α2‐Adrenoceptor Subtypes Identified by [3H]RX821002 Binding in the Human Brain: The Agonist Guanoxabenz Does Not Discriminate Different Forms of the Predominant α2A Subtype

Competition [3H]RX821002 ([3H]2-methoxyidazoxan) binding experiments with alpha 2-adrenoceptor subtype-specific antagonists--BRL 44408 (alpha 2A selectively), ARC 239 (alpha 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 alpha 2-adrenoceptors appears to belong to the alpha 2A subtype (100%; Bmax = 34-90 fmol/mg of protein). In the frontal cortex, the predominant receptor was the alpha 2A subtype (87%; Bmax = 53 fmol/mg of protein), although a small population of the alpha 2B/C subtype (13%; Bmax = 8 fmol/mg of protein) was also detected. In the caudate nucleus, a mixed population of alpha 2A (64%; Bmax = 9 fmol/mg of protein) and alpha 2B/C (36%; Bmax = 5 fmol/mg of protein) subtypes was detected. In the cortex and caudate and in the presence of ARC 239 (to mask the alpha 2B/C-adrenoceptors), competition experiments with the agonist guanoxabenz clearly modeled the high- and low-affinity states of the alpha 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 alpha 2A-adrenoceptor) guanoxabenz only recognized the low-affinity alpha 2A-adrenoceptor. The results indicate that in the human brain the predominant alpha 2-adrenoceptor is of the alpha 2A subtype and that this functionally relevant receptor subtypes is not heterogeneous in nature.