Amphetamine pretreatment induces a change in both D2-receptor density and apparent affinity:: A [11C]raclopride positron emission tomography study in cats

Background: Measuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in disease and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on radioligand binding. To test this, we used PET and a Scatchard approach to investigate whether the decrease in [C-11]raclopride binding following amphetamine results from competitive or noncompetitive interactions with DA. Methods. Scatchard analyses of [C-11]raclopride/PET data were used to quantify changes inapparent D-2-receptor density (Bmax) and radioligand apparent affinity (K-D')at baseline and after amphetamine pretreatment (2 mg/kg; intravenous) in cats. Results. Amphetamine induced a 46% decrease in [C-11]raclopride binding in the striatum of five cats, Scatchard analyses revealed that this decrease in binding was due to a 28016 decrease in Bmax and a concomitant 35% increase in K-D'. Conclusions: Competition with DA is an insufficient explanation for the decrease in [C-11]raclopride binding observed after amphetamine. Noncompetitive interactions, likely representing D-2-receptor internalization, also play an important role in this phenomenon. This finding may have important implications for the interpretation of amphetamine-raclopride PET studies in schizophrenia because dysregulation of the agonist-induced internalization of D-2 receptors was recently suggested in this disorder.