Characterizing the behavioral effects of nerve agent-induced seizure activity in rats: Increased startle reactivity and perseverative behavior

US Army Medical Research Institute of Chemical Defense, Analytical Toxicology Division, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, MD 21010-5400, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 01/2012; 100(3):382-91. DOI: 10.1016/j.pbb.2011.09.011
Source: PubMed


The development and deployment of next-generation therapeutics to protect military and civilian personnel against chemical warfare nerve agent threats require the establishment and validation of animal models. The purpose of the present investigation was to characterize the behavioral consequences of soman (GD)-induced seizure activity using a series of behavioral assessments. Male Sprague-Dawley rats (n=24), implanted with a transmitter for telemetric recording of encephalographic signals, were administered either saline or 1.0 LD₅₀ GD (110 μg/kg, sc) followed by treatment with a combination of atropine sulfate (2 mg/kg, im) and the oxime HI-6 (93.6 mg/kg, im) at 1 min post-exposure. Seizure activity was allowed to continue for 30 min before administration of the anticonvulsant diazepam (10 mg/kg, sc). The animals that received GD and experienced seizure activity had elevated startle responses to both 100- and 120-dB startle stimuli compared to control animals. The GD-exposed animals that had seizure activity also exhibited diminished prepulse inhibition in response to 120-dB startle stimuli, indicating altered sensorimotor gating. The animals were subsequently evaluated for the acquisition of lever pressing using an autoshaping procedure. Animals that experienced seizure activity engaged in more goal-directed (i.e., head entries into the food trough) behavior than did control animals. There were, however, no differences between groups in the number of lever presses made during 15 sessions of autoshaping. Finally, the animals were evaluated for the development of fixed-ratio (FR) schedule performance. Animals that experienced GD-induced seizure activity engaged in perseverative food trough-directed behaviors. There were few differences between groups on other measures of FR schedule-controlled behavior. It is concluded that the GD-induced seizure activity increased startle reactivity and engendered perseverative responding and that these measures are useful for assessing the long-term effects of GD exposure in rats.

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    • "However, we have also found that in addition to neuronal damage, soman exposure causes pathophysiological alterations in the basolateral amygdala (BLA), which are accompanied by an increase in anxiety-like behavior (Prager et al., 2014). Increased anxiety is the most welldocumented behavioral deficit resulting from nerve agentinduced brain damage in animals (Coubard et al., 2008; Filliat et al., 2007; Hoffman et al., 2007; Langston et al., 2012; Moffett et al., 2011), but also in humans, as we know from the enduring psychiatric symptoms presented by the victims of the sarin attack in Japan (Hoffman et al., 2007; Ohtani et al., 2004). Therefore, in the present study, we examined whether the efficacy of LY293558 against seizures and neuropathology translates into protection against the pathophysiological changes seen in the BLA and the development of anxiety-like behavior. "
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    ABSTRACT: Exposure to nerve agents can cause brain damage due to prolonged seizure activity, producing long-term behavioral deficits. We have previously shown that LY293558, a GluK1/AMPA receptor antagonist, is a very effective anticonvulsant and neuroprotectant against nerve agent exposure. In the present study, we examined whether the protection against nerve agent-induced seizures and neuropathology conferred by LY293558 translates into protection against pathophysiological alterations in the basolateral amygdala (BLA) and the development of anxiety, which is the most prevalent behavioral deficit resulting from exposure. LY293558 (15 mg/1<g) was administered to rats, along with atropine and HI-6, at 20 min after exposure to soman (1.2 x LD50). At 24 h, 7 days, and 30 days after exposure, soman-exposed rats who did not receive LY293558 had reduced but prolonged evoked field potentials in the BLA, as well as increased paired-pulse ratio, suggesting neuronal damage and impaired synaptic inhibition; rats who received LY293558 did not differ from controls in these parameters. Long-term potentiation of synaptic transmission was impaired at 7 days after exposure in the soman-exposed rats who did not receive anticonvulsant treatment, but not in the LY293558-treated rats. Anxiety-like behavior assessed by the open field and acoustic startle response tests was increased in the soman-exposed rats at 30 and 90 days after exposure, while rats treated with LY293558 did not differ from controls. Along with our previous findings, the present data demonstrate the remarkable efficacy of LY293558 in counteracting nerve agent-induced seizures, neuropathology, pathophysiological alterations in the BLA, and anxiety-related behavioral deficits. Published by Elsevier Ltd.
    Neuropharmacology 09/2014; 89. DOI:10.1016/j.neuropharm.2014.08.014 · 5.11 Impact Factor
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    • "In this study, we used a rat model of nerve agent exposure in which the anticonvulsant treatment was delayed to at least 1 hour, and compared the efficacy of DZP with that of another GluK1R antagonist UBP302 [(S)-3-(2-carboxybenzyl)willardiine], which selectively antagonizes the GluK1Rs (More et al., 2004), against soman-induced seizures, as well as acute and long-term neuropathology . We also examined the efficacy of DZP and UBP302 in preventing the development of anxiety, which is a prevalent behavioral deficit resulting from nerve agent–induced brain damage, in both animals (Coubard et al., 2008; Langston et al., 2012; Prager et al., 2014) and humans (Ohtani et al., 2004; Hoffman et al., 2007). "
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    ABSTRACT: Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the presently FDA-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302‒an antagonist of the kainate receptors that contain the GluK1 subunit‒against seizures, neuropathology, and behavioral deficits induced by soman, in rats. DZP, administered 1 h or 2 h post-exposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 h after soman exposure was similar to (DZP at 1 h) or longer than (DZP at 2 h) that in the soman-exposed rats that did not receive anticonvulsant. Compared to DZP, UBP302 stopped SE with a slower time-course, but reduced dramatically the total duration of SE within 24 h. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 h after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior, assessed in the open field and by the acoustic startle response, 30 days after soman exposure, was increased in the group that did not receive anticonvulsant treatment and in the DZP-treated group, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage, and suggest that targeting GluK1-containing receptors is a more effective approach.
    Journal of Pharmacology and Experimental Therapeutics 08/2014; 351(2). DOI:10.1124/jpet.114.217299 · 3.97 Impact Factor
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    • "Victims of the Tokyo and Matsumoto sarin attacks, for example, reported symptoms associated with anxiety disorders over a decade after the attacks (Hoffman et al., 2007; Ohtani et al., 2004). Similarly, animals display enduring anxiety and fear-like behaviors after exposure to soman (Coubard et al., 2008; Filliat et al., 2007; Langston et al., 2012; Moffett et al., 2011; Prager et al., 2014). The mechanisms underlying the development of anxiety after nerve agent exposure are unknown. "
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    ABSTRACT: The recent sarin attack in Syria killed 1,429 people, including 426 children, and left countless more to deal with the health consequences of the exposure. Prior to the Syrian chemical assault, nerve agent attacks in Japan left many victims suffering from neuropsychiatric illnesses, particularly anxiety disorders, more than a decade later. Uncovering the neuro-pathophysiological mechanisms underlying the development of anxiety after nerve agent exposure is necessary for successful treatment. Anxiety is associated with hyperexcitability of the basolateral amygdala (BLA). The present study sought to determine the nature of the nerve agent-induced alterations in the BLA, which could explain the development of anxiety. Rats were exposed to soman, at a dose that induced prolonged status epilepticus. Twenty-four hours and 14-days after exposure, neurons from the BLA were recorded using whole-cell patch-clamp techniques. At both the 24h and 14-day post-exposure time-points, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the BLA were reduced, along with reduction in the frequency but not amplitude of miniature IPSCs. In addition, activation of α7-nicotinic acetylcholine receptors, a cholinergic receptor that participates in the regulation of BLA excitability and is involved in anxiety, increased spontaneous excitatory postsynaptic currents (sEPSCs) in both soman-exposed rats and controls, but was less effective in increasing sIPSCs in soman-exposed rats. Despite the loss of both interneurons and principal cells after soman-induced status epilepticus, the frequency of sEPSCs was increased in the soman-exposed rats. Impaired function and cholinergic modulation of GABAergic inhibition in the BLA may underlie anxiety disorders that develop after nerve agent exposure.
    NeuroToxicology 08/2014; 44. DOI:10.1016/j.neuro.2014.08.007 · 3.38 Impact Factor
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