Abstracts

RATIONALE: Catamenial epilepsy affects up to 72% of women with epilepsy. Perimenstrual catamenial epilepsy may in part be due to withdrawal of the endogenous progesterone-derived neurosteroid allopregnanolone that potentiates GABA-A receptor-mediated inhibition. Currently there are few effective treatment approaches for catamenial epilepsy. Here we sought to determine whether the anticonvulsant potencies of neuroactive steroids, benzodiazepines, and valproate are altered during the heightened seizure susceptibility accompanying neurosteroid withdrawal in a rat model of perimenstrual catamenial epilepsy. METHODS: Young adult female rats were treated with gonadotropins to induce a state of pseudopregnancy characterized by chronic elevations in progesterone and neurosteroids. Neurosteroid withdrawal was induced by treatment with 5(-reductase inhibitor finasteride. Test drugs were evaluated for their ability to alter the convulsant activity of pentylenetetrazol in young adult female rats, in pseudopregnant rats chronically exposed to high levels of progesterone (and its neurosteroid metabolites), and in pseudopregnant rats 24 h following acute withdrawal of neurosteroids by treatment with finasteride. RESULTS: Finasteride induced withdrawal of neurosteroids was associated with a marked reduction in seizure threshold. The anticonvulsant activity of allopregnanolone, pregnanolone, allotetrahydrodeoxycorticosterone and tetrahydrodeoxycorticosterone were enhanced by 34 to 127% following neurosteroid withdrawal. The anticonvulsant activity of phenobarbital was also enhanced by 24% in neurosteroid withdrawn animals. In contrast, the anticonvulsant activity of diazepam, bretazenil and sodium valproate were reduced or unchanged in neurosteroid withdrawn animals. CONCLUSIONS: The anticonvulsant activity of neuroactive steroids is potentiated following neurosteroid withdrawal, supporting the use of such agents in the treatment of perimenstrual catamenial epilepsy.