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Title: Different modulation of RPS6 phosphorylation by risperidone in striatal cells sub populations: involvement of the mTOR pathway in antipsychotic-induced extrapyramidal symptoms in mice
Author: Garcia Cerro, Susana
Mas Herrero, Sergi
Gortat, Anna
Sindreu Balet, Carlos
Martinez Pinteño, Albert
Marmol Carrera, Federico
Boloc, Daniel
Rodríguez Ferret, Natalia
Gassó Astorga, Patricia
Lafuente, Amàlia, 1952-
Keywords: Esquizofrènia
Malaltia de Parkinson
Antipsychotic drugs
Parkinson's disease
Issue Date: Jan-2018
Publisher: Future Medicine
Abstract: Objective: Acute extrapyramidal symptoms (EPS) are frequent and serious adverse reactions to antipsychotic (AP) drugs. Although the proposed mechanism is an excessive blockade of dopamine D2 receptors in the striatopallidal pathway of the striatum, previous studies implicated the mTOR pathway in the susceptibility to EPS. The objective of the present study is to analyze the mTOR-mediated response to risperidone in subpopulations of striatal neurons and its relationship to risperidone-induced motor side effects. Methods: Two mouse strains (A/J and DBA/2J) with different susceptibility to developing EPS were treated with risperidone 1 mg/kg for three consecutive days. Here we monitored, by double labeling immunohistochemistry, ribosomal protein S6 (rpS6) phosphorylation (Ser235/236 and Ser244/247 sites), a marker of mTOR signaling, in the striatonigral pathway (D1-medium spiny neurons (MSNs)), the striatopallidal pathway (D2-MSNs) and striatal cholinergic interneurons. Results: We found that EPS-resistant DBA/2J mice show higher baseline levels of phosphoactivated rpS6 protein in striatal MSNs, compared with EPS-prone A/J mice. Moreover, risperidone differentially targeted rpS6 phosphorylation in direct and indirect pathway neurons in a strain-specific manner: a significant decrease in the phosphorylation of rpS6 at Ser235/236 and Ser240/244 in DRD1-MSNs EPS-resistant DBA/2J mice after; and a significant increase of phospho-Ser235/236-rpS6 in the striatopallidal pathway of the EPS-prone A/J mice in response to risperidone. Conclusions: Our results reveal the vital role of genetic background in the response to risperidone, and point to the mTOR pathway as an important factor in EPS susceptibility. Keywords: Schizophrenia, Antipsychotic, Risperidone, Extrapyramidal symptoms. mTOR pathway, Striatum, Medium spiny neurons
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It is part of: Neuropsychiatry, 2018, vol. 8, num. 3, p. 1083-1093
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ISSN: 1758-2008
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (Institut de Neurociències (UBNeuro))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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