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 [H-3]spiperone or [H-3]raclopride, [H-3]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 [H-3]dopamine. Increased labeling of D2High sites occurred with [H-3]domperidone after severe disruption of the cells, suggesting that [H-3]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [H-3]domperidone-labeled D2 receptors was the same as that of the [H-3]raclopride-labeled D2 receptors, but twice the density of [H-3]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [H-3]domperidone readily labels the D2High sites in postmortem human brain homogenates. Although [H-3]spiperone or [H-3]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 [C-11]methylspiperone or [C-11]raclopride in humans. (C) 2003 Wiley-Liss, Inc.