Parkinson’s Disease & Movement Disorders

Biography

Biography: Kjell Fuxe

Abstract

Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. Changes in the function of the DA heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson’s disease (PD) with levodopa and DA receptor agonists. In the indirect pathway the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD will be covered and in the direct pathway the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes. D1R and D2R heteroreceptor complexes in the brain open up a new understanding of the wearing off of the antiparkinson actions of levodopa and DAR agonists and the production of levodopa induced dyskinesias. To-day it seems as if the major advantage of DA receptor agonists is that they can postpone in early PD the use of levodopa, which gives a higher incidence of dyskinesias in PD patients vs ropinirole and pramipexol The motor complications can involve a reorganization of the D1R and D2R heteroreceptor complexes and a disbalance of the D1R and D2R homomers versus non-DA receptor homomers in the direct and indirect pathways. Through understanding these mechanisns new strategies for the treatment of motor function deficits in PD can be offered with reduced motor complications. However, the motor deficits due to degeneration of non-dopaminergic neurons will remain. The relevance of interactions of the receptor protomers in the signaling cascades and the transcriptional regulation will also be discussed including downstream target proteins.