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The Journal of Neuroscience, March 15, 1998, 18(6):2004-2008

A Point Mutation (D79N) of the 2A Adrenergic Receptor Abolishes the Antiepileptogenic Action of Endogenous Norepinephrine

Sridevi Janumpalli¹, Linda S. Butler¹, Leigh B. MacMillan², Lee E. Limbird², and James O. McNamara¹

¹ Epilepsy Research Laboratory, Departments of Medicine (Neurology), Neurobiology, and Pharmacology, Duke University Medical Center, Durham, North Carolina 27710-3676, and ² Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Norepinephrine serves as a neurotransmitter for a population of neurons the cell bodies of which reside in a brainstem nucleus and the axons of which project widely to discrete subsets of forebrain neurons. Norepinephrine powerfully inhibits epileptogenesis in the kindling model. Pharmacological methods have demonstrated that the antiepileptogenic actions of norepinephrine are exerted via 2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three 2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual 2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the 2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the 2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the 2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the 2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.

Key words: 2A adrenergic receptor; norepinephrine; epileptogenesis; mutant mouse; adrenergic receptor; kindling

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1862004-05$05.00/0

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