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α 2 ‐Adrenoceptor subtypes and imidazoline‐like binding sites in the rat brain
Author(s) -
Brown C.M.,
MacKin A.C.,
McGrath J.C.,
Spedding M.,
Kilpatrick A.T.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb13010.x
Subject(s) - idazoxan , yohimbine , imidazoline receptor , chemistry , binding site , endocrinology , methysergide , medicine , prazosin , receptor , biology , antagonist , biochemistry
1 The binding of [ 3 H]‐yohimbine and [ 3 H]‐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 [ 3 H]‐yohimbine in the cortex ( B max 121 ± 10 fmol mg −1 , protein; K d 5.2 ± 0.9 n m ) and hippocampus ( B max 72 ± 6 fmol mg −1 protein; K d 5.8 ± 0.7 n m ). [ 3 H]‐idazoxan labels one site in the cortex ( B max 87 ± 8 fmol mg −1 protein; K d 4.1± 0.9 n m ) and hippocampus ( B max 30 ± 6 fmol mg −1 protein; K d 3.5 + 0.5 n m ), when 3 μ m phentolamine is used to define non‐specific binding. A second distinct [ 3 H]‐idazoxan binding site ( B max 110 ± 21fmolmg _1 protein; K d 3.6 ± 0.07 n m ) is identified in rat cortex if 0.3 μ m cirazoline is used to define non‐specific binding and 3 μ m yohimbine is included to prevent binding to α 2 ‐adrenoceptors. 2 Displacement studies indicate that the α 1 ‐adrenoceptor antagonist prazosin and the 5‐HT 1 ligands 8‐OH‐DPAT, RU 24969 and methysergide differentiate [ 3 H]‐yohimbine binding into two components; a high and low affinity site. In contrast the displacement of [ 3 H]‐idazoxan by each ligand was monophasic. 3 The affinities of 8‐OH‐DPAT, RU 24969 and methysergide determined against [ 3 H]‐idazoxan binding to the cortex and hippocampus correlate significantly with the binding site displaying low affinity for prazosin and previously designated α 2A . In contrast, a poor correlation exists for the high affinity site for prazosin designated α 2B . 4 [ 3 H]‐idazoxan, in the presence of 3 μ m yohimbine, labels a site that displays high affinity towards cirazoline, naphazoline and guanabenz, but low affinity towards clonidine, p ‐aminoclonidine, adrenaline, noradrenaline and the α 2 ‐adrenoceptor antagonists yohimbine, rauwolscine, WY 26703 and BDF 6143. 5 The results of this study indicate that [ 3 H]‐yohimbine labels two sites; the α 2A ‐ and α 2B ‐adrenoceptors whereas [ 3 H]‐idazoxan labels an α 2 ‐adrenoceptor with a profile consistent with the α 2A ‐adrenoceptor subtype. In addition, [ 3 H]‐idazoxan labels an imidazoline binding site in the rat cortex that is pharmacologically distinct from α 2 ‐adrenoceptors. The low affinity of clonidine and p ‐aminoclonidine indicates that the imidazoline‐like binding site in rat cortex is different from the site labelled by [ 3 H]‐clonidine and [ 3 H]‐p‐aminoclonidine in human, rat and bovine brain stem, providing evidence of potential heterogeneity within this class of binding sites.