Agonist high- and low-affinity states of dopamine D2 receptors: methods of detection and clinical implications

Abstract

Dopamine D(2) receptors, similar to other G-protein-coupled receptors, exist in a high- and low-affinity state for agonists. Based upon a review of the methods for detecting D(2) receptor agonist high-affinity states, we discuss alterations of such states in animal models of disease and the implications of such alterations for their labelling with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. The classic approach of detecting agonist high-affinity states compares agonist competition for antagonist radioligands, in most cases using [(3)H]-spiperone as the radioligand; alternative approaches and radioligands have been proposed, but their claimed advantages have not been substantiated by other investigators. In view of the advantages and disadvantages of various techniques, we critically have reviewed reported findings on the detection of D(2) receptor agonist high-affinity states in a variety of animal models. These data are compared to the less numerous findings from human in vivo studies based on PET and SPECT tracers; they are interpreted in light of the finding that D(2) receptor agonist high-affinity states under control conditions may differ between rodent and human brain. The potential advantages of agonist ligands in studies of pathophysiology and as diagnostics are being discussed.

Synthesis and Evaluation in Rats of the Dopamine D2/3Receptor Agonist18F-AMC20 as a Potential Radioligand for PET

“…One is the low signal-to-noise ratio, dependent on the association and dissociation rates of tracer binding to the receptors. Signal-to-noise ratio may be limited by the nonspecific binding of the tracer in the tissue, which leaves less free tracer available for specific binding, or by the quick release of specifically bound agonist tracer from the receptors due to the receptor's relaxation into the low-affinity state after G-protein activation by an agonista known potential issue for agonist tracers of G-protein-coupled receptors (11).…”

“…Saline and raclopride (in random order) were injected intravenously about 30 min before tracer injection. An extra group of rats (n 5 4) was pretreated with saline and injected with 11 C-raclopride to serve as positive controls for D 2/3 -specific brain uptake.…”

“…Indeed, 11 C-labeled D 2/3 R agonists demonstrated greater sensitivity to amphetamine-induced dopamine release in humans than the antagonist 11 C-raclopride (9,10).…”

“…Moreover, dysregulated relative abundance of the high-affinity state of D 2/3 R might underlie the state of dopamine supersensitivity, which is associated with psychosis, Parkinson disease, and addiction (11). Agonist tracers might provide new insights for the research into and (early) diagnosis of such disorders.…”

Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users

“…11 C]-(+)-PHNO and the validity of the dichotomy of 'high' vs 'low' D 2 status in vivo (Seeman, 2012;Skinbjerg et al, 2012;van Wieringen et al, 2013), the significance of possible differences in functional status of striatal D 2 /D 3 receptors in MA users in the interpretation of our finding is not entirely clear.…”