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 D1 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 D1 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 and Ggamma7 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 D1 response on cAMP production in
dopamine-depleted striatum. In lesioned rats,
Galphaolf levels were normalized by a 3 week treatment with
l-dopa or a D1 agonist but not with aD2-D3 agonist, supporting a
Galphaolf regulation by D1 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 D1 receptor
hypersensitivity and contribute to the genesis of long-term complications of
L-dopa.