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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

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 manu...

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Autores principales: Williams, Larry R., Aroniadou-Anderjaska, Vassiliki, Qashu, Felicia, Finne, Huckelberry, Pidoplichko, Volodymyr, Bannon, Desmond I., Braga, Maria F. M.
Formato: Texto
Lenguaje:English
Publicado: National Institute of Environmental Health Sciences 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059999/
https://www.ncbi.nlm.nih.gov/pubmed/21362589
http://dx.doi.org/10.1289/ehp.1002588
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author Williams, Larry R.
Aroniadou-Anderjaska, Vassiliki
Qashu, Felicia
Finne, Huckelberry
Pidoplichko, Volodymyr
Bannon, Desmond I.
Braga, Maria F. M.
author_facet Williams, Larry R.
Aroniadou-Anderjaska, Vassiliki
Qashu, Felicia
Finne, Huckelberry
Pidoplichko, Volodymyr
Bannon, Desmond I.
Braga, Maria F. M.
author_sort Williams, Larry R.
collection PubMed
description 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. METHODS AND 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.
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spelling pubmed-30599992011-03-21 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 Williams, Larry R. Aroniadou-Anderjaska, Vassiliki Qashu, Felicia Finne, Huckelberry Pidoplichko, Volodymyr Bannon, Desmond I. Braga, Maria F. M. Environ Health Perspect Research 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. METHODS AND 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. National Institute of Environmental Health Sciences 2011-03 2010-11-10 /pmc/articles/PMC3059999/ /pubmed/21362589 http://dx.doi.org/10.1289/ehp.1002588 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.
spellingShingle Research
Williams, Larry R.
Aroniadou-Anderjaska, Vassiliki
Qashu, Felicia
Finne, Huckelberry
Pidoplichko, Volodymyr
Bannon, Desmond I.
Braga, Maria F. M.
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059999/
https://www.ncbi.nlm.nih.gov/pubmed/21362589
http://dx.doi.org/10.1289/ehp.1002588
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