Dopamine displaces [3H]domperidone from high-affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography.
Because the high-affinity state of the dopamine D2 receptor, D2High, is the functional state of the receptor, has a role in demarcating typical from atypical antipsychotics, and is markedly elevated in amphetamine-sensitized rats, it is important to have a method for the convenient detection of this state by a ligand. The present data show that, in contrast to [(3)H]spiperone or [(3)H]raclopride, [(3)H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [(3)H]dopamine. Increased labeling of D2High sites occurred with [(3)H]domperidone after severe disruption of the cells, suggesting that [(3)H]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [(3)H]domperidone-labeled D2 receptors was the same as that of the [(3)H]raclopride-labeled D2 receptors, but twice the density of [(3)H]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [(3)H]domperidone readily labels the D2High sites in postmortem human brain homogenates. Although [(3)H]spiperone or [(3)H]raclopride can occupy D2High sites, the inability of 1-10 nM dopamine to displace these ligands under isotonic conditions suggests that these ligands may not be suitable for monitoring the physiological high-affinity state of the dopamine D2 receptor by means of [(11)C]methylspiperone or [(11)C]raclopride in humans.
Seeman
Philip
P
Department of Pharmacology, University of Toronto, 1 King's College Circle, Medical Sciences Building Room 4344, Toronto, Ontario, Canada M5S JA8. philip.seeman@utoronto.ca
Tallerico
Teresa
T
Ko
Françoise
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D000818:Animals; D004294:Domperidone / Q000493:pharmacokinetics / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D007552:Isotonic Solutions; D020891:Raclopride / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013134:Spiperone / Q000493:pharmacokinetics / Q000494:pharmacology*; D014055:Tomography, Emission-Computed; D014316:Tritium
D018492:Dopamine Antagonists; D007552:Isotonic Solutions; D017448:Receptors, Dopamine D2; D014316:Tritium; D020891:Raclopride; D013134:Spiperone; D004294:Domperidone; D012964:Sodium; D004298:Dopamine