title: Dopamine-Induced Changes in GαolfProtein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice.
abstract: The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by theGNALgene, is highly concentrated in the striatum, where it positively couples with dopamine D1(D1R) receptor and adenosine A2Areceptor (A2AR) to increase intracellular cAMP levels in MSNs. In the striatum, D1Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D2Rs and A2ARs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gαolfprotein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognitionin situproximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gαolfprotein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gαolfprotein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gαolflevels in the dopamine-depleted striatum could be a key event in generating LID.
authors.affiliation: Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima UniversityTokushima, Japan; Parkinson's Disease and Dystonia Research Center, Tokushima University HospitalTokushima, Japan; Department of Neurosurgery, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima UniversityTokushima, Japan.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Morigaki
authors.affiliation: Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima UniversityTokushima, Japan; Parkinson's Disease and Dystonia Research Center, Tokushima University HospitalTokushima, Japan; Department of Neurosurgery, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima UniversityTokushima, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okita
authors.affiliation: Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima UniversityTokushima, Japan; Parkinson's Disease and Dystonia Research Center, Tokushima University HospitalTokushima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto
keywords: L-DOPA-induced dyskinesia; Parkinson’s disease; dopamine; olfactory type G-protein α subunit; striatum