Dopaminergic hypersensitivity of the opioid-responsive striatal-entopeduncular pathway in a rodent model of restless legs syndrome.

We hypothesized that Restless Legs Syndrome (RLS) and the restlessness of opioid withdrawal share common neurobiological mechanisms based on the efficacy of μ-opioid receptor (MOR) agonists in RLS and the common RLS-like phenotype of patients with opioid withdrawal. We also hypothesized this involves an increased sensitivity of the striatal striosomal neurons that co-express MORs and dopamine D1 receptors (D1Rs) and release GABA in the internal segment of the globus pallidus (GPi). This hypothesis was tested in mice with diet-induced brain iron deficiency (BID), a rodent model of RLS. Fiber-photometry experiments were performed in mice with BID using a viral GABA biosensor injected in the entopeduncular nucleus (EPN), the GPi equivalent in rodents. EPN GABA release was measured after the systemic administration of the D1R agonist SKF81297 and the MOR agonist methadone. Locomotor activation and striatal mRNA expression of D1Rs, MORs and adenosine A1 receptors (A1Rs) were also analyzed. A minimal locomotor-activating dose of SKF81297 induced a significant EPN GABA release in mice with BID but not controls, while a maximal locomotor-activating dose of the MOR agonist methadone significantly reduced EPN GABA release in mice with BID after saline or SKF81297 administration. BID was associated with a significant reduction in the striatal expression of MORs and A1Rs. The results indicate that BID induces an increased dopaminergic sensitivity of the opioid-responsive striatal-EPN pathway, which might represent a pivotal pathogenetic mechanism of the restlessness of RLS and opioid withdrawal.