Figure 2.

Scheme of cortical-striatal-pallidal-thalamic and cortical-striatal-pallidal-habenular basal ganglia circuits. Glutamatergic, GABAergic, and dopaminergic neurons are represented in green, red, and blue, respectively. D₁R and D₂R represent two main subtypes of striatal GABAergic neurons, the striatonigral and the striatopallidal neurons, expressing dopamine D₁ receptors (D₁Rs) and dopamine D₂ receptors (D₂Rs), respectively. The GABAergic striosomal D₁R-MOR neurons are represented in black. It is postulated that an imbalance in the normal dopaminergic receptor activation of the D₁R and D₂R neurons and the specific increased activation of the striosomal D₁R-MOR neurons, leading to inactivation of the pallidal-habenular neurons, mediates the akathisia/restlessness in RLS, NIA, and opioid withdrawal (see text). In NIA, this is dependent on an increased dopamine release (a), secondary to autoreceptor blockade, and a concomitant blockade of postsynaptic D₂Rs (b). In RLS, there is also an increased dopamine release (a), secondary to glutamate release, a downregulation of D₂Rs (b), and a concomitant increase in D₁R sensitivity (c). With opioid withdrawal, there is no presynaptic component, but a significant increase in the sensitivity of the striosomal D₁R-MOR neurons (c). Abbreviations: eGP/VP, external segment of the globus pallidus/ventral pallidum; iGP, internal segment of the globus pallidus; lHb, lateral habenula; rmTg, rostromedial tegmental nucleus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; VTA, ventral tegmental area. For simplification, the indirect connection of the GPe to the GPi and SNpr through the subthalamic nucleus is not included. Also, only the cortex is shown as an input to the striatum, but it also receives inputs from the midline and intralaminar thalamic nuclei, and the ventral striatum also receives inputs from the hippocampus and amygdala.