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The dopamine D(2) receptors exist in two states: a high-affinity state (D(2)(high)) that is linked to second messenger systems, is responsible for functional effects, and exhibits high affinity for agonists; and a low-affinity state that is functionally inert and exhibits lower affinity for agonists. The dopamine D(3) receptors have high-affinity for agonist (eg dopamine) and the existence of the two affinity states is controversial. Although preclinical studies in animal models of psychosis have shown a selective increase of D(2)(high) as the common pathway to psychosis, the D(3) has been suggested to be involved in the pathophysiology of psychosis. We report the first study of the D(2)(high) and D(3) in schizophrenia using the novel PET radiotracer, [(11)C]-(+)-PHNO. We recruited 13 patients with schizophrenia-spectrum disorder amidst an acute psychotic episode, drug free for at least 2 weeks, and 13 age-sex-matched healthy controls. The binding potential no-displaceable (BP(ND)) was examine in the main regions of interest (caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and anterior thalamus) and in a voxel-wise analysis. The BP(ND) between patients and controls was not different in any of the regions. The voxel-wise analysis did not reveal any difference and no correlations were found between the BP(ND) and positive and negative syndrome scale subscales. Our results do not find support for the hypothesis linking psychosis to a selective increase in D(2)(high) and/or D(3) in schizophrenia. It is possible that receptors with high affinity are not accessible by [(11)C]-(+)-PHNO because they are occupied by endogenous dopamine, a possibility that can be ruled out in future experiments.

The Dopamine D2 Receptors in High-Affinity State and D3 Receptors in Schizophrenia: A Clinical [11C]-(+)-PHNO PET Study