On the mechanisms of dopamine receptor agonists in restless legs syndrome

Several dopaminergic compounds, including the clinically used pramipexole, are labelled as preferential dopamine D3 receptor (D3R) agonists based on their moderately higher affinity for the D3R versus other D2-like receptor subtypes. It is therefore generally believed that D3R is the main target for their initial therapeutic response in restless legs syndrome (RLS). Here, we review the results of recent comprehensive pharmacological studies that demonstrate that in addition to their binding affinities, their functional responses at the different D2-like receptors depend on other pharmacodynamic factors, including intrinsic efficacy, biased agonism, functional efficacy and receptor heteromerization, and pharmacokinetic factors, including brain penetrability. When considering all these factors, the short isoform of the D2 receptor (D2SR) localized in the dopaminergic neurons and D2SRs and D4Rs localized in corticostriatal glutamatergic terminals become preferential targets of low doses of these D2-like receptor agonists. On the other hand, higher doses are necessary to promote activation of postsynaptic striatal D3Rs forming heteromers with D1Rs, which can be associated with the phenomenon of augmentation, the worsening of the RLS symptoms with their chronic use. The putative role of spinal D3Rs, specially with the periodic leg movements of sleep (PLMS) component of RLS, is also discussed. This analysis should provide therapeutic clues for a better targeting of the dopamine receptor subtypes involved in the therapeutic and not in the secondary effects of D2-like receptor agonists in RLS.