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

Abstract

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 nodisplaceable (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.

Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls while performing a cognitive task

“…In an attempt to solve this problem, we compared the present BP ND values with baseline (resting) BP ND data from a previous study in patients with schizophrenia. 63 We found no significant difference between the baseline BP ND reported in our previous study 19 and the ones observed under cognitive activation in the present study in all of the ROIs tested (group F 1,19 = 0.735, p = 0.40; region F 4,16 = 21.821, p < 0.001; group × region F 4,16 = 1.014, p = 0.43). In addition, the lack of difference in [ 11 C]-(+)-PHNO binding among the groups may reflect the small DA releasing effect of this particular cognitive task or the lack of participants' own resting state baselines, which may have translated into a statistically nonsignificant difference among the groups.…”

“…In agreement with a previous study involving patients with first-episode schizophrenia in a restingstate condition, we found no significant evidence of increased D 2 high or D 3 binding among our study groups. 19 Moreover, to our knowledge, we present the first observations that CHR individuals showed no elevation in D 2 high or D 3 , consistent with the patient population, even while performing a cognitive task. The present results are also corroborated by voxelwise analysis.…”

“…19 However, the study was carried out while participants were in a resting state, whereas DA function is highly dependent on the environ ment. Recent data comparing resting, cognitive task and motor task binding potentials showed striatal DA release occurs during behavioural challenges, but not in a resting condition.…”

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

“…Overall, these results are suggestive of a decline in DRD3 binding with age, in particularly among ADP. No previous [ 11 C]PHNO study has reported a relationship between age and DRD2/3 binding (Boileau et al, 2009;Boileau et al, 2012;Ginovart et al, 2007a;Graff-Guerrero et al, 2009a;Graff-Guerrero et al, 2009b;Shotbolt et al, 2012a;Willeit et al, 2006), which could be due to the narrower age range in their reports and/or to the effect of alcohol.…”

Differential sensitivity of the Brattleboro rat to glutamatergic and dopaminergic perturbation

“…Although the etiology of schizophrenia is unclear, there is evidence supporting genetic, environmental, and developmental vulnerabilities to disease [1][2][3][4][5][6]. Current evidence supports two main theories regarding the pathophysiology of schizophrenia, which are the glutamate and dopamine hypotheses [7][8][9].…”