    rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3\u03b2, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1013535108","type":"journal-article","created":{"date-parts":[[2010,12,27]],"date-time":"2010-12-27T20:45:14Z","timestamp":1293482714000},"page":"1158-1163","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":67,"title":["<i>DRD2\/AKT1<\/i>\n                    interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia"],"prefix":"10.1073","volume":"108","author":[{"given":"Giuseppe","family":"Blasi","sequence":"first","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Napolitano","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate, 80145 Naples, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Ursini","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"},{"name":"Mendel Laboratory,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Taurisano","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Romano","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Caforio","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Fazio","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gelao","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabella","family":"Di Giorgio","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Iacovelli","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201dV. Erspamer,\u201d University of Rome \u201dLa Sapienza,\u201d 00185 Rome, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Sinibaldi","sequence":"additional","affiliation":[{"name":"Mendel Laboratory,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Popolizio","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Istituto Di Ricovero e Cura a Carattere Scientifico \u201cCasa Sollievo della Sofferenza,\u201d 71013 San Giovanni Rotondo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate, 80145 Naples, Italy;"},{"name":"Department of Environmental Sciences, Second University of Naples, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bertolino","sequence":"additional","affiliation":[{"name":"Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University \u201cAldo Moro,\u201d 70124 Bari, Italy;"},{"name":"Department of Neuroradiology, Istituto Di Ricovero e Cura a Carattere Scientifico \u201cCasa Sollievo della Sofferenza,\u201d 71013 San Giovanni Rotondo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,12,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1176\/ajp.156.2.286","article-title":"Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia","volume":"156","author":"Kapur S","year":"1999","unstructured":"S Kapur, RB Zipursky, G Remington, Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. 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