Pharmacological characterization of the alpha 2‐adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency

Abstract

Pharmacological characteristics of the α2 adrenergic receptor (AR) that inhibits epileptiform activity in the hippocampal CA3 region were studied in rat brain slices. The effects of a large number of αAR antagonists on epinephrine (EPI)‐mediated inhibition of epileptiform activity were scrutinized with Schild plot analysis and compared to binding values for the rat and human α1, α2, 5‐HT1A, D2, I1, and I2 receptor subtypes. A perfect correlation and slope was found for the rat α2AAR, but not the other receptors, indicating that α2AARs solely mediate this effect. The actions of different chemical classes of α2AAR agonists at inhibiting epileptiform activity were then determined. While the imidazolines and guanidines exhibited the highest potency, the catecholamines had greater intrinsic activity compared to norepinephrine (NE). Dexmedetomidine, an imidazoline and guanabenz, a guanidine, were the most potent. In contrast, the catecholamines EPI and α‐methyl‐NE were the most efficacious. Furthermore, the α2AAR‐mediated inhibitory actions of EPI on hippocampal CA3 epileptiform burst frequencies were neither sex nor age‐dependent. These findings suggest that the activation of α2AARs could provide a new pharmacotherapeutic strategy for treating epilepsy and highlight the need for selective α2A agonists. Supported by ND EPSCoR, NSF CAREER 0347259, NSF REU Site 0639227, NIH P20 RR016741, APS and ASPET SURF.