Androgen-Mediated Effects On Ictal Behavior Among Male Rats Is Mediated Through Pregnane Xenobiotic Receptors, Which Mediated Neurosteroidognesis (P1.265)

BACKGROUND: Androgens have well-known important physiological functions throughout the lifespan. Testosterone is decreased with advanced aging in male rodents (13-24 months of age). Furthermore, blocking synthesis of testosterone to 3alpha-diol (via pharmacological techniques or in 5alpha-reductase knockout mice) produces similar as increase in seizure activity following chemoconvulsant administration to male rodents, as is observed with aging. The pregnane xenobiotic receptor (PXR) plays an important role in biosynthesis of neurosteroids. OBJECTIVE: Little is known how PXR mediates andogen synthesis in male brains and effects on seizures. DESIGN/METHODS: In-house Sprague Dawley rats (SD-WT), SAGE Sprague Dawley rats, and PXR knockout rats (PXR KO) were injected with vehicle or testosterone prior to pentylenetetrazol. RESULTS: Administration of T and PXR KO increased latencies to intial myoclonic twitch compared to vehicle and SDWT. The incidence of myoclonic twitch increased with T admin. Among SDWT rats incidence of Forelimb clonus and barrel rolls were greater with T. With T administration latency to initial Tonic Clonic seizures, barrels rolls, and death were increased with admin of T. Among PXR KO rats there was a longer latency to Forelimb clonus and Hindlimb clonus with admin of T. CONCLUSION: These findings suggest that PXR regulation of androgenic neurosteroids influences ictal activity. Studies Supported by: INBREDisclosure: Dr. Koonce has nothing to disclose. Dr. Moore has nothing to disclose. Dr. Mitra has nothing to disclose. Dr. Frye has nothing to disclose.Monday, April 28 2014, 3:00 pm-6:30 pm