Targeting Hypersensitive Corticostriatal Terminals in Restless Legs Syndrome

ABSTRACT

Objective: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of Restless Legs Syndrome (RLS). The second aim was to determine if these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α₂δ ligands (gabapentin).

Methods: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows to analyze the effect of local perfusion of compounds within the same area being sampled for glutamate.

Results: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole and gabapentin, which significantly counteracted optogenetically-induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D₄ and D₂ receptor subtypes on the effects of pramipexole.

Interpretation: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D₄ receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with less secondary effects. This article is protected by copyright. All rights reserved.

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