An initial series of studies will investigate basic physiological actions of norephrine (NE) and serotonin (5-HT) in the somatosensory and visual areas of the rat cerebral cortex. The goal of these studies is to establish a basis for assessing noradrenergic and serotonergic function in two animal models of epilepsy; cortically kindled and genetically epilepsy prone (GEPR) rats. Furthermore, tests used to examine biogenic amine function can be employed to clarify the mode of anticonvulsant drug action at synaptic levels within central neuronal circuits. A combination of microiontophoretic techniques, stimulation of biogenic amine, visual and somatosensory afferent pathways and computer assisted analysis of peri-event histograms will be employed to quantitatively assess the effects of NE, 5-HT and several anti-epileptic agents on cerebrocortical neuronal responsiveness to synaptic inputs and putative transmitter substances. The primary concept to be tested is that NE and 5-HT exert modulatory influences on synaptic efficacy within the cerebral cortex. Specific studies in seizure prone animals will use the same protocols to assay for an alteration in cerebrocortical biogenic amine function which might correlate with increased susceptibility for convulsive episodes. Anticonvulsant drug effects on synaptically mediated and transmitter induced cortical neuronal responses will be compared with NE/5-HT actions to determine if these compounds share in common mechanisms to modify transmission of information through neocortical circuits. Additional studies will use the 14C-2-deoxy-D-glucose (2-DG) technique in conjunction with a computer-based neuroanatomical image analysis system to determine glucose utilization patterns in the brains of normal and seizure susceptible animals before and after presentation of seizure-inducing stimuli and anticonvulsant drug administration.
The aim of these studies will be to correlate regional differences in glucose metabolism, particularly in the monoamine nucleii and their target structures in the CNS, with seizure susceptibility and anti-epileptic drug efficacy. The proposed research will contribute to a basic understanding of noradrenergic and serotonergic function in the cerebral cortex and clarify the role of these biogenic amines in seizure disorders and mechanisms of anticonvulsant drug action.
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