{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:27:28Z","timestamp":1791840448154,"version":"4.3.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["ZIA DA000493"],"award-info":[{"award-number":["ZIA DA000493"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Several dopaminergic compounds, including the clinically used pramipexole, are labeled as preferential dopamine D3 receptor (D3R) agonists based on their moderately higher affinity for the D3R versus other D2-like receptor subtypes. It is therefore generally believed that D3R is the main target for their initial therapeutic response in restless legs syndrome (RLS). Here, we review the results of recent comprehensive pharmacological studies that demonstrate that in addition to the binding affinities of D3R agonists, their functional responses at the different D2-like receptors depend on other pharmacodynamic factors, including intrinsic efficacy, biased agonism, functional efficacy, and receptor heteromerization, and pharmacokinetic factors, including brain penetrability. When considering all these factors, the short isoform of the D2 receptor (D2SR) localized in the dopaminergic neurons and D2SRs and D4Rs localized in corticostriatal glutamatergic terminals become preferential targets of low doses of these D2-like receptor agonists. On the other hand, higher doses are necessary to promote activation of postsynaptic striatal D3Rs forming heteromers with D1Rs, which could be associated with the phenomenon of augmentation, the worsening of RLS symptoms with their chronic use. The putative role of spinal D3Rs, especially with the periodic leg movements of sleep component of RLS, is also discussed. This analysis should provide therapeutic clues for better targeting of the dopamine receptor subtypes involved in the therapeutic and not in the secondary effects of D2-like receptor agonists in RLS.<\/jats:p>\n                  <jats:p>Statement of Significance We discuss recent pharmacological studies demonstrating that the targets of the therapeutic effects of dopamine receptor agonists in restless legs syndrome depend on more than just binding affinities. Several other pharmacodynamic and pharmacokinetic factors also need to be considered when evaluating the main dopamine receptor subtype involved. These studies suggest that striatal presynaptic D2 receptors (D2Rs) and D4Rs are preferentially involved in the therapeutic effects of dopamine receptor agonists, while striatal postsynaptic D1Rs and D3Rs are involved in the worsening of RLS symptoms with their chronic use. The putative role of spinal D3Rs, especially with the periodic leg movements of sleep component of RLS, is also discussed.<\/jats:p>","DOI":"10.1093\/sleep\/zsaf305","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T11:50:27Z","timestamp":1758973827000},"source":"Crossref","is-referenced-by-count":10,"title":["On the mechanisms of dopamine receptor agonists in restless legs syndrome"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-1779","authenticated-orcid":false,"given":"Sergi","family":"Ferr\u00e9","sequence":"first","affiliation":[{"name":"Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1083-9654","authenticated-orcid":false,"given":"Diego","family":"Garc\u00eda-Borreguero","sequence":"additional","affiliation":[{"name":"Sleep Research Institute , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Earley","sequence":"additional","affiliation":[{"name":"Center for Restless Legs Study, Department of Neurology, Johns Hopkins University , Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"issue":"21","key":"2026011300172062000_ref1","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1056\/NEJMcp021288","article-title":"Clinical practice. 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