Synergistic interactions of D1- and D2-selective dopamine agonists in animal models for Parkinson's disease: sites of action and implications for the pathogenesis of dyskinesias.

The addition of a D2 agonist such as bromocriptine to L-Dopa therapy can often improve the response of patients with Parkinson's disease dramatically. Simultaneous activation of D1 and D2 dopamine receptors can produce a synergistic effect on locomotion in rats and primates. However, despite the importance of this addition of a D2 agonist to the D1/D2 agonist L-Dopa, little is known of the sites of action of these agents. Recent work suggests that, in addition to D1 and D2 dopamine receptor sites in the striatum (caudate-putamen), L-Dopa and D1 agonists have important effects at D1 dopamine receptors in the substantia nigra. Animal experiments suggest that D1 and D2 dopamine receptor agonists probably also affect different outflow pathways from the striatum. An understanding of these pathways and how dopamine agonists affect them gives insight into some of the clinical problems experienced in treating Parkinson's disease (the "on-off" phenomenon, for example). D1/D2 dopamine receptors also differentially affect gene expression and regulation in the striatum. An understanding of the anatomical and biochemical location of the actions of dopamine receptor agonists will be important in maximizing the beneficial effects and minimizing the side-effects of both presently-used drugs and new treatments.