Fluoxetine adjunct to therapeutic exercise promotes motor recovery in rats with cerebral ischemia: Roles of nucleus accumbens

Yan Hua; Ce Li; Jian Hu; Yu-Yuan Wang; Pei-Le Liu; Bei-Yao Gao; Chan Chen; Dong-Sheng Xu; Bei Zhang; Yu-Long Bai

doi:10.1016/j.brainresbull.2019.07.022

Fluoxetine adjunct to therapeutic exercise promotes motor recovery in rats with cerebral ischemia: Roles of nucleus accumbens

Brain Res Bull. 2019 Nov:153:1-7. doi: 10.1016/j.brainresbull.2019.07.022. Epub 2019 Jul 29.

Authors

Yan Hua¹, Ce Li¹, Jian Hu¹, Yu-Yuan Wang¹, Pei-Le Liu¹, Bei-Yao Gao¹, Chan Chen¹, Dong-Sheng Xu², Bei Zhang³, Yu-Long Bai⁴

Affiliations

¹ Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China.
² Rehabilitation Section, Spine Surgery Division of Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Key Laboratory of spine and spinal cord injury repair and regeneration (Tongji University), Ministry of Education of the People's Republic of China, Shanghai 200065, China.
³ Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: loftywaters@sina.com.
⁴ Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: dr_baiyl@fudan.edu.cn.

PMID: 31369829
DOI: 10.1016/j.brainresbull.2019.07.022

Abstract

The study aimed to explore the molecular mechanism of fluoxetine as an adjunct to therapeutic exercise to improve motor recovery using a rat cerebral ischemic model with middle cerebral artery occlusion (MCAO). We hypothesized that the nucleus accumbens (NAc) may be one of the responding areas to fluoxetine where relevant elevations in 5-hydroxytryptamine (5-HT) and ΔFosB were associated with motor behavioral recovery. Male Sprague-Dawley rats were randomly divided into five groups: rats without intervention; rats that underwent MCAO without exercise or fluoxetine; rats that underwent MCAO treated only with fluoxetine; rats that underwent MCAO treated only with exercise; and rats that underwent MCAO treated with both exercise and fluoxetine. Motor function and motivation were assessed by the fault footsteps test and the forced swimming test. 5-HT level in the bilateral NAc and the expression of 5-HT_2C receptor (5-HT_2CR) and ΔFosB in the ipsilesional (left) NAc were measured. Correlation was explored by Pearson correlation analysis. Our results indicated that either treatment helped improve the grasp dexterity of the affected limb, motor motivation, and resilience to adverse environment in MCAO rats. The dual treatment with fluoxetine and exercise may hasten the recovery process. The dual treatment helped restore the balance of 5-HT level between the bilateral NAc by significantly increasing its level in the ipsilesional side. Either treatment could resume the expression of 5-HT_2CR in the ipsilesional side of the NAc close to the normal level, which was correlated with motor recovery. The dual treatment significantly increased the expression of ΔFosB in the ipsilesional side of the NAc, which was correlated with the balance of 5-HT in the bilateral NAc, but not directly with motor recovery. In conclusion, the NAc may play an important role in driving physical motivation, which was possibly related to motor recovery after stroke. Fluoxetine may hasten the effectiveness of therapeutic exercise, possibly via regulating 5-HT and its receptors in the NAc.

Keywords: 5-HT; Cerebral ischemia; Exercise; Fluoxetine; Nucleus accumbens; motor function; ΔFosB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Ischemia / drug therapy*
Exercise Therapy / methods
Fluoxetine / pharmacology*
Infarction, Middle Cerebral Artery / metabolism
Male
Motor Activity / drug effects*
Nucleus Accumbens / drug effects
Physical Conditioning, Animal / physiology
Rats
Rats, Sprague-Dawley

Substances

Fluoxetine