Striatal Gα(olf)/cAMP Signal-Dependent Mechanism to Generate Levodopa-Induced Dyskinesia in Parkinson’s Disease

The motor symptoms of Parkinson’s disease (PD) result from striatal dopamine (DA) deficiency due to a progressive degeneration of nigral dopaminergic cells. Although DA replacement therapy is the mainstay to treat parkinsonian symptoms, a long-term daily administration of levodopa often develops levodopa-induced dyskinesia (LID). LID is closely linked to the dysregulation of cyclic adenosine monophosphate (cAMP) signaling cascades in the medium spiny neurons (MSNs), the principal neurons of the striatum, which are roughly halved with striatonigral MSNs by striatopallidal MSNs. The olfactory type G-protein α subunit (Gα(olf)) represents an important regulator of the cAMP signal activities in the striatum, where it positively couples with D(1)-type dopamine receptor (D(1)R) and adenosine A(2A) receptor (A(2A)R) to increase cAMP production in the MSNs. Notably, D(1)Rs are primarily expressed in striatonigral MSNs, whereas D(2)Rs and A(2A)Rs are expressed in striatopallidal MSNs. Based on the evidence obtained from parkinsonian mice, we hypothesized that in the DA-denervated striatum with D(1)R hypersensitivity, a repeated and pulsatile exposure to levodopa might cause a usage-induced degradation of Gα(olf) proteins in striatal MSNs, resulting in increased and decreased levels of Gα(olf) protein in the striatonigral and striatopallidal MSNs, respectively. As a principal cause for generating LID, this might lead to an increased responsiveness to levodopa exposure in both striatonigral and striatopallidal MSNs. Our hypothesis reinforces the long-standing concept that LID might result from the reduced activity of the striatopallidal pathway and has important clinical implications.