Behavioral assessment of NIH Swiss mice acutely intoxicated with tetramethylenedisulfotetramine

Abstract

Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison that is thought to trigger seizures by inhibiting the function of the type A gamma-aminobutyric acid receptor (GABAAR). Acute intoxication with TETS can cause vomiting, convulsions, status epilepticus (SE) and even death. Clinical case reports indicate that individuals who survive poisoning may exhibit long-term neuropsychological issues and cognitive deficits. Therefore, the objective of this research was to determine whether a recently described mouse model of acute TETS intoxication exhibits persistent behavioral deficits. Young adult male NIH Swiss mice received a seizure-inducing dose of TETS (0.15 mg/kg, ip) and then were rescued from lethality by administration of diazepam (5 mg/kg, ip) approximately 20 min post-TETS-exposure. TETS-intoxicated mice typically exhibited 2 clonic seizures prior to administration of diazepam with no subsequent seizures post-diazepam injection as assessed using behavioral criteria. Seizures lasted an average of 72 seconds. Locomotor activity, anxiety-like and depression-relevant behaviors and cognition were assessed at 1 week, 1 month and 2 months post-TETS exposure using open field, elevated-plus maze, light↔dark transitions, tail suspension, forced swim and novel object recognition tasks. Interestingly, preliminary validation tests indicated that NIH Swiss mice do not respond to the shock in fear conditioning tasks. Subsequent evaluation of hot plate and tail flick nociception tasks revealed that this strain exhibits significantly decreased pain sensitivity relative to age- and sex-matched C57BL/6J mice, which displayed normal contextual fear conditioning. NIH Swiss mice acutely intoxicated with TETS exhibited no significant anxiety-related, depression-relevant, learning or memory deficits relative to vehicle controls at any of the time points assessed with the exception of significantly increased locomotor activity at 2 months post-TETS intoxication. The general absence of long-term behavioral deficits in TETS-intoxicated mice on these six assays suggests that the neurobehavioral consequences of TETS exposure described in human survivors of acute TETS intoxication are likely due to sustained seizure activity, rather than a direct effect of the chemical itself. Future research efforts are directed towards developing an animal model that better recapitulates the SE and seizure duration reported in humans acutely intoxicated with TETS.

Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

“…Subject mice were placed in the center area of a black Plexiglas automated elevated plus-maze (Med-Associates, St. Albans City, VT), under 300 lux white light illumination, for a 5 minute test session as previously described (Flannery et al 2015; Silverman et al. 2015).…”

Behavioral intoxication following voluntary oral ingestion of tetramethylenedisulfotetramine: Dose-dependent onset, severity, survival, and recovery

“…Lethargy typically presented as immobility and a lack of the explorative behaviors typically shown by the animals. Our description, described as lethargy, has also been referred to as quiescence [16, 26] and somnolence [25] by others. The ataxia observed was often characterized by poor motor control of the limbs while walking and sometimes animals dragged themselves along the floor instead of walking.…”

“…Previous studies examining TETS intoxication and potential treatments [3, 13–16, 25, 26] have relied upon TETS dosing methods that do not mimic the many historical real-world exposures. By far the most common route of poisoning from TETS in humans is via voluntary consumption of TETS-adulterated foods or liquids [1, 7, 22].…”

Influence of tetramethylenedisulfotetramine on synchronous calcium oscillations at distinct developmental stages of hippocampal neuronal cultures

“…Recent evidence with [ 14 C]TETS indicates that the binding sites for TETS and PTX are distinct, and may preferentially interact with distinct GABA A receptor subunits (Zhao et al, 2014). When administrated orally, TETS was 40-times more potent than picrotoxin although the estimated blood/brain concentration ratio was comparable for TETS (0.2) and picrotoxin (0.35) (Zolkowska et al, 2012, Flannery et al, 2015, Shakarjian et al, 2015). Thus the molecular mechanisms responsible for the acute seizurogenic potency of TETS remain unclear, and its neuropathological sequelae appear to have a neuroinflammatory component (Zolkowska et al, 2012).…”

“…However, several accidental and intentional poisonings have been reported since the ban, predominantly in China (Cao et al, 2012a), but also in the United States (Barrueto et al, 2003). Administration of TETS to animals produces convulsive activity, which resembles those produced by other GABA A receptor blockers such as picrotoxin (PTX) (Zolkowska et al, 2012, Flannery et al, 2015, Shakarjian et al, 2015). The specificity of TETS in blocking GABA A receptors is supported by binding experiments.…”