PET imaging of dopamine-D2 receptor internalization in schizophrenia

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (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 D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge 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 after 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 with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [¹¹C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg^-1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP_ND) and derived percent reduction from baseline (ΔBP_ND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP_ND to baseline differed between SZ and HCs, we implemented a linear model with ΔBP_ND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after 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 that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.