D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia

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Abstract

Background

Abnormalities in the dopaminergic system are implicated in schizophrenia. [F-18]fallypride is a highly selective, high affinity PET ligand well suited for measuring D2/D3 receptor availability in the extrastriatal regions of the brain including thalamus, prefrontal, cingulate, and temporal cortex, brain regions implicated in schizophrenia with other imaging modalities.

Methods

Resting [F-18]fallypride PET studies were acquired together with anatomical MRI for accurate coregistration and image analysis on 15 drug naïve schizophrenics (10 men, 5 women, mean age 28.5 years) and 15 matched controls (9 men, 6 women, mean age 27.4 years). Dopamine D2/D3 receptor levels were measured as binding potential (BP). The fallypride BP images of each subject were spatially normalized and subsequently smoothed for group comparison. Measures of significance between the schizophrenic and control groups were determined using statistical parametric mapping (SPM). The medial dorsal nucleus and pulvinar were also traced on coregistered MRI for detailed assessment of BP in these regions.

Results

The thalamus of patients with schizophrenia had lower [F-18]fallypride BP than normal controls and this was the brain area with the greatest difference (range − 8.5% to − 27.2%). Left medial dorsal nucleus and left pulvinar showed the greatest decreases (− 21.6% and − 27.2% respectively). The patients with schizophrenia also demonstrated D2/D3 BP reduction in the amygdala region, cingulate gyrus, and the temporal cortices.

Conclusions

These findings suggest that drug naïve patients with schizophrenia have significant reductions in extrastratial D2/D3 receptor availability. The reductions were most prominent in regions of the thalamus, replicating other studies both with high affinity D2/D3 ligands and consistent with FDG-PET studies, further supporting the hypothesis of thalamic abnormalities in this patient population.

Introduction

The clinical efficacy of neuroleptics and their main action of blocking D2 receptors suggested that PET studies of dopamine receptor ligands would reveal differences between patients with schizophrenia and normal volunteers. The first study by Comar et al. (1979) with [C-11]chlorpromazine revealed a widespread pattern of cortical and subcortical uptake due to nonspecific binding. Subsequent studies with more specific ligands such as [C-11]methylspiperone (Wong et al., 1986) and [C-11]raclopride (Farde et al., 1990) focused exclusively on the striatum and had variable results (see review (Tune et al., 1993)). The development of high-affinity ligands such as [C-11]FLB 457 (Olsson et al., 1999) and [F-18]fallypride (Mukherjee et al., 1999) opened the possibility of examining other brain regions identified as abnormal in functional activation imaging with PET, SPECT, EEG, and fMRI (see recent reviews) — the prefrontal cortex (Molina et al., 2005) (Andreasen et al., 1997, Buchsbaum and Hazlett, 1998) (Eyler et al., 2004, Suzuki et al., 2005), thalamus (Andreasen, 1997, Buchsbaum et al., 1996, Hazlett et al., 2004), cingulate gyrus (Haznedar et al., 2004, Quintana et al., 2004, Yasuno et al., 2005), and temporal lobe (Eyler et al., 2004) (Eyler et al., 2004). The medial dorsal nucleus (MDN), the largest association nucleus in the thalamus, has its major reciprocal connections with the prefrontal cortex, and is thus a prime candidate region for a schizophrenia diathesis. When thalamic nuclei were traced on coregistered MRI, decreased metabolic rates were found in the MDN in patients with schizophrenia in comparison to normal controls (Hazlett et al., 2004). This region is also known to have cell loss and volume reduction in patients with schizophrenia in postmortem studies (Byne et al., 2002, Danos et al., 2005, Pakkenberg, 1992, Popken et al., 2000, Young et al., 2000). In an early postmortem study, Oke suggested elevated thalamic dopamine as important in schizophrenia (Oke et al., 1992).

Autoradiographic and PET studies confirm moderate density D2/D3 sites in the MDN. Epidepride binding was about twice as high in the MDN than lateral dorsal or geniculate nuclei in autoradiographic studies (Rieck et al., 2004). PET studies have also confirmed thalamic D2/D3 binding (Farde et al., 1997, Mukherjee et al., 2002, Okubo et al., 1999, Rieck et al., 2004, Sedvall and Farde, 1995, Suhara et al., 2002, Talvik et al., 2003). There was markedly higher D2/D3 binding in the MDN and anterior nuclei of the thalamus than other thalamic areas (Okubo et al., 1999) and nearly twice as high in medial than in lateral thalamus in normal controls in PET measurement with [C-11]FLB 457 (Talvik et al., 2003).

Several studies in patients with schizophrenia with high affinity ligands have found low D2 binding in the medial regions of the thalamus. After dividing the thalamus into lateral and medial segments, low D2 binding was found in previously untreated patients with schizophrenia (Talvik et al., 2003). Using a thalamic map derived from our earlier report (Buchsbaum et al., 1996), Yasuno found diminished [C-11]FLB 457 binding in the ventral medial and posterior subregions of the thalamus in 10 never previously medicated schizophrenics in comparison to 19 normal controls (Yasuno et al., 2004). Another PET study with [C-11]FLB 457 (Suhara et al., 2002) found significantly decreased binding potential in the anterior cingulate with a smaller effect in the whole thalamus (3.31 in never previously medicated patients and 3.58 in normals was p = 0.06, approximate effect size 0.79).

The goal of this work was to use the high affinity, D2/D3 dopamine selective PET radioligand, [F-18]fallypride to confirm and extend these earlier findings in never-medicated patients with significance probability mapping and anatomical tracing of the major nuclei of the thalamus.

Section snippets

Schizophrenia and related conditions

Fifteen psychotic patients (10 men; 5 women; mean age, 28.5; SD, 8.9; 15 right-handed) were recruited from the greater Dayton, Ohio, area, and were evenly divided between inpatients and outpatients. After complete description of the study, all subjects completed a verbal “informed consent post-test.” All participants passed this test and gave written informed consent. Subjects underwent evaluation using the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen et al., 1992) Brief

MDN and pulvinar

Patients with schizophrenia had lower BP in the MDN (1.78 ± 0.53) than normal volunteers (2.16 ± 0.36; t = 2.15, df = 1,24, p = 0.041, mean of left and right sided ROI). This was also true for the pulvinar (0.94 ± 0.27 vs. 1.15 ± 0.18, t = 2.27, p = 0.03). However the remainder of the thalamus after removal of the areas of the medial dorsal and pulvinar showed no significant group difference (2.21 ± 0.92 vs. 2.47 ± 0.46, t = 0.89, p = 0.37). The entire thalamus did differ (1.34 ± .36 vs. 1.58  ± 21, t = 2.12, p = 0.04). When

Discussion

We found decreased binding potential with [F-18]fallypride, a D2/D3 high-affinity ligand in the MDN and pulvinar regions of the thalamus in patients with schizophrenia in comparison to normal controls. These data are consistent with three other studies. First, the reduced binding potential in the medial half of the thalamus divided geometrically has been reported in 9 never-medicated patients and 8 controls using [C-11]FLB 457 (Talvik et al., 2003). These findings were more prominent in the

Acknowledgements

This work was supported by the Boonshoft Schizophrenia Center, the Wallace–Kettering Neuroscience Center, and by a grant to Dr. Buchsbaum, Anatomy and function of the thalamus in schizophrenia MH60023. The support of the United States Air Force, Air Force Research Laboratory (AFRL/HEOP), Air Force Materiel Command, under cooperative agreement F33615-98-2-6002, for use of imaging resources, is gratefully acknowledged. Marylin Brackney, Dr. King-Wai Chu, Kelly Dunigan, Kerry Kovacs, Candice Lee,

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