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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: The authors would like to thank the financial support of the European Regional Development Fund (ERDF), through the COMPETE 2020 - Operational Program for Competitiveness and Internationalization and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, I.P., under projects: PO-CI-01-0145-FEDER- 30943 (ref.: PTDC/MEC-PSQ/30943/2017), PTDC/MED-NEU/27946/2017, and UIDB/ 04539/2020 and UIDP/04539/2020, and the National Mass Spectrometry Network (RNEM) [PO-CI-01-0145-FEDER-402-022125 Ref. ROTEIRO/0028/2013). CS was supported by Ph.D. fellowship SFRH/BD/88419/2012, co-financed by the European Social Fund (ESF) through the POCH - Programa Operacional do Capital Humano and national funds via FCT. Research in the Monteiro laboratory was funded by the FEBS (Federation of European Biochemical Societies) Excellence Awards 2021, and FCT grants 2022.05228.PTDC and 2021.01032.CEECIND. D.R. was supported by FCT doctoral fellowship reference PD/BD/ PD/BD/127823/2016 through the Inter- University Doctoral Program in Ageing and Chronic Disease (PhDOC). 
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.
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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