Abstract
The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α(1), α(2), and other receptor subtypes. Correlation and slope of unity were found for the α(2A)-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC(50)) and relative efficacy (RE) were determined. Compared with NE (pEC(50), 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC(50), 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC(50), 7.94; RE, 37.9%), exhibited the highest potency (pEC(50)). In contrast, the catecholamines, EPI (pEC(50), 6.95; RE, 120%) and α-methyl-NE (pEC(50), 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α(2A)-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α(2A)-AR agonists that can cross the blood-brain barrier.