Characterizing the behavioral effects of nerve agent-induced seizure activity in rats: Increased startle reactivity and perseverative behavior
ABSTRACT 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.
- SourceAvailable from: Eric Michael Prager
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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. "
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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- "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. "
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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- "One group of animals was sacrificed at the onset of Stage 3 seizures, and therefore did not receive atropine sulfate. Stage 3 behavioral seizures have previously been found to coincide with the initiation of electrographically monitored SE (Figueiredo et al., 2011a; Langston et al., 2012; Rossetti et al., 2012). The control groups received saline instead of soman and were injected with atropine. "
ABSTRACT: Organophosphorus nerve agents are powerful neurotoxins that irreversibly inhibit acetylcholinesterase (AChE) activity. One of the consequences of AChE inhibition is the generation of seizures and status epilepticus (SE), which cause brain damage, resulting in long-term neurological and behavioral deficits. Increased anxiety is the most common behavioral abnormality after nerve agent exposure. This is not surprising considering that the amygdala, and the basolateral nucleus of the amygdala (BLA) in particular, plays a central role in anxiety, and this structure suffers severe damage by nerve agent-induced seizures. In the present study, we exposed male rats to lethal doses of the nerve agent soman, and determined the time course of recovery of AChE activity, along with the progression of neuropathological and pathophysiological alterations in the BLA, during a 30-day period after exposure. Measurements were taken at 24 hours, 7 days, 14 days, and 30 days after exposure, and at 14 and 30 days, anxiety-like behavior was also evaluated. We found that more than 90% of AChE is inhibited at the onset of SE, and AChE inhibition remains at this level 24 hours later, in the BLA, as well as in the hippocampus, piriform cortex, and prelimbic cortex, which we analyzed for comparison. AChE activity recovered by day 7 in the BLA and day 14 in the other three regions. Significant neuronal loss and neurodegeneration were present in the BLA at 24 hours and throughout the 30-day period. There was no significant loss of GABAergic interneurons in the BLA at 24 hours post-exposure. However, by day 7, the number of GABAergic interneurons in the BLA was reduced, and at 14 and 30 days after soman, the ratio of GABAergic interneurons to the total number of neurons was lower compared to controls. Anxiety-like behavior in the open-field and the acoustic startle response tests was increased at 14 and 30 days post-exposure. Accompanying pathophysiological alterations in the BLA ‒ studied in in vitro brain slices ‒ included a reduction in the amplitude of field potentials evoked by stimulation of the external capsule, along with prolongation of their time course and an increase in the paired-pulse ratio. Long-term potentiation was impaired at 24 hours, 7 days, and 14 days post-exposure. The loss of GABAergic interneurons in the BLA and the decreased interneuron to total number of neurons ratio may be the primary cause of the development of anxiety after nerve agent exposure.Neuropharmacology 01/2014; 81. DOI:10.1016/j.neuropharm.2014.01.035 · 5.11 Impact Factor