title: RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures.
abstract: BACKGROUND
  Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown.
  
  
  OBJECTIVE
  We investigated the mechanism by which RDX induces seizures.
  
  
  RESULTS
  By screening the affinity of RDX for a number of neurotransmitter receptors, we found that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric acid type A (GABA(A)) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents. In extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges.
  
  
  CONCLUSIONS
  These results suggest that binding to the GABA(A) receptor convulsant site is the primary mechanism of seizure induction by RDX and that reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism of RDX action with respect to seizure induction can guide therapeutic strategies, allow more accurate development of safe thresholds for exposures, and help prevent the development of new explosives or other munitions that could pose similar health risks.
authors.affiliation: U.S. Army Public Health Command, Aberdeen Proving Ground, Maryland, USA.
authors.forename: Larry R
authors.initials: LR
authors.lastname: Williams
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aroniadou-Anderjaska
authors.forename: Felicia
authors.initials: F
authors.lastname: Qashu
authors.forename: Huckelberry
authors.initials: H
authors.lastname: Finne
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Pidoplichko
authors.forename: Desmond I
authors.initials: DI
authors.lastname: Bannon
authors.forename: Maria F M
authors.initials: MF
authors.lastname: Braga
mesh_terms: D000679:Amygdala / Q000187:drug effects*; D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D053834:Explosive Agents / Q000633:toxicity*; D058787:GABA-A Receptor Antagonists / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects; D014227:Triazines / Q000633:toxicity*
chemical_list: D003292:Convulsants; D004785:Environmental Pollutants; D053834:Explosive Agents; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D014227:Triazines; C009160:cyclonite