Jenna S Franowicz1, Amy F T Arnsten. 1. Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8001, USA.
Abstract
RATIONALE: 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. OBJECTIVES: 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.
RATIONALE: 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. OBJECTIVES: 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.
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