Parmipexole Regulates The Depressive-like Symptoms Via Dopamine 3 Receptor In A Mouse Model Of Parkinson's Disease

Objective:This study aimed to explore the effect of the dopamine D2/D3 receptor agonist pramipexole on the remission of depression in Parkinson's disease(PD)mice and the role of D2R and D3R in the antidepressant effect of pramipexoleMaterials and methods:C57BL/6J mice,D2R knockout mice and D3R knockout mice were used in our study.First,C57BL/6J male mice were injected with 1-methy-4-phenyl-1.2.3.6-tetreahydropyridine(MPTP)or saline.Then mice exhibiting depressive-like behaviors were screened by behavioral tests.For depressive PD mice,mice were treated with three kinds of dopamine agonists,pramipexole,ropinirole and piribedil,and madopar for 2 weeks followed by behavioral tests.Western blot was performed to detect the level of TH protein in the striatum.HPLC was used to determine monoamine neurotransmitter in the striatum.Second,the forced swimming test and tail suspension test were performed to determine whether there are depressive-like behaviors in D2R knockout mice.Moreover,we established the model of chronic mild stress(CMS)in D2R knockout mice and treated them with pramipexole.After two weeks treatment,a series of behaviors tests were used to detect its antidepressant in D2R knockout mice.Western blot was used to examine the expressions of D2R and D3R in the hippocampus.Third,the forced swimming test,tail suspension test and sucrose preference test were performed to detect the depressive-like behaviors of D3R knockout mice.In order to verify the antidepressant effect of pramipexole in the absence of dopamine D3 receptor.D3R knockout mice were received with a 14-day intraperitoneal administration of pramipexole,and a series of behavioral tests were performed to detect the antidepressant effects of pramipexole in D3R knockout mice.Results:After two weeks of MPTP treatment,the rotarod test showed the time on the rod was reduced,and the pole test showed the time to reach the floor in the MPTP group were significantly longer than those in the control group.Meanwhile,compared with sham group,the level of TH protein in the striatum were decreased,indicating that our animal model is successful.Moreover,the results of tail suspension test and forced swimming test showed the immobility time was increased.Together these results suggested that MPTP mice had motor defects and depressive-like behaviors,Pramipexole,piribedil and madopar improved motor ability of MPTP-treated mice,but only pramipexole obviously rescued depressive-like behaviors of MPTP-treated mice.The HPLC results showed that DA transmitters in the striatum significantly decreased in MPTP groups and increased after pramipexole treatment.The tail suspension test and the forced swimming test showed that there is no depressive-like behaviors in D2R knockout mice.The depressive-like behaviors induced by chronic mild stress were eased at two weeks after pramipexole treatment for two weeks.Compared with sham group,western blot showed D3R was reduced in CMS group,and was reversed after pramipexole treatment.D3R knockout mice existed depressive-like behaviors.We found that pramipexole has an antidepressant effect for wild type mice,but not for D3R knockout mice.Conclusions:Compared with other dopamine D2 like receptor agonists,pramipexole can improve depressive-like behaviors along with alleviating dyskinesia in mouse model of Parkinson's disease,and exerts antidepressant effects depend on dopamine D3 receptor.