Effect of Acute Soman Exposure on GABAA Receptors in Rat Hippocampal Slices and Cultured Hippocampal Neurons

Wang, Yushan; Liu, Lidong; Weiss, T; Stewart, Christine; Mikler, John

doi:10.1007/s12640-011-9248-9

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…Previous studies have shown that soman administered directly to brain slices (Wang et al, 2011), or epileptiform activity and SE induced by other mechanisms (Goodkin et al, 2008; Goodkin et al, 2005; Naylor et al, 2005) lead to internalization of GABA A receptors in the hippocampus and reduced effectiveness of GABA agonists. However, recovery in the expression of GABA A receptors has also been observed to occur rapidly upon cessation of SE (Naylor, 2010).…”

Section: Discussionmentioning

confidence: 99%

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

et al. 2014

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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 24 h 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.

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Section: Discussionmentioning

confidence: 99%

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

et al. 2014

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“…However, benzodiazepines exhibit a time-dependency for efficacy to stop SE caused in part by the internalization of post-synaptic GABA A Rs (Naylor et al, 2005; McDonough et al, 2009, 2010). Soman exposure is reported to elicit reduced GABA A R function in rat brain (Lallement et al, 1993) and reduced surface expression of GABA A Rs specifically in the hippocampus (Wang et al, 2011). In vitro studies with soman in hippocampal slices suggest that a 30% reduction of surface expression of GABA A Rs renders hippocampal neurons unresponsive to diazepam (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Soman exposure is reported to elicit reduced GABA A R function in rat brain (Lallement et al, 1993) and reduced surface expression of GABA A Rs specifically in the hippocampus (Wang et al, 2011). In vitro studies with soman in hippocampal slices suggest that a 30% reduction of surface expression of GABA A Rs renders hippocampal neurons unresponsive to diazepam (Wang et al, 2011). These remaining GABA A Rs may be extrasynaptic receptors responsible for setting the background tone of global neuronal inhibition (Farrant and Nusser, 2005; Chuang and Reddy, 2018).…”

Section: Introductionmentioning

confidence: 99%

Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning

et al. 2019

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Seizures induced by organophosphorus nerve agent exposure become refractory to treatment with benzodiazepines because these drugs engage synaptic γ-aminobutyric acid-A receptors (GABA A Rs) that rapidly internalize during status epilepticus (SE). Extrasynaptic GABA A Rs, such as those containing α 4 β 3 δ subunits, are a putative pharmacological target to comprehensively manage nerve agent-induced seizures since they do not internalize during SE and are continuously available for activation. Neurosteroids related to allopregnanolone have been tested as a possible replacement for benzodiazepines because they target both synaptic and extrasynaptic GABA A Rs receptors. A longer effective treatment window, extended treatment efficacy, and enhanced neuroprotection represent significant advantages of neurosteroids over benzodiazepines. However, neurosteroid use is limited by poor physicochemical properties arising from the intrinsic requirement of the pregnane steroid core structure for efficacy rendering drug formulation problematic. We tested a non-steroidal enaminone GABA A R modulator that interacts with both synaptic and extrasynaptic GABA A Rs on a binding site distinct from neurosteroids or benzodiazepines for efficacy to control electrographic SE induced by diisopropyl fluorophosphate or soman intoxication in rats. Animals were treated with standard antidotes, and experimental therapeutic treatment was given following 1 h (diisopropyl fluorophosphate model) or 20 min (soman model) after SE onset. We found that the enaminone 2-261 had an extended duration of seizure termination (>10 h) in the diisopropyl fluorophosphate intoxication model in the presence or absence of midazolam (MDZ). 2-261 also moderately potentiated MDZ in the soman-induced seizure model but had limited efficacy as a stand-alone anticonvulsant treatment due to slow onset of action. 2-261 significantly reduced neuronal death in brain areas associated with either diisopropyl fluorophosphate- or soman-induced SE. 2-261 represents an alternate chemical template from neurosteroids for enhancing extrasynaptic α 4 β 3 δ GABA A R activity to reverse SE from organophosphorous intoxication.

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Retrograde activation of CB1R by muscarinic receptors protects against central organophosphorus toxicity

et al. 2019

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Effect of Acute Soman Exposure on GABAA Receptors in Rat Hippocampal Slices and Cultured Hippocampal Neurons

Cited by 4 publications

References 36 publications

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning

Retrograde activation of CB1R by muscarinic receptors protects against central organophosphorus toxicity

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