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

Bing Zhang,Fu-Yi Shen,Yang Li,Rong Lin,Fei Guo,Guo-Zhang Jin,Yuqin Ma,Zhi-Qiang Liu,Yingcai Song

doi:10.1038/s41598-017-03680-2

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.

Highlights

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by low mood, decreased pleasure, feelings of despair, loss of motivation and anhedonia, and is one of the leading causes of total disability worldwide[1, 2]
Preclinical and clinical studies had shown that l-SPD could relieve both positive and negative symptoms of schizophrenia mediated by D2-like receptors (D2R) antagonism in the nucleus accumbens (NAc) and D1-like receptors (D1R) agonism in the medial prefrontal cortex (mPFC), respectively[20, 24]
The depressive-like behavior was examined by forced swimming, and the results showed that l-SPD-treated animals significantly reversed the abnormal of chronic unpredictable mild stress (CMS)-induced immobility with just one week of administration; this reversal course required 3 weeks with fluoxetine treatment compared with vehicle-treated animals (Fig. 2C)

Summary

Introduction

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by low mood, decreased pleasure, feelings of despair, loss of motivation and anhedonia, and is one of the leading causes of total disability worldwide[1, 2]. Mechanism investigations reveal that l-SPD worked as a specific D1R agonist in the PFC to activate downstream signaling of PKA/mTOR intracellular signaling pathway, which in turn produced an increase of synaptic proteins and further triggers the long-term enhancement of synaptic neurotransmission. This process of D1R mediated signal transduction may be the underlying mechanism of fast antidepressant effect of l-SPD

Methods

Results

Conclusion