Role of norepinephrine in forebrain and brainstem seizures: chemical lesioning of locus ceruleus with DSP4.

The role of norepinephrine in regulating brainstem seizures has been well documented. These seizures are characterized by running/bouncing clonus and tonic extensor convulsions. Evidence for noradrenergic regulation of brainstem seizures comes partially from studies with genetic models of epilepsy which are characterized by innate noradrenergic deficits and from selective lesioning of noradrenergic neurons and/or pathways. The present study was conducted to evaluate whether destruction of the noradrenergic system using DSP4 (N-(2-chloroethyl)-N-2-bromobenzylamine) influences forebrain seizure severity. Accordingly, 90 female Sprague-Dawley rats (49-55 days old) received DSP4 (50 mg/kg ip) after a pretreatment of desipramine (a norepinephrine reuptake inhibitor), fluoxetine (a serotonin reuptake inhibitor), or saline. A control group of 30 animals received two administrations of saline. Three weeks later, these animals were tested for facial and forelimb clonus (FFC) threshold (convulsive current50; CC50) via corneal electroshock stimulation. The FFC CC50 thresholds in the animals treated with saline plus DSP4 were significantly reduced compared to control (vehicle-vehicle) values. Also, desipramine pretreatment, which partially protected the noradrenergic system from the neurotoxicity of DSP4, completely obviated the reduction in FFC thresholds. A subsequent evaluation of brainstem seizure response using maximal electroshock through earclip electrodes confirmed the noradrenergic influence on brainstem seizure regulation. These observations provide additional support for a noradrenergic role in forebrain as well as brainstem seizure regulation.