Activation and blockade of dorsal hippocampal serotonin4 receptors produce antidepressant effects in the hemiparkinsonian rats

Jia-Wei Wang; Feng Gao; Zhao-Long Wang; Xiao-Chen Wang; Jie Yang; Bo-Rui Ma; Hui-Sheng Wang; Wen Xie; Yuan Guo; Li Zhang

doi:10.1016/j.brainres.2021.147426

Activation and blockade of dorsal hippocampal serotonin4 receptors produce antidepressant effects in the hemiparkinsonian rats

Brain Res. 2021 Mar 15:147426. doi: 10.1016/j.brainres.2021.147426. Online ahead of print.

Authors

Jia-Wei Wang¹, Feng Gao¹, Zhao-Long Wang¹, Xiao-Chen Wang¹, Jie Yang¹, Bo-Rui Ma¹, Hui-Sheng Wang², Wen Xie², Yuan Guo³, Li Zhang⁴

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; The Key Laboratory of Environment and Disease-Related Genes, Ministry of Education, Xi'an 710061, China.
³ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; The Key Laboratory of Environment and Disease-Related Genes, Ministry of Education, Xi'an 710061, China. Electronic address: guoyuan@mail.xjtu.edu.cn.
⁴ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; The Key Laboratory of Environment and Disease-Related Genes, Ministry of Education, Xi'an 710061, China. Electronic address: zhangli1998@mail.xjtu.edu.cn.

PMID: 33737063
DOI: 10.1016/j.brainres.2021.147426

Abstract

Depression is a common non-motor symptom in Parkinson's disease (PD). Although serotonin4 (5-HT₄) receptors and the dorsal hippocampus (dHIP) are regarded to be involved in the depression, the mechanism underlying the effects of 5-HT₄ receptors in the dHIP on PD-related depression should be further investigated. In the present study, unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) increased the expressions of 5-HT₄ receptors and its co-localization with glutamate neurons in the CA1, CA3 and dentate gyrus. Additionally, MFB lesions induced depressive-like behaviors in the sucrose preference and forced swimming tests. The activation or blockade of dHIP 5-HT₄ receptors produced antidepressant effects in the MFB lesioned rats but not in control rats. Neurochemical results showed no changes of monoamines levels in the striatum, medial prefrontal cortex (mPFC), lateral habenula (LHb), and ventral hippocampus (vHIP) in control rats after intra-dHIP injection of 5-HT₄ receptors agonist BIMU8 (26 μg/rat), antagonist GR 113808 (16 μg/rat) or GR 113808/BIMU8 (26 μg/16 μg/rat). But in the lesioned rats, BIMU8, GR113808 or GR 113808/BIMU8 injection increased dopamine levels in the striatum, mPFC, LHb, and vHIP and increased 5-HT levels in the LHb. Intra-dHIP injection of GR 113808 or GR 113808/BIMU8 also increased the noradrenaline levels in the mPFC and LHb. All these results suggest that activation or blockade dHIP 5-HT₄ receptors produce antidepressant effects in the hemiparkinsonian rats, which may be related to the upregulation of 5-HT₄ receptors in the dHIP and the changes of monoamines in the limbic and limbic-related brain regions.

Keywords: Depression; Dorsal hippocampus; Parkinson’s disease; Serotonin4 receptors.