Autoradiographic characterization of alpha(2C)-adrenoceptors in the human striatum.
Indirect experimental evidence suggests that drugs acting on the alpha(2C)-adrenoceptor could be useful in the treatment of neuropsychiatric disorders such as depression and schizophrenia. In rodent brain, the highest levels of alpha(2C)-adrenoceptors are found in the striatum, with lower levels in cerebral cortex and hippocampus. In human brain, because of the poor subtype-selectivity of the available alpha(2)-adrenoceptor ligands, the localization of alpha(2C)-adrenoceptors has remained unknown. Recently, a selective alpha(2C)-adrenoceptor antagonist, JP-1302, was characterized, and to assess the presence of alpha(2C)-adrenoceptors in human brain, we performed competition binding in vitro receptor autoradiography with JP-1302 and the alpha(2)-adrenoceptor subtype nonselective antagonist [ethyl-(3)H]RS79948-197 on rat and human postmortem brain sections. In striatum of both species, JP-1302 vs. [ethyl-(3)H]RS79948-197 competition binding was biphasic, identifying high- and low-affinity binding sites, whereas in cortex and cerebellum, only low-affinity binding sites were detected. The results indicate that a significant portion of the alpha(2)-adrenoceptors in striatum is of the alpha(2C) subtype, whereas non-alpha(2C)-adreocneptors predominate in cortex and cerebellum. Because the alpha(2C)-adrenoceptor subtype distribution pattern appears to be conserved between rodents and humans, results obtained from studies on the role of the alpha(2C)-adrenoceptor in rodent models of neuropsychiatric disorders may be relevant also for human diseases.
Fagerholm
Veronica
V
Turku PET Centre, Turku, Finland. veronica.fagerholm@abo.fi
Rokka
Johanna
J
Nyman
Leena
L
Sallinen
Jukka
J
Tiihonen
Jari
J
Tupala
Erkki
E
Haaparanta
Merja
M
Hietala
Jarmo
J
D000166:Acridines / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology*; D002395:Catecholamines / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000378:metabolism; D010802:Phylogeny; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000032:analysis / Q000378:metabolism*; D013045:Species Specificity; D014316:Tritium
C547774:ADRA2C protein, human; D000166:Acridines; C547776:Adra2c protein, rat; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D007546:Isoquinolines; C518829:JP-1302; D008024:Ligands; D009287:Naphthyridines; D010879:Piperazines; C104875:RS 79948-197; D018341:Receptors, Adrenergic, alpha-2; D014316:Tritium