α2‐Adrenoceptor subtypes and imidazoline‐like binding sites in the rat brain

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Abstract
The binding of [3H]‐yohimbine and [3H]‐idazoxan to rat cortex and hippocampus is rapid, reversible and of high affinity. Saturation data indicate that a single population of binding sites exist for [3H]‐yohimbine in the cortex (Bmax121 ± 10 fmol mg−1, protein;Kd5.2 ± 0.9 nm) and hippocampus (Bmax72 ± 6 fmol mg−1protein;Kd5.8 ± 0.7 nm). [3H]‐idazoxan labels one site in the cortex (Bmax87 ± 8 fmol mg−1protein;Kd4.1± 0.9 nm) and hippocampus (Bmax30 ± 6 fmol mg−1protein;Kd3.5 + 0.5 nm), when 3 μmphentolamine is used to define non‐specific binding. A second distinct [3H]‐idazoxan binding site (Bmax110 ± 21fmolmg_1protein;Kd3.6 ± 0.07 nm) is identified in rat cortex if 0.3 μmcirazoline is used to define non‐specific binding and 3 μmyohimbine is included to prevent binding to α2‐adrenoceptors. Displacement studies indicate that the α1‐adrenoceptor antagonist prazosin and the 5‐HT1ligands 8‐OH‐DPAT, RU 24969 and methysergide differentiate [3H]‐yohimbine binding into two components; a high and low affinity site. In contrast the displacement of [3H]‐idazoxan by each ligand was monophasic. The affinities of 8‐OH‐DPAT, RU 24969 and methysergide determined against [3H]‐idazoxan binding to the cortex and hippocampus correlate significantly with the binding site displaying low affinity for prazosin and previously designated α2A. In contrast, a poor correlation exists for the high affinity site for prazosin designated α2B. [3H]‐idazoxan, in the presence of 3 μmyohimbine, labels a site that displays high affinity towards cirazoline, naphazoline and guanabenz, but low affinity towards clonidine,p‐aminoclonidine, adrenaline, noradrenaline and the α2‐adrenoceptor antagonists yohimbine, rauwolscine, WY 26703 and BDF 6143. The results of this study indicate that [3H]‐yohimbine labels two sites; the α2A‐ and α2B‐adrenoceptors whereas [3H]‐idazoxan labels an α2‐adrenoceptor with a profile consistent with the α2A‐adrenoceptor subtype. In addition, [3H]‐idazoxan labels an imidazoline binding site in the rat cortex that is pharmacologically distinct from α2‐adrenoceptors. The low affinity of clonidine andp‐aminoclonidine indicates that the imidazoline‐like binding site in rat cortex is different from the site labelled by [3H]‐clonidine and [3H]‐p‐aminoclonidine in human, rat and bovine brain stem, providing evidence of potential heterogeneity within this class of binding sites.

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