Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox

Sleep Med Clin. 2021 Jun;16(2):249-267. doi: 10.1016/j.jsmc.2021.02.012. Epub 2021 Apr 10.


Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D1 receptors, which form complexes (heteromers) with dopamine D3 and adenosine A1 receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A1 receptors.

Keywords: Adenosine; Akathisia; Dopamine; Glutamate; Receptor heteromers; Restless legs syndrome; Striatum.

Publication types

  • Review

MeSH terms

  • Dopamine / metabolism*
  • Humans
  • Psychomotor Agitation / etiology*
  • Restless Legs Syndrome / diagnosis*


  • Dopamine