Reproducibility of repeated measures of endogenous dopamine competition with [¹¹C]raclopride in the human brain in response to methylphenidate

The measure of changes in synaptic dopamine (DA) concentration in response to the psychostimulant drug methylphenidate (MP) has been used as an indicator of responsiveness of the DA system. The purpose of this study was to assess the reproducibility of these measures. Methods: Seven healthy subjects were scanned with PET and [¹¹C]raclopride twice in the same day: 7 min after placebo or methylphenidate (0.5 mg/kg) administration. In parallel we also measured the physiologic and behavioral responses to placebo and to methylphenidate. The same procedures were repeated 1-2 wk later to assess test-retest reproducibility. Results: Measures of plasma to brain transfer constant (K1), striatal distribution volume (DV(str)) and DA D₂ receptor availability (Bmax/Kd), for the placebo condition were similar for the first (E1) and second (E2) evaluations (Bmax/Kd, E1: 2.77 ± 0.44; E2: 2.97 ± 0.44). MP administration did not change K1, but it significantly decreased DV(str) (E1: -25.9% ± 8.7%, P ≤ 0.0002; E2: -20.7% ± 11.7%, P ≤ 0.007) and Bmax/Kd (E1: -18.4% ± 8.7%, P ≤ 0.002; E2: -13.4% ± 9.2%, P ≤ 0.008), and the magnitude of these changes, though lower for E2, did not differ significantly. MP increased pulse rate(E1: +64% ± 43%, P ≤ 0.002; E2: +69% ± 33%, P ≤ 0.001), systolic pressure (E1: +37% ± 19%, P ≤ 0.0006; E2: +29% ± 15%, P ≤ 0.0009), self reports for drug effects (0: nothing to 10: extreme) of 'rush' (E1: +8 ± 3, P ≤ 0.0004; E2: +6 ± 4, P ≤ 0.01) and 'high' (E1: +8 ± 3, P ≤ 0.0001, E2: +8 ± 3, P ≤ 0.0003), anxiety (E1: +5 ± 4, P ≤ 0.02; E2: +4 ± 4, P = 0.1) and restlessness (E1: +4 ± 4, P ≤ 0.04; E2: +4 ± 5, P = 0.1). The magnitude of the cardiovascular and behavioral effects did not differ between E1 and E2. Conclusion: MP-induced changes in striatal DV and in Bmax/Kd, as well as the behavioral and cardiovascular effects, were reproducible with repeated administration.