LACK OF DISCRIMINATION BY AGONISTS FOR D-2 AND D-3 DOPAMINE-RECEPTORS

The affinities of D-3 dopamine receptors for antagonists are similar t o those of D-2 receptors D-3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D-2 receptors fo r some agonists, including (+/-)-7-hydroxy-n, n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. This has led to the use of these agonists to try to identify functional responses mediated by D-3 receptors in vivo. However, D-2 receptors exist in multiple states having high and low affinities for agonists. The G protein-coupled state of D-2 recept ors is believed to be the functional stare of these receptors. When re ceptors were labeled with the D-2 receptor antagonist (S)-3-iodo-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5,6- dimethoxysalicylamide ([I-125]-NCQ- 298) under conditions that promote uncoupling of receptors from G prot eins, the affinities of D-3 receptors Were approximately 130-fold high er than those of D-2 receptors for 7-OH-DPAT and quinpirole. When rece ptors were labeled with the D-2 receptor agonist 2-[N-propyl-N-(3'-iod o-2'-propenyl)-amino]tetralin ([I-125]-7-OH-PIPAT) under conditions th at favor interactions of receptors with G proteins, the affinities of D-3 receptors were less than sevenfold higher than the affinities of D -2 receptors for the same drugs. Similarly, small differences in the a ffinities of D-2 and D-3 receptors for other agonists were seen when r eceptors were labeled with [I-125]-7-OH- PIPAT. These data demonstrate that putative D-3 receptor-selective agonists also interact with a hi gh-affinity, G protein-coupled state of D-2 receptors. The similaritie s in affinities of the agonist-preferring state of D-2 and D-3 recepto rs means that currently available agonists cannot be used to discrimin ate between behavioral effects mediated by D-2 and D-3 receptors.