The GABAergic striatonigral and nigrotectal pathways appear to play a major role in the control of seizure activity. It is possible that similar changes in inhibitory GABAergic transmission in these pathways occur with different proconvulsant treatments such as kindling or ethanol withdrawal. However, the pattern of changes that occur in pre- or postsynaptic GABA function may be complex because the inhibitory GABAergic circuits are connected in series from striatum to substantia nigra (SN) to superior colliculus (SC) and possibly beyond. GABAergic transmission in the inferior colliculus (IC) has been shown to decrease in animals susceptible to audiogenic seizures, however it is not clear whether these changes are the basis for the seizure susceptibility or are caused by seizure activity transmitted through the auditory pathways including IC. This proposal will measure changes in GABAergic transmission, including GABA release, GABA, receptor binding and GABA, receptor-mediated Cl- flux, in the terminal regions of the striatonigral and nigotectal pathways and in the inferior colliculus in three proconvulsant models that have opposite initial effects on GABAA receptor function. The first model of increased seizure susceptibility will use rats chemically kindled with the benzodiazepine inverse agonist, FG7142, which suppresses withdrawn rats with increased susceptibility receptor function. The second model will use alcohol-withdrawn rats with increased susceptibility to handling-induced seizures. Ethanol enhances GABAA receptor function. The third model will use rats kindled via repeated electrical stimulation of the amygdala. This procedure does not directly affect GABA systems. It is proposed that after each of these proconvulsant treatments, GABA function will decrease in the striatonigral pathway and increase in the nigrotectal pathway and that these changes are not dependent on the occurance of a seizure. This pattern of changes would greatly increase inhibitory output to the SC, thereby decreasing SC output to reticular formation and spinal cord which and increasing seizure susceptibility. If a similar pattern of changes occurs in GABAergic transmission in the striatonigral and nigrotectal pathways in each of these three models, than a more general role of these GABAergic pathways is indicated. It has been proposed that these pathways may be implicated as a final common pathway for seizure propagation such that increased nigral output determines long-term increases in sensitivity to seizures. For this to be true, the time course of GABAergic changes in each of these models should be correlated with the time course of increased seizure sensitivity but not seizure occurance. It is expected that these studies will have important implications in the characterization and potential treatment of seizures.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Alcohol Biomedical Research Review Committee (ALCB)
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University of Florida
Schools of Pharmacy
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