Targeting hypersensitive corticostriatal terminals in restless legs syndrome

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Restless legs syndrome (RLS) is a common neurologic disorder1 characterized by a rest‐induced, movement‐responsive, mostly nocturnal urge to move the legs commonly associated with periodic leg movements during sleep (PLMS) and hyperarousal.2 Altered dopamine function plays an important role in PLMS symptomatology, which is supported by the remarkable therapeutic response to L‐dopa and dopamine receptor agonists (such as pramipexole and ropinirole), and the repeated demonstration of biochemical changes related to the dopamine system.5 Conversely, glutamate mechanisms seem to be involved in both PLMS and the hyperarousal component of RLS. This is supported by the efficacy of ligands of the α2δ subunits of the calcium channels (such as gabapentin) for both types of disturbances.6 Thus, α2δ‐containing calcium channels are preferentially localized in neuronal glutamate terminals.9
The clinical success of dopamine agonists and α2δ ligands is utterly empirical, and there is no consensus about the identity (receptor subtypes) and localization (neuronal elements, circuits) of their main therapeutic targets. Both supraspinal and spinal mechanisms have been invoked to be involved in the pathophysiology of RLS.10 Supraspinal mechanisms favor a predominant subcortical, striatal impairment of sensorimotor integration.11 The striatum is the brain area with the highest dopamine innervation and highest density of dopamine receptors and the main point of interaction of dopamine within the cortical–striatal–thalamic–cortical circuits. Furthermore, the main 2 extrinsic striatal inputs are dopaminergic mesencephalic inputs and glutamatergic cortical, limbic, and thalamic inputs.13
Brain iron deficiency (BID) is now well recognized as a main initial pathogenetic mechanism in the development of RLS. This is based on extensive research studies using cerebrospinal fluid, autopsy material, and brain imaging indicating reduced regional brain iron content,5 and is further supported by the efficacy of iron therapy for RLS,6 including RLS refractory to other treatments.17 Animal models have established a causal relation between BID and altered dopamine function in RLS. BID during the postweaning period in rats or mice produces changes in the dopamine system that parallel those found in RLS, therefore representing a valuable pathophysiological model of RLS (see Discussion).18
We have recently shown that the brain iron‐deficient rodent is associated with specific alterations in adenosine neurotransmission that can provide a pathogenetic link between BID and the glutamate mechanisms involved in the PLMS and hyperarousal of RLS.19 Those include changes in the density of striatal adenosine receptors that modulate corticostriatal glutamate release, which would be expected to increase the sensitivity of corticostriatal glutamatergic neurotransmission. We therefore postulated that an increased sensitivity of corticostriatal glutamatergic neurotransmission can be a pathogenetic factor in the development of PLMS in RLS.8
Using a recently introduced in vivo optogenetic–microdialysis approach,21 we can now demonstrate the existence of hypersensitivity of corticostriatal glutamatergic terminals in rodents with BID. Significantly, hypersensitive and control glutamatergic terminals were targeted by pramipexole, ropinirole, and gabapentin. Using specific dopamine receptor antagonists, we demonstrate the involvement of D2 and D4 receptors (D2R and D4R) in the effect of pramipexole, specially indicating that D4R‐selective agonists may provide a better treatment for RLS.
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