A Point Mutation (D79N) of the alpha 2A 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 methods have demonstrated that the antiepileptogenic actions of norepinephrine are exerted via alpha 2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three alpha 2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual alpha 2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the alpha 2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the alpha 2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the alpha 2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the alpha 2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.