Persistent increase in olfactory type G-protein α subunit levels may underlie D1 receptor functional hypersensitivity in Parkinson disease

Although L-dopa remains the most effective treatment of Parkinson disease, its long-term administration is hampered by the appearance of dyskinesia. Hypersensitivity of dopamine D-1 receptors in the striatum has been suggested to contribute to the genesis of these delayed adverse effects. However, D1 receptor amounts are unchanged in Parkinson disease, suggesting alterations of downstream effectors. In rodents, striatal D-1 receptors activate adenylyl cyclase through olfactory type G-protein alpha subunit (Galphaolf) and G-protein gamma 7 subunit (Ggamma7). We found that Galphaolf was enriched in human basal ganglia and was markedly diminished in the putamen of patients with Huntington disease, in relation with the degeneration of medium spiny neurons. In contrast, in the putamen of patients with Parkinson disease, Galphaolf andGgamma7 levels were both significantly increased. In the rat, the degeneration of dopamine neurons augmented Galphaolf levels in the striatal neurons, specifically at the plasma membrane, an effect accounting for the increase of D-1 response on cAMP production in dopamine-depleted striatum. In lesioned rats, Galphaolf levels were normalized by a 3 week treatment with L-dopa or aD(1) agonist but not with aD(2)-D-3 agonist, supporting a Galphaolf regulation by D-1 receptor usage. In contrast, the increases of Galphaolf levels in patients were not affected by the duration of L-dopa treatment but correlated with duration of disease. In conclusion, our results revealed in the parkinsonian putamen a prolonged elevation of Galphaolf levels that may lead to a persistent D-1 receptor hypersensitivity and contribute to the genesis of long-term complications of L-dopa.