Adrenergic receptor modulation of hippocampal CA3 network activity

Abstract Norepinephrine (NE) has demonstrated proconvulsant and antiepileptic properties; however, the specific pharmacology of these actions has not been clearly established. To address this, we studied the effect of NE on hippocampal CA3 epileptiform activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations reduced their frequency, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of βAR blockade, increasing concentrations of NE caused a monophasic decrease in epileptiform activity. Antagonists selective for α 1 or α 2 ARs were then used to determine which αAR type was involved. While discriminating concentrations of the α 1 AR antagonists prazosin and terazosin had no effect, selective amounts of the α 2 AR antagonists RS79948 and RX821002 significantly reduced the potency of NE in decreasing epileptiform activity. Furthermore, this antiepileptic action of NE persisted when all GABA-mediated inhibition was blocked. This data suggests that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 epileptiform activity are mediated primarily via β and α 2 ARs, respectively. Moreover, our results imply that the antiepileptic effect of α 2 AR activation in CA3 is not dependent on the GABAergic system.