Noradrenergic modulation of epileptiform activity in the hippocampus

Norepinephrine has been proposed to have both pro- and anticonvulsant properties. In the CA3 region of rat hippocampal slices, we studied the effects of norepinephrine and selective adrenergic agonists and antagonists on spontaneously occurring epileptiform discharges produced by either picrotoxin, a convulsant that impairs GABAA-mediated inhibition, or by elevated extracellular potassium ([K+]o). Bath application of 5 microM norepinephrine (NE) increased the rate of discharges produced by 7.5 mM [K+]o but not the rate of picrotoxin-induced discharges. At higher concentrations (> or = 10 microM), NE slowed the rate of spontaneous epileptiform discharges produced by picrotoxin. Spontaneous discharges produced by either picrotoxin or 7.5 mM [K+]o were slowed or stopped by alpha-adrenergic receptor activation, the alpha 1 receptor being most responsible for this slowing effect. The alpha 2 agonist clonidine had minimal effects on the discharge rate; however, the alpha 2 antagonists yohimbine and idazoxan slowed the rate. In contrast, beta receptor or adenylate cyclase activation increased the rate of spontaneous discharges. This acceleration in rate was accompanied by a decrease in the amplitude and duration of the afterhyperpolarization (AHP) that follows the intracellularly recorded paroxysmal depolarizing shift (PDS). These results confirm that beta-adrenergic receptor activation increases the rate of epileptiform discharges and suggest that the acceleration is a result of a decrease in the AHP duration and amplitude. Activation of alpha-adrenergic receptors slowed the rate of epileptiform discharges without an associated change in the AHP. The AHP that follows the PDS helps define the maximal rate of epileptiform discharges in the hippocampal slice and a decrease in the duration of the AHP may contribute to the transition from an interictal to ictal pattern of epileptiform activity.