Seizure activity is increased in endocrine states characterized by decline in endogenous levels of the neurosteroid 3 alpha,5 alpha-THP.
To examine the role of progesterone (P) and its 5alpha-reduced metabolite, the neurosteroid 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP), in endogenous variations in ictal activity rats were tested for kainic acid-induced seizures in different hormonal milieu. Corresponding plasma and central P and 3alpha,5alpha-THP levels were measured. Cycling Long-Evans rats in estrus and proestrus had seizures of significantly shorter duration and more central and plasma 3alpha,5alpha-THP and P than animals in metestrus or diestrus. Females with luteal functioning had seizures of significantly shorter duration and increased central and plasma 3alpha,5alpha-THP and P compared to animals that recently had luteal functioning discontinued. Pregnant rats had significantly shorter seizures and greater central and plasma 3alpha,5alpha-THP and central P than animals tested 1-2 days postparturition. In all test paradigms, seizure activity was increased in animals that had decreased 3alpha, 5alpha-THP or P; overall, central 3alpha,5alpha-THP was more inversely related to ictal activity than central P or plasma P and 3alpha,5alpha-THP. To investigate a causal relationship between 3alpha,5alpha-THP and seizures, a 5alpha-reductase inhibitor, finasteride, or vehicle was administered to pregnant rats. Finasteride administration significantly decreased central and plasma 3alpha,5alpha-THP, but had no significant effect on plasma or central P of pregnant rats. Finasteride, but not vehicle administration, to pregnant rats significantly increased seizure duration. These findings support the hypothesis that variations in seizure threshold over endogenous hormonal milieu may be related to endogenous 3alpha,5alpha-THP. Of all of the endocrine conditions, seizure durations were greatest in diestrus animals; this group did not experience the lowest or the greatest decrease in 3alpha, 5alpha-THP concentrations; however, of all of the endocrine conditions, cycling rats experienced the most rapid cycles of 3alpha, 5alpha-THP variation. This suggests that cycles of endogenous variations in 3alpha,5alpha-THP may influence seizure threshold.
Frye
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Neuroscience Program, Connecticut College, New London, Conn., USA.
Bayon
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D000818:Animals; D001921:Brain / Q000187:drug effects; D001923:Brain Chemistry; D003338:Corpus Luteum / Q000502:physiology; D004703:Endocrine System / Q000503:physiopathology*; D004971:Estrus / Q000187:drug effects / Q000502:physiology; D005260:Female; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007536:Isomerism; D007608:Kainic Acid / Q000008:administration & dosage / Q000494:pharmacology; D049590:Postpartum Period / Q000187:drug effects; D011247:Pregnancy; D011280:Pregnanolone / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D011374:Progesterone / Q000097:blood / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013997:Time Factors
D011374:Progesterone; D018120:Finasteride; D011280:Pregnanolone; D007608:Kainic Acid