PET imaging of dopamine-D2 receptor internalization in schizophrenia

Recent genetic, molecular and postmortem studies suggest impaired D2R trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using dopamine-D2 receptor (D2R) radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when post-challenge dopamine (DA) levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used “late”-phase imaging post-challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late phase displacement, or a faster return to baseline, in patients compared to healthy controls (HC). We imaged 10 patients with SZ and 9 HC with PET and [(11)C]raclopride at baseline and twice (3–5hr and 6–10hr) following 0.5 mg/kg dextro-amphetamine. We measured binding potential relative to non-displaceable compartment (BP(ND)) and derived percent reduction from baseline (ΔBP(ND)) for each post-amphetamine scan. To test the hypothesis that time course of return of striatal BP(ND) to baseline differed between SZ and HC, we implemented a linear model with ΔBP(ND) as dependent variable, time post-amphetamine as repeated measure, and time post-amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time post-amphetamine significantly affected striatal ΔBP(ND) (F=1.38, p=0.26; F=0.51, p=0.61). These results show similar pattern of return of BP(ND) to baseline as a function of time in patients with SZ and HC, suggesting striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.