title: Absolute abundances and affinity states of dopamine receptors in mammalian brain: A review.
abstract: The abundances of dopamine (DA) D(1) and D(2) receptors have been assayed with radioligands in membrane preparations and by autoradiography in vitro, and also in living brain using positron emission tomography (PET). This review compares the saturation binding parameters (B(max) and K(D) ) obtained in striatum by these several methods, and in different species. Some uncertainty in quantitation is derived from the incomplete specificities of commonly used ligands, especially Sch 23,390 for D(1) sites and spiperone for D(2) -like sites. In striatal membrane preparations, the D(1) B(max) ranges from 10 to 139 pmol g(-1) tissue, whereas the D(2) B(max) ranges from 8 to 42 pmol g(-1) tissue. Receptor concentrations in human material, despite the more extended post mortem interval, are roughly similar to those reported in rodent and nonhuman primate. Estimates of B(max) by quantitative autoradiography are generally five times higher than corresponding results for similar ligands in membrane preparations. The saturation binding parameters in living striatum have been estimated by serial PET studies with ligands over a range of specific activities. The few PET estimates of D(1) B(max) , (40-80 pmol g(-1) ) and numerous PET estimates of D(2) B(max) (20-40 pmol g(-1) ) are in general agreement with membrane estimates, but fall far short of the mean of autoradiographic results in vitro. Apparent affinities for D(1) and D(2) ligands in vivo are typically 10 times lower than for corresponding in vitro studies, presumably because the unbound ligand concentration is not corrected for the free fraction in living brain tissue. The disparate B(max) results by method suggest the presence of a large reservoir or reserve of D(1) and D(2) receptors in intact brain sections, which are unavailable to PET ligands in vivo, and which may be lost during the preparation of washed membranes. A subset of receptors existing in a high affinity state for agonists is detected in washed membrane preparations, in which the coupling to intracellular G-proteins may have become artificially limiting. However, in most PET and autoradiographic studies in vitro, agonist and antagonist ligands have similar B(max) . Discrepancies in the literature highlight the need for a better understanding of affinity states in vivo and trafficking of G-protein coupled receptors between plasma membrane and intracellular compartments.
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilian's University Munich, Germany. paul.k.cumming@gmail.com
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002090:Butyrophenones / Q000494:pharmacology; D015259:Dopamine Agents / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008322:Mammals; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011868:Radioisotopes / Q000493:pharmacokinetics; D011954:Receptors, Dopamine / Q000145:classification / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D002090:Butyrophenones; D015259:Dopamine Agents; D008024:Ligands; D011868:Radioisotopes; D011954:Receptors, Dopamine