α 2 ‐Adrenoceptor Subtypes Identified by [ 3 H]RX821002 Binding in the Human Brain: The Agonist Guanoxabenz Does Not Discriminate Different Forms of the Predominant α 2A Subtype

Competition [ 3 H]RX821002 ([ 3 H]2‐methoxyidazoxan) binding experiments with α 2 ‐adrenoceptor subtype‐specific antagonists—BRL 44408 (α 2A selective), ARC 239 (α 2B selective), and others—were performed to delineate through rigorous computer modeling receptor subtypes in the postmortem human brain. In the hippocampus, hypothalamus, cerebellum, and brainstem the whole population of α 2 ‐adrenoceptors appears to belong to the α 2A subtype (100%; B max = 34–90 fmol/mg of protein). In the frontal cortex, the predominant receptor was the α 2A subtype (87%; B max = 53 fmol/mg of protein), although a small population of the α 2B/C subtype (13%; B max = 8 fmol/mg of protein) was also detected. In the caudate nucleus, a mixed population of α 2A (64%; B max = 9 fmol/mg of protein) and α 2B/C (36%; B max = 5 fmol/mg of protein) subtypes was detected. In the cortex and caudate and in the presence of ARC 239 (to mask the α 2B/C ‐adrenoceptors), competition experiments with the agonist guanoxabenz clearly modeled the high‐ and low‐affinity states of the α 2A subtype. In the presence of ARC 239 and the GTP analogue guanylyl‐5′‐imidodiphosphate together with NaCl and EDTA (to eliminate the high‐affinity α 2A ‐adrenoceptor) guanoxabenz only recognized the low‐affinity α 2A ‐adrenoceptor. The results indicate that in the human brain the predominant α 2 ‐adrenoceptor is of the α 2A subtype and that this functionally relevant receptor subtype is not heterogeneous in nature.