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Haloperidol is a typical antipsychotic medication used in the treatment of schizophrenia that is known to antagonize dopamine D2 receptors, which are abundantly expressed in the striatum. However, haloperidol\u2019s delayed therapeutic effect also suggests a mechanism of action that may go beyond the acute blocking of D2 receptors. Here, we performed proteomic analysis of striatum brain tissue and found more than 400 proteins significantly altered after 30 days of chronic haloperidol treatment in mice, namely proteins involved in glutamatergic and GABAergic synaptic transmission. Cell-type specific electrophysiological recordings further revealed that haloperidol not only reduces the excitability of striatal medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) but also affects D1-MSNs by increasing the ratio of inhibitory\/excitatory synaptic transmission (I\/E ratio) specifically onto D1-MSNs but not D2-MSNs. Therefore, we propose the slow remodeling of D1-MSNs as a mechanism mediating the delayed therapeutic effect of haloperidol over striatum circuits. Understanding how haloperidol exactly contributes to treating schizophrenia symptoms may help to improve therapeutic outcomes and elucidate the molecular underpinnings of this disorder.<\/jats:p>","DOI":"10.1038\/s41398-023-02609-w","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T08:02:49Z","timestamp":1696579369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Chronic treatment with D2-antagonist haloperidol leads to inhibitory\/excitatory imbalance in striatal D1-neurons"],"prefix":"10.1038","volume":"13","author":[{"given":"C\u00e1tia","family":"Santa","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0607-1953","authenticated-orcid":false,"given":"Diana","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Joana F.","family":"Coelho","sequence":"additional","affiliation":[]},{"given":"Sandra I.","family":"Anjo","sequence":"additional","affiliation":[]},{"given":"Vera M.","family":"Mendes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5977-341X","authenticated-orcid":false,"given":"Diogo","family":"Bessa-Neto","sequence":"additional","affiliation":[]},{"given":"Michael J.","family":"Dunn","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4308-0648","authenticated-orcid":false,"given":"David","family":"Cotter","sequence":"additional","affiliation":[]},{"given":"Gra\u00e7a","family":"Baltazar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3288-4560","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Monteiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4042","authenticated-orcid":false,"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"2609_CR1","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/S0140-6736(20)30925-9","volume":"396","author":"Global burden of 369 diseases and injuries in 204 countries and territories.","year":"2020","unstructured":"Global burden of 369 diseases and injuries in 204 countries and territories. 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. 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