Pharmacological evidence for alpha-2 adrenoceptor heterogeneity: differential binding properties of [3H]rauwolscine and [3H]idazoxan in rat brain.

In the preceding paper, we have reported that the two alpha-2 adrenoceptor antagonists, [3H]rauwolscine and [3H]idazoxan, exhibit markedly different autoradiographic distributions throughout rat brain. Although [3H]idazoxan labeling appears over brain regions receiving noradrenergic innervation, [3H]rauwolscine binding sites are localized most densely in several areas corresponding to dopaminergic terminal fields. We have presently characterized the pharmacological binding properties of high affinity [3H]rauwolscine and [3H]idazoxan labeled sites, using tissue preparation and incubation protocols which are identical to those used in the previous autoradiographic study. Endogenous monoamines inhibited radioligand binding with a rank order of potency of epinephrine = norepinephrine greater than dopamine greater than serotonin. Numerous dopaminergic compounds failed to inhibit either [3H]rauwolscine or [3H]idazoxan binding with high potency, and rauwolscine was a poor inhibitor of [3H]spiroperidol binding. Several adrenergic compounds which selectively label alpha-1 or beta adrenoceptors also exhibited low potency in inhibiting either radioligand. In contrast, alpha-2 adrenoceptor agonists and antagonists possessed high affinity for both [3H]rauwolscine and [3H]idazoxan labeled sites. Their relative potencies at the two sites differed, however. Whereas idazoxan was equipotent in inhibiting either [3H]rauwolscine or [3H]idazoxan binding, rauwolscine exhibited 10-fold higher affinity for its own labeled site. These pharmacological data are consistent with anatomical data presented in the preceding paper, which support the existence of a heterogenous population of alpha-2 adrenoceptors within rat brain, labeled entirely by [3H]idazoxan and only in part by [3H]rauwolscine.