Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect?

Abstract

Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures. Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. In particular, dysfunction of D2-like receptors that mediate function of the indirect pathway in the basal ganglia may play a key role. We have demonstrated with positron emission tomography that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [(18)F]spiperone, a nonselective D2-like radioligand with nearly equal affinity for serotonergic 5-HT(2A) sites. We then repeated the study with [(18)F]N-methyl-benperidol (NMB), a more selective D2-like receptor radioligand with minimal affinity for 5-HT(2A). Surprisingly, there was no decrease in NMB binding in the putamen of subjects with dystonia. Our findings excluded reductions of putamenal uptake greater than 20% with 95% confidence intervals. The analysis of the in vitro selectivity of NMB and spiperone demonstrated that NMB was highly selective for D2 receptors relative to D3 receptors (200-fold difference in affinity), whereas spiperone has similar affinity for all three of the D2-like receptor subtypes. These findings when coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia.

Figure 1. Competitive radioligand binding of NMB and spiperone to human D2 and D3 dopamine receptor subtypes in vitro

Competitive radioligand binding studies were performed to compare the binding affinity and selectivity of spiperone and NMB for human D2 (○) and D3 (●) dopamine receptors. Competition experiments were performed using ¹²⁵I-IABN and human dopamine receptors expressed in stably transfected HEK-293 cells. Representative competition curves obtained using NMB (A) and spiperone (B) are shown.