Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD

Abstract Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression pro...

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Autores principales:	Bing Zhang, Fei Guo, Yuqin Ma, Yingcai Song, Rong Lin, Fu-Yi Shen, Guo-Zhang Jin, Yang Li, Zhi-Qiang Liu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8fda276857c044b6b4df46fe5d93ac53
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spelling	oai:doaj.org-article:8fda276857c044b6b4df46fe5d93ac532021-12-02T15:05:19ZActivation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD10.1038/s41598-017-03680-22045-2322https://doaj.org/article/8fda276857c044b6b4df46fe5d93ac532017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03680-2https://doaj.org/toc/2045-2322Abstract Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.Bing ZhangFei GuoYuqin MaYingcai SongRong LinFu-Yi ShenGuo-Zhang JinYang LiZhi-Qiang LiuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bing Zhang Fei Guo Yuqin Ma Yingcai Song Rong Lin Fu-Yi Shen Guo-Zhang Jin Yang Li Zhi-Qiang Liu Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
description	Abstract Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.
format	article
author	Bing Zhang Fei Guo Yuqin Ma Yingcai Song Rong Lin Fu-Yi Shen Guo-Zhang Jin Yang Li Zhi-Qiang Liu
author_facet	Bing Zhang Fei Guo Yuqin Ma Yingcai Song Rong Lin Fu-Yi Shen Guo-Zhang Jin Yang Li Zhi-Qiang Liu
author_sort	Bing Zhang
title	Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
title_short	Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
title_full	Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
title_fullStr	Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
title_full_unstemmed	Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD
title_sort	activation of d1r/pka/mtor signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-spd
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8fda276857c044b6b4df46fe5d93ac53
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Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD

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