) Although demonstrably anticonvulsant when applied systemically in animal seizure models, fluoxetine's neuroanatomical substrates of anticonvulsant action are largely unknown. In the rat focally evoked model of complex partial seizures, the substantia nigra had been the only identified site of fluoxetine's anticonvulsant effect. In preliminary experiments, I found that the fluoxetine was also anticonvulsant in the anterior piriform cortex. One goal of the proposed studies is to test the anticonvulsant site specificity of fluoxetine through focal microinjections in structures in the rat limbic seizure circuitry known to be crucial in regulating or propagating limbic motor seizure. Fluoxetine will be microinjected intracerebrally through chronically implanted cannulae in freely moving rats. Behavioral and encephalographic measures of seizure activity will be assessed. Other Selective Serotonin Reuptake Inhibitors will be used in similar sets of experiments to test whether fluoxetine's anticonvulsant effects extend to other members of this class of drugs. Having identified rodent neuroanatomical substrates of fluoxetine's anticonvulsant effect against partial complex seizures, I will then test whether the rodent observations can be extended to a primate model. Using a pig-tailed macaque monkey model of focally evoked complex partial seizures, I will test if fluoxetine's known anticonvulsant substrates in rodents have primate correlates. The results of these studies will indicate the extent to which serotonergic projections may serve to regulate limbic system excitability and seizure susceptibility.
