By Daniel A. Barone, MD, FAASM
Assistant Professor of Neurology, Weill Cornell Medical College, Center for Sleep Medicine
Dr. Barone reports no financial relationships relevant to this field of study.
Based on this innovative study using optogenetic microdialysis, the mechanisms underlying restless legs syndrome include dopamine-mediated hypersensitivity of corticostriatal neurons to glutamate release.
Yepes G, Guitart X, Rea W, et al. Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Ann Neurol 2017;82:951-960.
Restless legs syndrome (RLS) is a common neurologic disorder characterized by a rest-induced, movement-responsive, nocturnal urge to move the legs. Often, it is associated with periodic leg movements during sleep (PLMS) and hyperarousal. Altered dopamine function plays a major role in PLMS symptomatology, supported by the therapeutic response to L-dopa and dopamine receptor agonists (i.e., pramipexole and ropinirole), as well as the biochemical changes related to the dopamine system. Additionally, it appears that glutamate mechanisms are involved in both PLMS and the hyperarousal component of RLS, supported by the efficacy of ligands of the subunits of calcium channels (i.e., gabapentin, pregabalin) on these symptoms, the subunits being localized preferentially in neuronal glutamate terminals.
Yepes et al reported two major aims: to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID) (a pathogenetic model of RLS), and to determine whether the glutaminergic terminals could be a target for drugs effective in RLS, particularly the dopamine agonists (pramipexole and ropinirole) and ligands (gabapentin).
The authors used optogenetic-microdialysis, which is a technique involving the use of light to control cells in living tissue, typically neurons that have been genetically modified to express light-sensitive ion channels. This technique allows the measurement of the extracellular concentration of glutamate on local light-induced stimulation of corticostriatal glutamatergic terminals. This method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate.
Rodents with BID showed hypersensitivity of corticostriatal glutamatergic terminals; that is, they required a lower frequency of optogenetic stimulation to induce glutamate release. In both the hypersensitive and control glutamatergic terminals, the authors demonstrated that the terminals were targets for locally perfused pramipexole, ropinirole, and gabapentin, as they all significantly counteracted optogenetically induced glutamate release. Furthermore, using selective antagonists, the authors demonstrated that there was involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole.
The authors concluded that hypersensitivity of corticostriatal glutamatergic terminals can comprise a major mechanism of RLS symptoms. They went on to point out that selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects.
This is scientifically sound study, and although done in rodents, the potential clinical implications in humans are quite robust. Others have studied dopamine, iron, and opioid systems extensively to identify the physiological mechanisms underlying RLS, and although no singular model has sufficed, this paper sheds light on a new approach. The ligands (gabapentin and pregabalin) already have been presumed to decrease glutamatergic neurotransmission and, thus, treat RLS. However, the ability of the dopamine agonists pramipexole and ropinirole to modulate the function of corticostriatal glutamatergic terminals implies a conceptual change in their presumed therapeutic mechanism. Dopamine D2SR and D4R are the D2-like receptor subtypes preferentially localized in corticostriatal glutamatergic terminals and involved in a direct modulation of striatal glutamate release. The implication is that more selective D2SR and D4R agonists could be potential medications for RLS. D4R agonist is more likely to be effective because it is more selectively expressed by corticostriatal neurons, and activation of D2LR might contribute to unwanted side effects in RLS, such as augmentation).
Decreased iron concentrations in the substantia nigra can precipitate RLS, as it is one of the primary brain regions in which dopamine-producing cells reside, and an inverse relationship has been demonstrated between iron concentrations in the substantia nigra and the severity of RLS symptoms. This study demonstrated that BID in rodents results in hypersensitive corticostriatal terminals, which show an increased sensitivity to depolarization-induced glutamate release. Prior studies have shown a higher prevalence of RLS symptoms in conditions that compromise iron availability, but most patients with RLS do not have systemic iron deficiency. Very little is known regarding how iron is regulated by the blood-brain barrier or by the different cells within the brain, or how a brain region can be low in iron yet other organs in the body have normal levels.
Opiate medications are considered alternative treatment for RLS, but the precise mechanisms by which they improve RLS are not well understood. Opiate receptors have been identified in the dorsal horn and are likely involved in regulating incoming nociceptive sensory information, as well as in brainstem areas (periaqueductal grey and in the basal ganglia), which could be sites involved in improvement of symptoms. Neither improvement in iron stores nor the use of opiate medications have clear mechanisms to explain RLS and the improvement of symptoms through their application, yet these interventions do tend to work. Although the authors have made a step forward in our understanding of RLS, there remains much to be discovered.