Receptor Antagonism and Dyskinesia in Parkinson’s Disease
Figure 1
Role of receptors on modifications in the activity of the striatal efferent pathways. Under physiological conditions (a), striatal neurons receive dopaminergic inputs from the substantia nigra pars compacta (SNc). Endogenous dopamine (DA) activates the neurons belonging to the so-called direct pathway (in green), which send GABAergic projections to the substantia nigra pars reticulata/globus pallidus pars interna (SNr/GPi) and express D1 stimulatory dopamine receptors, together with the neuropeptide dynorphin (dyn). At the same time, dopamine also depresses the neurons belonging to the so-called indirect pathway (in red) which send GABAergic projections to the SNr/GPi via globus pallidus pars externa (GPe) and subthalamic nucleus (STN) and express D2 inhibitory dopamine receptors and the neuropeptide enkephalin (enk). Adenosine receptors stimulate the indirect pathway where they are selectively expressed, and their activation negatively modulates the function of D2 receptors. A balanced level of activity of the direct and indirect pathways is at the basis of the correct processing of motor information and movement execution. In Parkinson’s disease (b), the degeneration of the neurons located in the SNc leads to a drop in the dopaminergic input to the striatum. This results in a reduced activation of the direct pathway and in a disinhibition of the indirect pathway, which is associated with the elevation of receptor transmission. Such unbalanced activity of the striatal output pathways is at the basis of the motor impairment observed in Parkinson’s disease (b). Administration of L-DOPA restores the compromised dopaminergic tone since it stimulates the direct pathway and inhibits the indirect one (not shown). However, chronic treatment with L-DOPA (c) leads to the overactivation of the direct pathway, which together with the increase of receptor activity [12, 15, 16] and enhanced indirect pathway transmission is at the basis of L-DOPA-induced dyskinesia and loss of efficacy. The addition of an antagonist to L-DOPA (d) although not counteracting the overactivity of the direct pathway (dyskinesia) stabilizes the activity of the indirect pathway, resulting in motor stimulation, potentially without a worsening of dyskinesia.
