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https://hdl.handle.net/10316/111224
Title: | Chronic treatment with D2-antagonist haloperidol leads to inhibitory/excitatory imbalance in striatal D1-neurons | Authors: | Santa, Cátia Rodrigues, Diana Coelho, Joana F. Anjo, Sandra I. Mendes, Vera M. Bessa-Neto, Diogo Dunn, Michael J. Cotter, David Baltazar, Graça Monteiro, Patrícia Manadas, Bruno |
Issue Date: | 6-Oct-2023 | Publisher: | Springer Nature | Project: | PTDC/MEC-PSQ/30943/2017 PTDC/MED-NEU/27946/2017 UIDB/ 04539/2020 info:eu-repo/grantAgreement/UIDP/04539/2020 SFRH/BD/88419/2012 2022.05228.PTDC 2021.01032.CEECIND PINFRA/22125/2016 PD/BD/127823/2016 |
Serial title, monograph or event: | Translational Psychiatry | Volume: | 13 | Issue: | 1 | Abstract: | Striatal dysfunction has been implicated in the pathophysiology of schizophrenia, a disorder characterized by positive symptoms such as hallucinations and delusions. 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's 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. | URI: | https://hdl.handle.net/10316/111224 | ISSN: | 2158-3188 | DOI: | 10.1038/s41398-023-02609-w | Rights: | openAccess |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais IIIUC - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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