Characteristics of norepinephrine and clonidine displacement of [³H]yohimbine binding to platelet alpha₂-adrenoreceptors in healthy volunteers

Clonidine's estimates of platelet α₂-adrenoreceptor (α₂AR) density are substantially lower than yohimbine's. This discrepancy could have contributed to inconsistent results from studies on the role of α₂AR in depression. Furthermore, few studies have investigated the relative distribution of α₂AR between the high- and low-affinity states or their G(i) protein coupling. [³H](y)ohimbine saturable binding to platelet α₂AR, its displacement by norepinephrine and clonidine, and the effects of Gpp(NH)p on agonist displacement curves were investigated in 11 healthy volunteers. Clonidine estimates of α₂AR density were close to norepinephrine estimates, and both were strongly correlated. Clonidine's K(L)/K(H) ratio was lower than norepinephrine's, consistent with its partial agonist nature. Norepinephrine and clonidine displacement curves revealed two affinity states. Gpp(NH)p induced a significant rightward shift to a single low-affinity state. When used in combination with a specific antagonist, clonidine's estimates of α₂AR density were similar to those of norepinephrine's, and both were higher than previously reported, when clonidine was used alone. Re-evaluation of previous studies on α₂AR in depression using clonidine is needed. The combined use of antagonist-saturation and agonist-displacement experiments to examine possible dysregulation in α₂AR coupling to G(i) protein in psychiatric-disorders is recommended.