Dataset Information

Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography.

ABSTRACT: Alterations in dopamine D(2)/D(3) receptor binding have been reported in schizophrenia, and a meta-analysis of imaging studies has shown a modest elevation in striatum. Newer radioligands now allow the assessment of these receptors in extrastriatal regions. We used positron emission tomography with [(18)F]fallypride to evaluate D(2)/D(3) receptors in both striatal and extrastriatal regions in schizophrenia.Twenty-one patients with schizophrenia and 22 matched healthy control subjects were scanned with an ECAT EXACT HR+ camera. Two-tissue compartment modeling and the reference tissue method gave binding potentials relative to nondisplaceable uptake, total plasma concentration, and free plasma concentration. These were compared between groups in five striatal and eight extrastriatal regions. Several regional volumes were lower in the patient group, and positron emission tomography data were corrected for partial volume effects.Binding potential values differed in three regions between groups. Values for binding potential relative to nondisplaceable uptake from two-tissue compartment modeling in patients and control subjects, respectively, were 28.7 ± 6.8 and 25.3 ± 4.3 in postcommissural caudate, 2.9 ± .7 and 2.6 ± .4 in thalamus, and 1.8 ± .5 and 2.1 ± .7 in uncus. Loss of D(2)/D(3) receptors with age was found in striatal and extrastriatal regions and was greater in neocortex.Our study found selective alterations in D(2)/D(3) receptors in striatal and extrastriatal regions, consistent with some but not all previously published reports. As previously shown for the striatum, a more sensitive imaging approach for studying the role of dopamine in the pathophysiology of schizophrenia might be assessment of neurotransmitter levels rather than D(2)/D(3) receptor levels in extrastriatal regions.

SUBMITTER: Kegeles LS

PROVIDER: S-EPMC2952433 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography.

Kegeles Lawrence S LS Slifstein Mark M Xu Xiaoyan X Urban Nina N Thompson Judy L JL Moadel Tiffany T Harkavy-Friedman Jill M JM Gil Roberto R Laruelle Marc M Abi-Dargham Anissa A

Biological psychiatry 20100731 7

<h4>Background</h4>Alterations in dopamine D(2)/D(3) receptor binding have been reported in schizophrenia, and a meta-analysis of imaging studies has shown a modest elevation in striatum. Newer radioligands now allow the assessment of these receptors in extrastriatal regions. We used positron emission tomography with [(18)F]fallypride to evaluate D(2)/D(3) receptors in both striatal and extrastriatal regions in schizophrenia.<h4>Methods</h4>Twenty-one patients with schizophrenia and 22 matched h ...[more]

PMID: 20673873

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Project description:ObjectiveDopamine is an endogenous neuromodulator in cortical circuits and the basal ganglia. In animal models of temporal lobe epilepsy (TLE), seizure threshold is modulated to some extent by dopamine, with D1-receptors having a pro- and D2-receptors an anticonvulsant effect. We aimed to extend our previously reported results on decreased D2/D3 receptor binding in the lateral epileptogenic temporal lobe and to correlate them with demographic and seizure variables to gain a more comprehensive understanding of the underlying involvement of the dopaminergic system in the epileptogenesis of TLE.MethodsTo quantify D2/D3 receptor binding, we studied 21 patients with TLE and hippocampal sclerosis (13 left- and eight right-sided) and 18 controls using PET with the high-affinity dopamine D2/D3-receptor ligand 18F-Fallypride to image striatal and extrastriatal binding. TLE was defined by interictal and ictal video-EEG, MRI and 18F-Fluorodeoxyglucose PET. Voxel-based statistical and regions-of-interest analyses were performed.Results18F-Fallypride binding potential was significantly reduced in the affected temporal lobe and bilateral putamen. A positive correlation between age at onset of epilepsy and [18F]FP BPnd (binding potential non-displaceable) in temporal regions on the epileptogenic side was found, as well as a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole on the epileptogenic side and a positive correlation between the estimated number of lifetime GTCS and [18F]FP BPnd in the hippocampus on the epileptogenic side.SignificanceThe areas of reduced D2/D3 receptor availability correspond to "the irritative zone" surrounding the epileptogenic area. Moreover, reduced D2/D3 receptor availability was detectable in the basal ganglia, which are suspected to be involved in a control circuit for epileptic seizures. The correlational analysis additionally suggests that increased epilepsy duration leads to increasing impairment of the dopaminergic system.

Project description:Dopamine D2 receptors (D2R) are expressed in the human retina and play an important role in the modulation of neural responses to light-adaptation. However, it is unknown whether dopamine D3 receptors (D3R) are expressed in the human retina. Using positron emission tomography (PET), we have observed significant uptake of the D3R-preferring agonist radiotracer [11C]-(+)-PHNO into the retina of humans in vivo. This led us to examine whether [11C]-(+)-PHNO binding in the retina was quantifiable using reference tissue methods and if D3R are expressed in human post-mortem retinal tissue. [11C]-(+)-PHNO data from 49 healthy controls (mean age: 39.96 ± 14.36; 16 female) and 12 antipsychotic-naïve patients with schizophrenia (mean age: 25.75 ± 6.25; 4 female) were analyzed. We observed no differences in [11C]-(+)-PHNO binding in the retina between first-episode, drug-naïve patients with schizophrenia and healthy controls. Post-mortem retinal tissues from four healthy persons (mean age: 59.75 ± 9.11; 2 female) and four patients with schizophrenia (mean age: 54 ± 17.11; 2 female) were analyzed using a targeted mass spectrometry technique: parallel reaction monitoring (PRM) analysis. Using targeted mass spectrometry, we confirmed that D3R are expressed in human retinal tissue ex vivo. Notably, there was far greater expression of D2R relative to D3R in the healthy human retina (∼12:1). Moreover, PRM analysis revealed reduced D2R, but not D3R, expression in the retinas of non-first episode patients with schizophrenia compared to healthy controls. We confirm that D3R are expressed in the human retina. Future studies are needed to determine what proportion of the [11C]-(+)-PHNO signal in the human retina in vivo is due to binding to D3R versus D2R. Knowledge that both D2R and D3R are expressed in the human retina, and potentially quantifiable in vivo using [11C]-(+)-PHNO, poses new research avenues for better understanding the role of retinal dopamine in human vision. This work may have important implications for elucidating pathophysiological and antipsychotic induced visual deficits in schizophrenia.

Dataset Information

Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography.

Publications

Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography.

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