The noradrenergic (NE) system of the brain is thought to have an important role in the development of epileptic seizures. Decreasing brain NE activity facilitates the development of seizures whereas augmentation of NE activity retards seizure development. This is mot obvious in the early stages of kindled seizures. Kindling is a phenomenon in which the repetition of a subconvulsive electrical stimulus to the amygdala eventually produces a generalized motor seizure. The development of kindled seizures is sensitive to brain NE levels and the nucleus locus coeruleus (LC) contains the majority of central NE neurons. The hypothesis to be tested is that epileptic discharges from the kindled amygdala produce an increase in the LC activity which then produces an inhibitory feedback effect on the spread of the seizures into the motor system. Contributing to this increase in LC activity is a decrease in the sensitivity of the alpha-2, autoinhibitory receptors on the LC neurons. The feedback inhibition eventually dissipates as the beta receptors decrease in response to the augmented release of NE. The eventual decrease in the feedback inhibitory effect facilitates the spread of the seizure. The following experiments will be done to test this hypothesized sequence of events during kindling: 1) The LC will be stimulated electrically 30 min. prior to each kindling episode to determine if enhanced LC activity retards the kindling process; 2) Extracellular recordings of LC neuron activity will be measured and correlated to amygdala afterdischarges (AD) during kindling of unanesthetized animals (multiple unit) and during amygdala AD's in anesthetized animals (single unit); 3) The measurement of changes in the activity of single LC neurons to alpha-2 receptor stimulation will be made before and after kindled after discharges to assess possible receptor sensitivity changes; 4 & 5) The density of the beta and alpha-2 receptors from limbic and motor areas in the LC will be measured using specific ligands and quantitative autoradiography in order to determine if the number of beta and/or the alpha-2 receptors are altered during kindling.
