title: 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 (0.15mg/kg, ip) and then were rescued from lethality by administration of diazepam (5mg/kg, ip) approximately 20min 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 72s. Locomotor activity, anxiety-like and depression-relevant behaviors and cognition were assessed at 1week, 1month and 2months 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 2months 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 toward developing an animal model that better recapitulates the SE and seizure duration reported in humans acutely intoxicated with TETS.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA. Electronic address: bflannery@ucdavis.edu.
authors.forename: Brenna M
authors.initials: BM
authors.lastname: Flannery
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA. Electronic address: jsilverman@ucdavis.edu.
authors.forename: Jill L
authors.initials: JL
authors.lastname: Silverman
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA. Electronic address: dabruun@ucdavis.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bruun
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA. Electronic address: krpuhger@ucdavis.edu.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Puhger
authors.affiliation: Department of Entomology, College of Agricultural and Environmental Sciences, University of California Davis, Davis, CA, USA. Electronic address: mmccoy2@csustan.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: McCoy
authors.affiliation: Department of Entomology, College of Agricultural and Environmental Sciences, University of California Davis, Davis, CA, USA; UCDMC Comprehensive Cancer Center, School of Medicine, University of California Davis, Sacramento, CA, USA. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA. Electronic address: jacqueline.crawley@ucdmc.ucdavis.edu.
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Crawley
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA; MIND Institute, School of Medicine, University of California Davis, Sacramento, CA, USA. Electronic address: pjlein@ucdavis.edu.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced; D003292:Convulsants / Q000633:toxicity*; D003975:Diazepam / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D018757:GABA Modulators / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D021641:Recognition, Psychology / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D013997:Time Factors
chemical_list: D001952:Bridged-Ring Compounds; D003292:Convulsants; D018757:GABA Modulators; C010349:tetramethylenedisulfotetramine; D003975:Diazepam
keywords: Behavioral testing; Mice; Seizures; TETS; Tetramethylenedisulfotetramine