Alpha2A adrenergic receptor-mediated inhibition of mouse hippocampal CA3 network activity

Alpha2 adrenergic receptor (AR) activation by epinephrine (EPI) inhibits network (epilepiform burst) activity in the rat hippocampal CA3 region. The specific pharmacology underlying this action is unclear. This study investigated which subtype(s) of alpha2 ARs are involved in this response using recordings of spontaneous CA3 epileptiform bursts in hippocampal brain slices from mice. First, equilibrium dissociation constants (pKb values) of selective alpha AR antagonists were functionally determined to identify the specific alpha2 AR subtype inhibiting hippocampal CA3 epileptiform activity. Apparent pKb values calculated for atipamezole, oxymetazoline, rauwolscine, WB-4101 and JP-1302 correlated best with the binding affinities previously determined for the mouse alpha2A, but not the alpha2B or alpha2C AR subtypes. Next, using transgenic knockout (KO) mice we confirmed that this effect was mediated by the alpha2A AR subtype as the inhibitory action of EPI on epileptiform burst frequency was abolished in slices from the alpha2A but not the alpha2C AR KO mice. These results indicate the EPI-mediated inhibition of mouse hippocampal CA3 epileptiform activity is through alpha2A ARs. This suggests a role for alpha2A AR agonists as novel antiepileptic drug therapies. Supported by the American Physiological Society, ND EPSCoR EPS-0447679, NSF 0347259, NSF 0639227, NIH 5RO1DA17963 and NIH P20RR0167141.