D3 receptor agonist efficacy in restless legs syndrome

Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a sleep related movement disorder characterized by an irresistible urge to move the limbs frequently associated with uncomfortable sensations that usually begin or worsen during inactivity and may be relieved by movement. The pathophysiology of the disorder involves several biological system; in particular, dopaminergic pathway and iron physiology have been extensively studied. Being a chronic condition, long-term treatments are required for an adequate management and strong evidence support the employment of dopamine agonists. D3 receptor agonists are of particular interest, because they act on receptors that are widely expressed in the spinal cord with an inhibitory action on sensory system. Pramipexole, rotigotine and ropinirole act on D3 receptors, even if not selectively, and are effective in reducing sensorimotor symptoms and improving sleep quality. However, despite an initial amelioration patients frequently experience augmentation, i.e., a worsening of symptoms induced by dopamine agonists. This can be explained by the activity of D1 receptor and by the non-selectiveness of D3 agonist drugs. Higher dopamine concentrations tend to activate the excitatory D1-like receptor that are associated with increased motor activity. The development of drugs that selectively target D3 receptors will be fundamental to provide alternative therapeutic strategies and to reduce the occurrence of augmentation.