Actions of α-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype

HeadingAbstractRationale. α-2 Noradrenergic agonists improve spatial working memory in animals and in humans. Of the three α-2 receptor subtypes, evidence has suggested that this cognitive improvement may be mediated by the α-2A receptor subtype, but this has not been established. α-2 Agonists are also known to decrease blood pressure significantly. Recent evidence using genetically altered mice indicates that the α-2A receptor subtype mediates this decrease in blood pressure.Objectives. The present study examined whether the cognitive improvement and hypotension produced by α-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 α-2 antagonists with differing affinities for the three α-2 receptor subtypes: MK912, a potent antagonist which shows preferential binding to the α-2C receptor subtype, and idazoxan, which slightly prefers the α-2A receptor subtype. If α-2C receptors contribute to the cognitive enhancement, MK912 should reverse the cognitive-enhancing effects of α-2 agonists at lower doses than those needed to reverse the hypotensive effects of these compounds. Conversely, if α-2A receptors contribute to cognitive enhancement, MK912 and idazoxan should reverse the cognitive-enhancing effects of α-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 α-2A receptor subtype.

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