Progesterone Reduces Pentylenetetrazol-Induced Ictal Activity of Wild-Type Mice But Not Those Deficient in Type I 5-Reductase *†‡§Cheryl A. Frye, *Madeline E. Rhodes, *Alicia Walf, and §Jacob Harney Departments of *Psychology, †Biological Sciences, and ‡The Center for Neurobiology, The University at Albany–SUNY, Albany, New York; and §The Department of Biology, University of Hartford, West Hartford, Connecticut, U.S.A. Summary: Purpose: To investigate the importance of proges- terone (P 4 ) metabolism by the 5-reductase type I enzyme in mitigating P 4 antiseizure effects. Methods: Ovariectomized, female homozygous and hetero- zygous 5-reductase type I knockout mice (n  23) and their wild-type siblings (n  31) were administered P 4 (1.0 mg), and their pentylenetetrazol (PTZ)-induced ictal behaviors were compared with those of vehicle-administered mice (n  49). Results: Mice deficient in the 5-reductase type I enzyme administered P 4 , or vehicle-administered control mice, had sig- nificantly shorter latencies and increased incidence of PTZ- induced hindlimb extension and death than did wild-type mice administered P 4 . Conclusions: These data suggest that P 4 ’s metabolism by the 5-reductase type I enzyme may mitigate some of P 4 ’s antis- eizure effects in the PTZ-induced seizure model. Key Words: Neurosteroid—Allopregnanollone—Nongenomic—GABA A receptors—NMDA receptors. Clinical evidence suggests that progesterone (P 4 ) has antiseizure effects. Seizure incidence is often increased during the perimenstrum (i.e., as is the case with cata- menial epilepsy), when P 4 levels are relatively low; typi- cally less seizure activity occurs midcycle, when P 4 concentrations are higher. Progesterone therapy is suc- cessfully used to manage seizure disorders among some women with epilepsy (1). There is evidence to suggest that a metabolite of P 4 may mediate some of P 4 ’s antiseizure effects. Both P 4 and its 5-reduced metabolite, 3-hydroxy-5-pregnan- 20-one (3,5-THP) have anticonvulsant effects. In ro- dents, when P 4 or 3  ,5  -THP is administered systemically, kainic acid-, pentamethylenetetrazol (metrazol)-, or perforant pathway stimulation–induced seizures are attenuated (2,3). There is a stronger negative correlation between circulating or central 3,5-THP concentrations and seizure threshold than for P 4 and sei- zures. For example, central 3,5-THP concentrations correlate better with seizures than do P 4 concentrations in naturally cycling or hormone-administered rats (4,5). Progesterone or 3,5-THP administration to rats pro- duces similar thresholds for chemical or electro- convulsant-induced seizures, yet P 4 administration in- creases central concentrations of P 4 and 3,5-THP, but in 3,5-THP-administered rats, only 3,5-THP and not P 4 concentrations are increased (2). Decreased sei- zure susceptibility in women with catamenial epilepsy is better correlated with increases in 3,5-THP rather than increases in P 4 itself (6). The latency for P 4 anticonvul- sant effects is longer for P 4 than for 3,5-THP. More than 50 years ago, Selye (3) reported that P 4 protected rodents from pentylenetetrazol (PTZ)-induced seizures (3). Progesterone’s anticonvulsant effects had a longer latency than did the anticonvulsant effects of 3,5- THP, which implies that the P 4 antiseizure activity may require sufficient time to allow its metabolism to 3,5- THP. The importance of P 4 metabolism in ictal behavior was examined in 5-reductase knockout mice. Two isoforms of the 5-reductase enzyme have been cloned and their distribution characterized (7,8). The type I isoform is constitutively expressed in the rodent central nervous system (CNS) at all stages of brain development. The type II isoform is transiently expressed in late fetal/early postnatal life (7). 5-Reductase knockout mice are a valuable research tool in which the expression of the type I5-reductase gene is perturbed, which results in defi- ciencies in its protein product, the 5-reductase enzyme Address correspondence and reprint requests to Dr. C.A. Frye at Department of Psychology, The University at Albany–SUNY, 1400 Washington Avenue, Albany, NY 12222, U.S.A. E-mail: cafrye@ cnsunix.albany.edu Epilepsia, 43(Suppl. 5):14–17, 2002 Blackwell Publishing, Inc. © International League Against Epilepsy 14