Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs

Abstract

Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum

“…It should be noted that eCB signaling modulates acetylcholine release in the hippocampus but has relatively little influence on acetylcholine release in the striatum (Gifford et al ., 2000; Kathmann et al ., 2001). Moreover, cholinergic signaling in the striatum may play an important role in motor signs associated with OP toxicity (Slater and Dickinson, 1982, Espinola et al ., 1999; O'Donnell et al ., 2010). We previously reported that extracellular AEA in the hippocampus was increased by both chlorpyrifos and parathion, with significantly greater elevation after chlorpyrifos.…”

The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology

“…Elevation in central extracellular ACh leads to widespread neural activation and seizure generation [2]. Following sustained seizure activity, the cholinergic crisis initiates changes in the levels of excitatory (glutamate) and inhibitory (γ-Aminobutyric acid, GABA) amino acid transmitters [2][3][4][5][6][7][8][9]. Numerous inhibitory compounds with different pharmacologic mechanisms have been investigated to combat this toxic sequelae.…”

Assessment of Potential Long Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances

“…Additionally, the ages of subjects in the studies was too widely varied to allow confident analysis. 143 Although the epidemiological data for an association between dioxins and other persistent organic pollutants is equivocal, findings from in-vitro and animal studies show that TCDD, PCBs, and other chlorinated POPs can influence insulin signaling, 147,148,149,150,151,152 glucose-stimulated insulin secretion, 153,154,155 and adipocyte differentiation or regulation. 156,157,154 Better designed and implemented epidemiological studies and efforts to align the laboratory work with the epidemiology, along with systematic gap identification is needed in order to see if a causal link exists.…”