Pivotal Role of Adenosine Neurotransmission in Restless Legs Syndrome

Abstract

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A1 receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α2δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…At a minimal dose of 30 mg/kg administered systemically, dipyridamole significantly decreased the locomotor-activating effect of equipotent doses of selective D 1 R and D 2 R agonists and this depressant effect was completely counteracted by caffeine. 236 These results suggest that basal extracellular levels of adenosine in the striatum were increased following the systemic administration of dipyridamole and this increase in adenosine levels could explain the observed ability of dipyridamole to depress both D 1 R and D 2 R agonist-mediated locomotor activation in the reserpinized mice. The fact that this depressant effect was counteracted by caffeine, a non-selective adenosine antagonist, suggests that an increase in basal levels of adenosine may exert influence on both the tonic activation of pre-and postsynaptic A 1 R and postsynaptic A 2A R. Since the activation of presynaptic A 1 R leads to a decrease in glutamate release, therapeutics that can increase tonic levels of adenosine may be a beneficial treatment in patients with HD…”

Obstructive sleep apnea, sleep symptoms, and their association with cardiovascular disease

“…Patients were therefore evaluated for multiple sleep symptoms, and we found that over half of our patients were experiencing at least one sleep symptom such as insomnia and RLS. All these sleep disorders have a component of hyperarousal, which could be one reason that multiple sleep disorders affect the cardiovascular system . Multiple meta‐analyses have demonstrated that hypertension is significantly more common in individuals with RLS; more recently, a meta‐analysis has confirmed the association between insomnia and incident cardiovascular disease and associated death …”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…Benzodiazepine anxiolytics were reported by Phillis and Wu (1982) as among many diverse, centrally active drugs to inhibit adenosine uptake, usually at micromolar concentrations, along with antipsychotics trifluoperazine, spiroperidol and sulpiride. Like gabapentin, benzodiazepines are also used to treat restless leg syndrome, which is now associated with the A1AR (Ferré et al, 2018). Curiously, some indirect effects of the benzodiazepine diazepam 53 on this receptor have been demonstrated, consistent with diazepam reversing some of the stimulant effects of caffeine.…”