Pharmacological Characterization Of The Alpha(2) Adrenergic Receptor Inhibiting Mouse Hippocampal Ca3 Epileptiform Activity

α 2 adrenergic receptor (AR) activation by epinephrine (EPI) inhibits epileptiform bursts in the mouse hippocampus. Which α 2 AR subtype(s) are involved is unclear. Pharmacological characteristics of α 2 ARs that inhibit epileptiform activity were investigated in mouse brain slices by examining AR agonists' efficacy and potency, and determining the equilibrium dissociation constants (pK b values) of selective α 2 AR antagonists. Dexmedetomidine, an imidazoline and guanfacine, a guanidine were the most potent. In contrast, the catecholamines EPI and norepinephrine were the most efficacious. Apparent pK b values calculated for selective α 2 AR antagonists correlated best with the mouse α 2A AR. EPI‐inhibited antiepileptic effects (pK b ) were competitively antagonized by atipamezole (8.79), rauwolscine (7.75), WB‐4101 (6.87), prazosin (5.71) and JP‐1302 (5.92). Transgenic α 2A AR and α 2C AR knockout mice further confirmed that the EPI‐mediated anti‐epileptic effect was through the α 2A AR subtype. The α 2A AR‐mediated inhibitory actions of EPI on hippocampal CA3 epileptiform burst frequencies were also not sex or age‐dependent. These findings suggest that the activation of α 2A AR could provide a new pharmacotherapeutic strategy for treating epilepsy and highlight the need for selective α 2A AR agonists. This project was supported by ND EPSCoR, NSF CAREER, NSF REU Site, UND REFUNDU, APS, ASPET and NIH INBRE.