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Targeting hypersensitive corticostriatal terminals in restless legs syndrome
Author(s) -
Yepes Gabriel,
Guitart Xavier,
Rea William,
Newman Amy H.,
Allen Richard P.,
Earley Christopher J.,
Quiroz César,
Ferré Sergi
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25104
Subject(s) - glutamatergic , glutamate receptor , pramipexole , optogenetics , neuroscience , dopamine , stimulation , pharmacology , chemistry , medicine , receptor , biology , biochemistry , disease , parkinson's disease
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 whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α 2 δ 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 analysis of 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 D 4 and D 2 receptor subtypes in the effects of pramipexole. Interpretation Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D 4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951–960