The major goal of this research is to explore whether a net dysfunction of the central noradrenergic system forms part of the pathological alterations that occur during the development of kindling. A research plan will be developed to study changes in LC function and NE neuromodulatory actions in the somatosensory cortex during the establishment of the kindle state. An initial series of investigations will explore changes in the physiological activity of LC neurons at different stages of kindling development in anesthetized animals. Experiments will examine possible alterations in terms of spontaneous LC firing rate and pattern of activity, and in changes in alpha-2 receptor sensitivity to agonist and antagonist compounds. In addition, studies will also investigate alterations in the behavior of LC responses to sensory evoked discharges and iontophoretically-induced excitation by the release of putative neurotransmitters that are known to mediate LC reaction to sensory stimulation. The primary concept to be tested by this set of experiments is that kindling development triggers a concomitant dysfunction in the physiological activity of LC cells which might form part of one of the mechanisms of seizure propagation and establishment. A second series of studies will examine changes in NE neuromodulatory actions in the somatosensory cortex, a target structure of LC noradrenergic innervation. Experiments using microiontophoretic application of putative neurotransmitters; Glutamate, GABA, and Acetylcholine, together with peripheral and central nervous system stimulation procedures will be employed to quantitatively assess NE modulatory actions on synaptic efficacy within brain circuits at different stages of kindling development. Finally, a set of experiments will employ intracellular recording techniques in brain tissue slices to investigate changes in LC membrane properties and possible alterations in second messenger systems that mediate the facilitatory actions of NE on neurotransmitter systems in the cortex. The purpose of these experiments is to identify possible seizure-induced alterations in LC cellular physiology and NE neuromodulatory actions which might contribute to the development and establishment of the kindle state.
Showing the most recent 10 out of 51 publications
