A point mutation (D79N) of the alpha2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine

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 met...

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Bibliographic Details
Published in:The Journal of neuroscience 1998-03, Vol.18 (6), p.2004-2008
Main Authors: Janumpalli, S, Butler, L S, MacMillan, L B, Limbird, L E, McNamara, J O
Format: Article
Language:English
Subjects:
Adrenergic alpha-Agonists - metabolism
Adrenergic alpha-Antagonists - pharmacology
Animals
Behavior, Animal - physiology
Electrophysiology
Epilepsy - etiology
Epilepsy - physiopathology
Epilepsy - prevention & control
Idazoxan - pharmacology
Kindling, Neurologic - physiology
Mice
Mice, Mutant Strains
Norepinephrine - antagonists & inhibitors
Norepinephrine - physiology
Point Mutation - genetics
Receptors, Adrenergic, alpha - genetics
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Summary: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 alpha2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three alpha2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual alpha2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the alpha2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the alpha2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the alpha2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the alpha2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.
ISSN:0270-6474