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RDX binds to the convulsant site of the GABAA receptor and increases spontaneous firing rates of cortical neurons in vitro
Citation:
Williams, L. R., A. Johnstone, D. I. Bannon, AND T. J. Shafer. RDX binds to the convulsant site of the GABAA receptor and increases spontaneous firing rates of cortical neurons in vitro. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
To assess the functional ramifications of RDX interaction with GABAA receptors, RDX effects were then examined in a well characterized model of cortical network electrophysiology, i.e., primary cortical neurons grown on microelectrode arrays (MEAs).
Description:
RDX (hexahydro-1 ,3,5-trinitro-1 ,3,5-triazine, hexogen, Royal Demolition eXplosive) is an explosive widely used by the military and has been found in soil and ground water in and surrounding training ranges, creating potential hazards to the environment and human health. Oral RDX over-exposure results in development of convulsions and epileptiform seizure in quail, mice, rats, monkeys and humans. The mechanism ofRDX-induced seizure is unknown. In this work, RDX was screened for affinity against a battery ofneurotransmitter receptors and found to bind exclusively to the convulsant site on the GABAA receptor. RDX competitively displaced [S3s]TBPS binding from GABAA receptors with an ICsoof22 ~M, compared to an ICso of233 nM for picrotoxin. To assess the functional ramifications ofRDX interaction with GABAA receptors, RDX effects were then examined in a well characterized model ofcortical network electrophysiology, i.e., primary cortical neurons grown on microelectrode arrays (MEAs). After 14-30 days in vitro, these cultures develop stable, spontaneous network activity in the form ofaction potentials (APs) and bursts of APs. Acute exposure to RDX caused a concentration-dependent increase in the rate ofspontaneous AP firing with an ECso of 12 ~M. RDXalsoincreasedtherate and duration ofburstsofAPs, aswellasthe % ofAPs that occurred within a burst. The GABAA receptor antagonist bicuculline caused similar changes in spontaneous activity. These data indicate that inhibition ofGABAA receptors and the resultant disruption of spontaneous neuronal network activity may underlie the seizure-inducing activity ofRDX. (This abstract does not reflect EPA policy).