Pharmacology of dopamine agonists in the treatment of Parkinson's disease

There is now increasing use of dopamine agonists as effective early monotherapy in the treatment of Parkinson's disease (PD). Dopamine agonists can induce an antiparkinsonian effect through actions on either D-1-like or D-2-like dopamine receptors, and the multiple receptor subtypes present in the brain may provide further opportunities to improve the treatment of PD. Functional interactions exist between D-1- and D-2-like receptors, and adaptive changes occur after denervation and repeated administration of a dopamine agonist. Long-acting dopamine agonists produce a lower incidence of dyskinesia than levodopa (L-dopa) when they are used as monotherapy in either PD or in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP)-treated primates. Continuous dopaminergic stimulation appears less likely to prime basal ganglia for involuntary movements compared with drugs, such as L-dopa, that produce pulsatile stimulation. However, once priming has occurred, dopamine agonists produce dyskinesia identical to that Of L-dopa. Continuous administration of long-acting dopamine agonists may reverse the priming process initiated by L-dopa, markedly decreasing dyskinesia intensity with a minimal loss of antiparkinsonian activity, at least in MPTP-treated primates. Dopamine receptors in brain areas other than the striatum, such as the globus pallidus and subthalamic nucleus, and in the mesolimbic and mesocortical regions may also contribute to antiparkinsonian activity of dopamine agonists and their associated side effects. The future potential of dopamine agonists may lie in the selective stimulation of dopamine receptor subtypes in different brain areas and through the actions of partial dopamine agonists and drugs that normalize dopamine receptor function.