Seizure Activity Is Increased in Endocrine States Characterized by Decline in Endogenous Levels of the Neurosteroid 3α,5α-THP

Abstract

To examine the role of progesterone (P) and its 5α-reduced metabolite, the neurosteroid 5α-pregnan-3α-ol-20-one (3α,5α-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 3α,5α-THP levels were measured. Cycling Long-Evans rats in estrus and proestrus had seizures of significantly shorter duration and more central and plasma 3α,5α-THP and P than animals in metestrus or diestrus. Females with luteal functioning had seizures of significantly shorter duration and increased central and plasma 3α,5α-THP and P compared to animals that recently had luteal functioning discontinued. Pregnant rats had significantly shorter seizures and greater central and plasma 3α,5α-THP and central P than animals tested 1–2 days postparturition. In all test paradigms, seizure activity was increased in animals that had decreased 3α,5α-THP or P; overall, central 3α,5α-THP was more inversely related to ictal activity than central P or plasma P and 3α,5α-THP. To investigate a causal relationship between 3α,5α-THP and seizures, a 5α-reductase inhibitor, finasteride, or vehicle was administered to pregnant rats. Finasteride administration significantly decreased central and plasma 3α,5α-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 3α,5α-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 3α,5α-THP concentrations; however, of all of the endocrine conditions, cycling rats experienced the most rapid cycles of 3α,5α-THP variation. This suggests that cycles of endogenous variations in 3α,5α-THP may influence seizure threshold.

Pregnancy increases baroreflex-independent GABAergic inhibition of the RVLM in rats

“…These investigators measured cerebrocortical concentrations of 3␣-OH-DHP at several time points during gestation and reported the highest brain concentrations of 3␣-OH-DHP on day 19 (our day 20) and levels not different from control at the next time point measured, day 21 (our day 22), which is immediately prior to delivery. Similar to our laboratory, Frye and colleagues (25,26) define the day following mating as day 1 of pregnancy and reported increased brain concentrations of 3␣-OH-DHP both on day 18 (26) and day 21 (25), the day the present experiments were performed. Therefore, available data indicate that brain levels of 3␣-OH-DHP are elevated on day 21 of pregnancy, as defined by our laboratory.…”

“…Importantly, both plasma and CNS concentrations of 3␣-OH-DHP are elevated during pregnancy (13,25,26,59). Reports differ on how gestational day is defined in rats, which has created confusion in interpretation of the literature regarding neurosteroid levels in pregnancy, and this issue warrants clarification.…”

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

“…Most likely the increase in seizures mid-cycle is triggered by estradiol which can enhance effects at excitatory synapses, while the increase in the late luteal phase may be related to THP withdrawal (2003). A number of groups have established rodent models where progesterone or THP withdrawal increased seizure susceptibility and seizure severity (Frye & Bayon, 1998;Smith et al, 1998a;Rogawski, 2003). That this may be a result of increased α4 expression was suggested by the finding that suppression of α4 expression in hippocampus prevented the increase in seizure susceptibility after steroid withdrawal (Smith et al, 1998a).…”

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

“…Alcohol use may also alter neuroactive steroid levels (VanDoren et al, 2000;Pierucci-Lagha et al, in press). In addition, it is possible that menstrual cycle phase in female premenopausal subjects (and hormone replacement status in postmenopausal subjects) may affect neuroactive steroid levels in human brain, since rodent evidence suggests that central allopregnanolone levels fluctuate across the estrous cycle Corpechot et al, 1997;Frye and Bayon, 1998). Peripheral plasma allopregnanolone levels also demonstrate variability across the menstrual cycle in humans (Genazzani et al, 1998(Genazzani et al, , 2002Paul and Purdy, 1992;Pearson Murphy and Allison, 2000).…”