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

The affinities of D-3 dopamine receptors for antagonists are similar to 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 for 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 receptors is believed to be the functional stare of these receptors. When receptors were labeled with the D-2 receptor antagonist [I-125]-(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 proteins, the affinities of D-3 receptors Were approximately 130-fold higher than those of D-2 receptors for 7-OH-DPAT and quinpirole. When receptors were labeled with the D-2 receptor agonist [I-125]-(R)trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino]tetralin ([I-125]-7-OH-PIPAT) under conditions that 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 affinities of D-2 and D-3 receptors for other agonists were seen when receptors were labeled with [I-125]-7-OH- PIPAT. These data demonstrate that putative D-3 receptor-selective agonists also interact with a high-affinity, G protein-coupled state of D-2 receptors. The similarities in affinities of the agonist-preferring state of D-2 and D-3 receptors means that currently available agonists cannot be used to discriminate between behavioral effects mediated by D-2 and D-3 receptors.