The dentate gyrus of intact urethane-anesthetized rats was employed to evaluate the effects of different convulsive agents on granule cell excitability. One purpose of this study was to determine whether mechanisms of action suggested from in vitro studies of these compounds could be demonstrated over clinically relevant dose ranges in vivo. The data demonstrate that drugs capable of antagonizing gamma aminobutyric acid (GABA)-mediated inhibition produced similar effects on the intact hippocampus. Bicuculline, picrotoxin, pentylenetetrazol and the insecticide lindane increased granule cell excitability to perforant path stimulation. The primary cause of this was an increase in the innate excitability of the granule cells. These compounds also modified field potentials in a manner consistent with a reduction in early GABA-mediated inhibition. They did not affect synaptically mediated facilitation. The magnitudes of the effects were dose dependent, and changes were clearly measurable at exposures that produce clinical effects in nonanesthetized rats. Other convulsants could be readily differentiated from those affecting GABA-mediated inhibition. Kainic acid depressed granule cell responses to perforant path stimulation and severely depressed both inhibition and facilitation. A decrease in granule cell responsiveness was also produced by exposure to beta carboline. Exposure to strychnine had little effect on granule cell excitability. These data indicate that for bicuculline, picrotoxin, pentylenetetrazol and lindane, an apparently selective antagonism of GABA-mediated inhibition is clearly demonstrable at exposures that also produce clinical intoxication. This supports the hypothesis that the antagonism of GABA-mediated inhibition is the major mechanism by which these drugs produce their actions in vivo. The data obtained with kainic acid suggest that this compound acutely reduces the excitability of the perforant path terminals or reduces the effectiveness of the excitatory transmitter, presumably glutamate, on postsynaptic receptors. It also produces a more global depression of both synaptically mediated inhibition and facilitation in the intact hippocampus than the GABA antagonists.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1988|
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