A consideration of the dopamine D2 receptor monomer-dimer equilibrium and the anomalous binding properties of the dopamine D2 receptor ligand, N-methyl spiperone

Some discrepancies between experimental results with the two D2 antagonists N-methyl spiperone (NMSP) and raclopride (RAC) have been observed. Among t hese are the observation that MK-801 increases NMSP binding but not RAC bin ding; pretreatment with reserpine increases RAC binding but decreases NMSP binding; and that the two ligands yield different: values for Bmax. It has been observed that the D2 receptor can exist in both a monomer and dimer fo rm and that a NMSP photolabel ligand binds primarily to the monomer form wh ile a RAG-like photolabel ligand binds both. Using a model of the dimerizat ion in which the equilibrium dissociation constant increases with increasin g dopamine (DA) concentration, the free monomer concentration can be shown to go through a maximum value with increasing DA. Using this model with dat a from a baboon PET study, it can be shown that under certain conditions an increase in binding could be observed. Further research may show that ther e are clusters of D2 receptors forming oligomers with more than two recepto rs in which NMSP binds to more sites on clusters with fewer receptors. If i ncreasing DA favors cluster with fewer receptors, an increase in NMSP bindi ng sites may also occur under some circumstances with an increase in DA.