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.