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  • The first ones class A receptors found as


    The first ones class A receptors found as heterodimers were reported by Gomes et al. (2000), who identified a heteromer constituted by two subtypes of opioid receptors (μ and δ) in heterologous cells. The same year, Ginés et al. (2000) showed the first heteromer composed of two different receptors, the adenosine A1 and dopamine D1 receptors, in cotransfected fibroblast cells. It is important to mention that many of the heterooligomeric assemblies that have been detected in vivo so far, demonstrate the preponderance of dopamine- and adenosine-containing receptors, indicating their major contribution to various neurological conditions and the full breadth of their therapeutic potential (Farran, 2017).
    Dopamine and adenosine in CNS Dopaminergic and purinergic signaling play a pivotal role in neurological diseases with motor symptoms, including Parkinson\'s disease (PD), motor neuron diseases, multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS) and ataxias (Oliveira-Giacomelli et al., 2018). Dopamine is a pleiotropic Apoptozole australia that acts as a neurotransmitter and a hormone (Borcherding et al., 2011), and plays a key role in numerous CNS processes including attention, behavior and cognition, motor control, motivation and reward, mood, sleep, learning and memory (Puig, Rose, Schmidt, & Freund, 2014; Rubí & Maechler, 2010). Dopamine acts on specific receptors (DRs) belonging to the GPCR family A, which are categorized in two main groups: D1-like (D1R and D5R) and D2-like (D2R, D3R and D4R), that are linked to stimulation (D1R-like) or inhibition (D2R-like) of adenylate cyclase (Cortés, Moreno, Rodríguez-Ruiz, Canela, & Casadó, 2016). DRs directly regulate neurotransmission of other neurotransmitters, release of cAMP, and also cell proliferation and differentiation (Mishra, Singh, & Shukla, 2018). The striatum receives the densest dopamine innervation and contains the highest density of DRs in the brain. D1Rs are expressed selectively by the direct pathway GABAergic spiny projection neurons, whereas D2Rs are expressed by the indirect pathway. Striatal direct and indirect pathways form the functional backbone of the basal ganglia circuit. Both D1R and D2R have distinctive linkages to intracellular signaling cascades and targets, leading to fundamentally different cellular responses to extracellular dopamine (Gerfen & Surmeier, 2011). Adenosine is a naturally occurring purine nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors and signaling pathways. By acting through four family A GPCRs (A1R, A2AR, A2BR and A3R), adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity to cognition, motor activity, neuroinflammation and cell death (Chen, Lee, & Chern, 2014). In addition, adenosine is a main endogenous homeostatic sleep-promoting substance and plays a very significant role in the modulation of dopaminergic transmission, with implications Apoptozole australia for psychomotor activity and reinforcement (Ferré, 2016; Nunes, Randall, Podurgiel, Correa, & Salamone, 2013). The two main ARs in the CNS are A1R and A2AR. A1R is predominantly present in cortex, hippocampus, cerebellum, nerve terminals, spinal cord and glia (Ballesteros-Yáñez, Castillo, Merighi, & Gessi, 2018; Chen et al., 2014; Fuxe et al., 2010). A2AR is mainly expressed in the striatum, but it is also detectable in the olfactory tubercle, hippocampus, glial cells and cerebral cortex (Ballesteros-Yáñez et al., 2018; de Lera Ruiz, Lim, & Zheng, 2014).
    Restless legs syndrome RLS, also known as Willis-Ekbom disease, is a very prevalent neurologic disorder with unique clinical features, characterized by a periodic, rest-induced, mostly nocturnal, movement-responsive urge to move the legs or periodic leg movements during sleep (PLMS) and hyperarousal (Allen, Stillman, & Myers, 2010; Ferré, Quiroz, et al., 2018; Ferri et al., 2015). Several neuropsychological studies have shown that RLS is associated with deficits in cognitive functions, such as attention, working memory and frontal executive functions (Cha, Choi, Jung, & Kim, 2017). Moreover, it has been indicated that RLS is a multifactorial network disorder involving many regions of the nervous system, from the spinal cord and peripheral nerves to the dopaminergic and glutamatergic nuclei of the CNS (Earley et al., 2014; Hartmann, Pfister, & Pfadenhauer, 1999; Paulus & Schomburg, 2006; Pitarokoili et al., 2018). RLS symptoms follow a circadian pattern becoming worse in the evening. This disease affects 5–10% of European and North American with 2–3% experiencing moderate to severe symptoms, it occurs twice as often in women as in men, and has a mean onset age between 30 and 40 years (Allen et al., 2014; Garcia-Borreguero & Cano-Pumarega, 2017; Hening et al., 1999; Kim & Deeks, 2016). Modifiable lifestyle factors can influence the risk of RLS; as an example, patients who are physically active, nonsmokers, with healthy weight and moderate alcohol consumption, are less likely to develop RLS (Batool-Anwar et al., 2016).