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Neurosci."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We co-treated selective class 1 HDAC inhibitor tacedinaline (CI-994) at different doses (10, 20, and 30 mg\/kg) with HAL (0.05 mg\/kg) in young (3 months) and aged (21 months) mice for 14 consecutive days, then motor and memory behavioral tests were conducted, followed by biochemical measurements.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> CI-994 at doses of 10 and 20 mg\/kg could decrease HAL-induced cataleptic episodes but only 20 mg\/kg was sufficient to improve motor coordination in aged mice. Additionally, CI-994 at 10 and 20 mg\/kg mitigate HAL-induced memory impairment in aged mice. Biochemical analyses showed increased acetylation of histone marks H3K27ac and H3K18ac at the dopamine 2 receptor (D2R) gene (<jats:italic>Drd2<\/jats:italic>) promoter and increased expression of the <jats:italic>Drd2<\/jats:italic> mRNA and D2R protein in the striatum of aged mice after administration of CI-994 at 20 mg\/kg.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the <jats:italic>Drd2<\/jats:italic> promoter, thereby restoring D2R expression and improving antipsychotic drug action.<\/jats:p>","DOI":"10.3389\/fnins.2021.674745","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T21:20:04Z","timestamp":1633555204000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Bryan","family":"McClarty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"B1","first-page":"517","article-title":"Amelioration of the haloperidol-induced memory impairment and brain oxidative stress by cinnarizine.","volume":"11","author":"Abdel-Salam","year":"2012","journal-title":"Excli. 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