Low density of dopamine D4 receptors in Parkinson's, schizophrenia, and control brain striata.
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 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 (< 1 pmol/g) for dopamine D4 receptors in the human striatum. This low or undetectable density of dopamine D4 receptors in the striatum is consistent with other data indicating that clozapine does not have its major action in the human striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Seeman
P
P
Department of Pharmacology, University of Toronto, Ontario, Canada.
Guan
H C
HC
Van Tol
H H
HH
Niznik
H B
HB
D000818:Animals; D001549:Benzamides; D003342:Corpus Striatum / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010300:Parkinson Disease / Q000378:metabolism*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines; D020891:Raclopride; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D012457:Salicylamides; D012559:Schizophrenia / Q000378:metabolism*; D013134:Spiperone; D013552:Swine; D014055:Tomography, Emission-Computed
D001549:Benzamides; C493599:DRD4 protein, human; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D012457:Salicylamides; D050638:Receptors, Dopamine D4; D020891:Raclopride; D013134:Spiperone; C030265:nemonapride