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Letter to the Editor   |    
Dr. Volkow and Colleagues Reply
NORA D. VOLKOW, M.D.; JOANNA S. FOWLER, PH.D.; JEAN LOGAN, PH.D.; SAMUEL J. GATLEY, PH.D.; GENE-JACK WANG, M.D.; ROBERT HITZEMANN, PH.D.
Am J Psychiatry 2000;157:1709-1710. doi:10.1176/appi.ajp.157.10.1709

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.

Hietala J, Nagren K, Lehikoinen P, Ruotsalainen U, Syvalahti E: Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: a test-retest analysis. J Cereb Blood Flow Metab  1999; 19:210–217
[PubMed]
 
Schlosser R, Brodie JD, Dewey SL, Alexoff D, Wang GJ, Fowler JS, Volkow N, Logan J, Wolf AP: Long-term stability of neurotransmitter activity investigated with 11C-raclopride PET. Synapse  1998; 28:66–70
[PubMed]
[CrossRef]
 
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N: Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature  1997; 386:830–833
[PubMed]
[CrossRef]
 
Wayment HK, Deutsch H, Schweri MM, Schenk JO: Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? J Neurochem 1999; 72:1266–  1274
 
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References

Hietala J, Nagren K, Lehikoinen P, Ruotsalainen U, Syvalahti E: Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: a test-retest analysis. J Cereb Blood Flow Metab  1999; 19:210–217
[PubMed]
 
Schlosser R, Brodie JD, Dewey SL, Alexoff D, Wang GJ, Fowler JS, Volkow N, Logan J, Wolf AP: Long-term stability of neurotransmitter activity investigated with 11C-raclopride PET. Synapse  1998; 28:66–70
[PubMed]
[CrossRef]
 
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N: Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature  1997; 386:830–833
[PubMed]
[CrossRef]
 
Wayment HK, Deutsch H, Schweri MM, Schenk JO: Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? J Neurochem 1999; 72:1266–  1274
 
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