Please use this identifier to cite or link to this item: 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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