Actions of alpha-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype.
BACKGROUND
alpha-2 Noradrenergic agonists improve spatial working memory in animals and in humans. Of the three alpha-2 receptor subtypes, evidence has suggested that this cognitive improvement may be mediated by the alpha-2A receptor subtype, but this has not been established. alpha-2 Agonists are also known to decrease blood pressure significantly. Recent evidence using genetically altered mice indicates that the alpha-2A receptor subtype mediates this decrease in blood pressure.


OBJECTIVE
The present study examined whether the cognitive improvement and hypotension produced by alpha-2 agonists are mediated by the same receptor subtype in rhesus monkeys. The hypotensive and cognitive-enhancing effects of clonidine and guanfacine were challenged with two alpha-2 antagonists with differing affinities for the three alpha-2 receptor subtypes: MK912, a potent antagonist which shows preferential binding to the alpha-2C receptor subtype, and idazoxan, which slightly prefers the alpha-2A receptor subtype. If alpha-2C receptors contribute to the cognitive enhancement, MK912 should reverse the cognitive-enhancing effects of alpha-2 agonists at lower doses than those needed to reverse the hypotensive effects of these compounds. Conversely, if alpha-2A receptors contribute to cognitive enhancement, MK912 and idazoxan should reverse the cognitive-enhancing effects of alpha-2 agonists at the same doses as those needed to reverse the hypotensive effects of these compounds.


RESULTS
MK-912 and idazoxan dose-dependently reversed both clonidine and guanfacine-induced cognitive improvement and hypotension. Both antagonists were equally potent in reversing either the cognitive enhancement or the hypotension.


CONCLUSIONS
The identical pattern of dose-dependent reversal of cognitive improvement and hypotension indicates that, in non-human primates, the same receptor subtype mediates both effects. Previous evidence suggests that the most likely candidate is the alpha-2A receptor subtype.
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8001, USA.
Jenna S
JS
Franowicz
Amy F T
AF
Arnsten
D018663:Adrenergic Agents / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D016316:Guanfacine / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D019329:Idazoxan / Q000494:pharmacology; D008253:Macaca mulatta; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D011807:Quinolizines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology
D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011807:Quinolizines; D018341:Receptors, Adrenergic, alpha-2; C054290:L 657743; D016316:Guanfacine; D019329:Idazoxan