Low density of dopamine D4 receptors in Parkinson's, schizophrenia, and control brain striata

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Abstract
The purpose of this study was to determine whether dopamine D4 receptors could be detected in the human brain striatum by means of an indirect ligand‐binding method, because no dopamine D4 receptor‐selective ligand presently exists. The antipsychotic clozapine is more selective for the dopamine D4 receptor than for other dopamine receptors. Although most antipsychotic drugs act in the striatum to elicit Parkinson‐like side‐effects, clozapine is atypical in that it does not produce Parkinsonism. To understand this atypical action of clozapine, it would be helpful to know whether the presumed target for clozapine, the dopamine D4 receptor, is or is not present in the human striatum. We measured dopamine D4 receptors indirectly, using [3H]emonapride Emonapride (or YM‐09151‐2; eis‐N‐[(2RS,3RS)‐l‐benzyl‐2‐methylpyrrolin‐ 3‐yll‐5‐chloro‐2‐methoxy‐4‐∼methylamino‐benzamide]) contains two asymmetric carbon atoms and is, therefore, a racemate of four enantiomers, two of which, (R,R)YM‐O9151‐2 and (S,S)YM‐09151‐2, are active with identical potency (see Refs. in Seeman et al., 1992). and [3H]raclopride. Emonapride has a high affinity (K = 90 pM) for the dopamine D4 receptor, while raclopride has a very low affinity for this receptor (K = 240 nM); thus, any difference in the densities of these two [3H]ligands (in the absence of dopamine) could be attributed to the presence of dopamine D4 receptors. Since the binding of [3H]raclopride is sensitive to endogenous dopamine, we used Parkinson‐diseased tissue which has little dopamine. We found that the densities of the two ligands were identical in Parkinson striata, indicating a low density (3H]emonapride was almost two‐fold higher than that of [3H]raclopride. Considering that there are few dopamine D4 receptors in the human striatum, this two‐fold difference is best explained by endogenous dopamine interfering with the binding of [3H]raclopride, but not that of [3H]emonapride.