Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome.
Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D2receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron-deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radioligand binding saturation experiments in rat brain tissue) of adenosine A1receptors (A1R) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A2Areceptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for A1R downregulation in the PLMS and hyperarousal in RLS.
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
César
C
Quiroz
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Seema
S
Gulyani
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Wan
W
Ruiqian
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Jordi
J
Bonaventura
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Roy
R
Cutler
Center for Restless Legs Study, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
Virginia
V
Pearson
Center for Restless Legs Study, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
Richard P
RP
Allen
Center for Restless Legs Study, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.
Christopher J
CJ
Earley
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Mark P
MP
Mattson
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: sferre@intra.nida.nih.gov.
Sergi
S
Ferré
D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D015536:Down-Regulation; D005293:Ferritins / Q000097:blood; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012148:Restless Legs Syndrome / Q000378:metabolism*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D017448:Receptors, Dopamine D2; D005293:Ferritins; D007501:Iron
Adenosine A(1) receptor; Adenosine A(2A) receptor; Brain iron deficiency; Dopamine D(2) receptor; Restless Legs Syndrome