Dr. Volkow and Colleagues Reply

To the Editor: Dr. Dagher is correct in pointing out that when [¹¹C]raclopride is used to measure D₂ receptors, elevated D₂ receptor occupancy by dopamine—which can masquerade as a decrease in receptor levels—presents a potential confounding variable. Since our experimental design did not allow us to exclude this possibility, we should have pointed out this limitation and used the term “D₂ receptor availability” rather than “D₂ receptor levels.” However, what follows is evidence that the differences in D₂ receptor availability between subjects who reported the effects of methylphenidate as pleasant and those who reported them as unpleasant reflect differences in D₂ receptor levels.

To start with, [¹¹C]raclopride is unlikely to be sensitive to day-to-day fluctuations of mental state as encountered during a PET experiment (i.e., differences in levels of anxiety and discomfort), as evidenced by its reproducibility when subjects are tested weeks (1) or months (2) apart.

To indirectly assess if the low D₂ receptor availability was due to lower D₂ receptors levels and not higher D₂ receptor occupancy by dopamine, we measured the correlation (Pearson’s product-moment) between D₂ receptor availability and the changes in [¹¹C]raclopride binding induced by 0.5 mg/kg of intravenous methylphenidate, which we had previously determined in these subjects (3). Because methylphenidate increases dopamine levels by blocking dopamine transporters (not by dopamine release) (4), the accumulation is a function of the amount of dopamine released at baseline, and hence the measure of methylphenidate-induced dopamine changes can be used as an indicator of baseline dopamine release. Measures of D₂ receptor availability were significantly correlated with the changes in raclopride binding (baseline minus methylphenidate) (r=0.55, df=22, p<0.007). The lower the D₂ receptor availability at baseline, the lower the dopamine changes, and vice versa. This is a strong indication that subjects with low D₂ receptor availability did not have enhanced synaptic dopamine (and thus enhanced D₂ receptor occupancy by dopamine) and those with high D₂ receptor availability did not have decreased dopamine release (and decreased D₂ receptor occupancy). Therefore, these results suggest that the differences in D₂ receptor availability reflect differences in D₂ receptor levels and support the involvement of D₂ receptors as one of the molecular targets that modulates vulnerability to drug addiction.