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 (PET) that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [ 18 F]spiperone a non-selective 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. Following 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 coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia.

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds

“…This release of inhibition is influenced by signals from the sensorimotor cortex. Furthermore, PET studies in humans suggest that changes in D3 receptor expression may play a role in the development of dystonia (Karimi et al, 2011).…”

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

“…The use of the novel D2R specific radioligand [ 11 C]NMB with insensitivity to displacement by endogenous DA facilitated measurement of D2R specific binding, in contrast to D2/D3R radioligands such as [ 11 C]raclopride which lacks the same specificity and may be displaced by varying levels of endogenous DA (Moerlein et al, 1997; Karimi et al, 2011). Therefore these studies replicate and extend previous findings from postmortem (Noble et al, 1991; Thompson et al, 1997; Ritchie and Noble, 2003) and PET studies (Pohjalainen et al, 1998; Jonsson et al, 1999; Savitz et al, 2013) performed with D2/D3R radioligands.…”

“…[ 11 C]raclopride (Thompson et al, 1997; Pohjalainen et al, 1998; Jonsson et al, 1999; Brody et al, 2006; Hirvonen et al, 2009a; Savitz et al, 2013; Wagner et al, 2014), [ 3 H]spiperone (Noble et al, 1991; Ritchie and Noble, 2003)) and the SPECT radioligand [ 123 I]IBZM (Laruelle et al, 1998), which do not discriminate between D2R and D3R and whose binding is affected by synaptic dopamine concentrations, leaving the link between DRD2/ANKK1 TaqIA genotype and D2R specific binding unclear. The novel PET radioligand ( N -[ 11 C]methyl)benperidol ([ 11 C]NMB) specifically binds to D2R in a reversible manner, does not undergo agonist-mediated internalization, is resistant to displacement by endogenous DA, and is selective for D2R over D3R by 200-fold (Moerlein et al, 1997; Karimi et al, 2011). Thus, [ 11 C]NMB is an ideal radioligand to use for the study of D2R binding under various conditions including disease states and genotype status.…”

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

“…For example, striatal D2-like receptor binding is decreased in patients with focal dystonia (Perlmutter et al, 1997) or nonmanifesting DYT1 mutations (Asanuma et al, 2005), but increased in patients with dopa-responsive dystonia (Rinne et al, 2004). A recent study suggests that at least some of these changes may be in the density of striatal D3 receptors (a member of the D2 receptor family) specifically (Karimi et al, 2011). D1 receptor density, at least in primary focal dystonia, however, seems to be unchanged from controls (Karimi et al, 2013).…”