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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 (Gα olf ), a stimulatory GTP-binding protein encoded by the  GNAL  gene, is highly concentrated in the striatum, where it positively couples with dopamine D 1  (D 1 R) receptor and adenosine A 2A  receptor (A 2A R) to increase intracellular cAMP levels in MSNs. In the striatum, D 1 Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D 2 Rs and A 2A Rs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gα olf  protein 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 recognition  in situ  proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gα olf  protein 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 Gα olf  protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that  l -DOPA-induced changes in striatal Gα olf  levels in the dopamine-depleted striatum could be a key event in generating LID.

frontiers in cellular neuroscience

Dopamine-Induced Changes in Gαolf Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice