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  • Until recently the first line treatment of RLS was the

    2020-03-07

    Until recently, the first line treatment of RLS was the administration of low dose of three dopaminergic drugs, which has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of moderate to severe RLS. These compounds are pramipexole (Mirapex), ropinirole (Requip) and rotigotine transdermal patch (Neupro), which act as agonists that mainly target the D3R (Cortés, Moreno, et al., 2016; Dinkins, Lallemand, & Clemens, 2017). While initially highly effective, these compounds lose their efficacy over time, and long-term therapy regularly leads to a worsening of the RLS symptoms. In fact, augmentation is the main complication of long-term dopaminergic therapy and was first reported with the dopamine precursor l-DOPA (Becker & Novak, 2014). Characteristic features of augmentation include an increase in RLS symptom intensity, the onset of symptoms earlier in the day, a shorter time to symptom onset during periods of rest, spread of symptoms to previously unaffected body parts and a shorter period of relief following the administration of medication (Anguelova et al., 2018; Becker & Novak, 2014; García-Borreguero et al., 2007). Recent experimental data indicate that the mechanisms leading to augmentation in RLS patients after long-term use of D3R drugs may be related to a parallel D3R-induced upregulation of the D1R system, suggesting that this receptor might serve as a target for the treatment of augmentation. Therefore, a combination therapy of activating the D3R system and adjuvant blocking of the D1R system may provide the initial relief sought by patients and also may maintain the efficacy of the treatment over time (Dinkins et al., 2017). Yepes et al. (2017) showed the existence of hypersensitivity of corticostriatal glutamatergic terminals in rodents with Tenatoprazole iron deficiency, which were targeted for locally perfused pramipexole, ropinirole and gabapentin. Furthermore, using selective antagonists they demonstrated that there was an involvement of D2R and D4R subtypes in the effects of pramipexole. The dopamine D2 short receptor (D2SR) and the D4R are preferentially localized in corticostriatal glutamatergic terminals and are involved in the direct modulation of striatal glutamate release (Bonaventura et al., 2017; Tenatoprazole Centonze et al., 2004; González et al., 2012). Therefore, more selective D2SR and D4R agonists could be potential medications for RLS. D4R can be particularly seen as the main therapeutic target, because it is more selectively expressed by corticostriatal neurons than D2SR and it has been recently shown to play a main role as a mediator of dopamine modulation of corticostriatal neurotransmission (Bonaventura et al., 2017). These data support a switch in the dopamine receptor subtype as a therapeutic target for RLS from the D3R to the D4R, with fewer secondary effects (Yepes et al., 2017).
    Adenosinergic neuromodulation and RLS In three separate studies Ferré\'s group pointed at a relation between adenosine and its two main receptor subtypes in the brain (A1R and A2AR) and brain iron deficiency (BID) in RLS. These authors found a consistent upregulation of striatal A2AR in rats and rodents with severe BID (Gulyani et al., 2009; Quiroz et al., 2016, Quiroz et al., 2010). In the same animal model, A1R density was found decreased in animals with mild, moderate and severe deficiency accompanied by dopaminergic D2R downregulation and an increased presynaptic A2AR density in animals submitted to a more iron deficient diet (Quiroz et al., 2016). These results indicate that downregulation of A1R might constitute a more significant correlate of BID in RLS, while changes on A2AR density would be only observed with severe BID (Ferré, Earley, Gulyani, & Garcia-Borreguero, 2017). There is increasing evidence from preclinical and clinical studies that links BID and impairments in glutamatergic and adenosinergic neurotransmission as pathogenetic mechanisms involved in RLS (Ferré et al., 2017; Garcia-Borreguero & Cano-Pumarega, 2017). A single alteration in the adenosinergic system, such as an A1R downregulation-mediated increased sensitivity of corticostriatal terminals, could produce presynaptic striatal hyperglutamatergic and hyperdopaminergic states, which could be a sufficient pathophysiological mechanism to explain PLMS in RLS. Downregulation of presynaptic D2R localized in glutamatergic and dopaminergic terminals could also be a significant contributing factor. Therefore, adenosine neurotransmission can provide the link between dopamine and glutamate mechanisms in RLS and a hypoadenosinergic state can explain the hyperdopaminergic and hyperglutamatergic state of RLS (Ferré, Quiroz, et al., 2018).