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Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABAA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABAA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10 mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20 min after SE onset. When 10 mg/kg SGE-516 was administered 40 min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABAA receptors may be candidates for further study in the treatment of OPNA-induced SE.

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

Several experiments explored the roles of nucleus accumbens (NA), ventral pallidum (VP) and medial preoptic area (MPOA) in the regulation of maternal behavior in rats. A preliminary experiment found that bilateral radiofrequency lesions of medial NA did not disrupt maternal behavior. Experiment 1 found that bilateral infusions of muscimol into VP, but not into medial NA, reversibly disrupted maternal behavior. Experiment 2 found that unilateral muscimol injections into VP disrupted maternal behavior to a greater extent when paired with a contralateral N-methyl-d-aspartic acid (NMDA) MPOA lesion than when paired with a sham MPOA lesion. Experiment 3 showed that a unilateral NMDA MPOA lesion paired with a contralateral NMDA VP lesion (Contra group) disrupted maternal behavior to a much greater extent than did sham NMLA lesions or NMDA lesions of MPOA and VP ipsilateral to one another. Experiment 3 focused on the specificity of the maternal behavior disruptions and found that the primary maternal deficit in the Contra females was a severe deficit in retrieval behavior. Importantly, these females showed normal hoarding behavior, home cage activity, and elevated plus maze activity. Experiment 3 used Neu N immunohistochemistry to define the extent of MPOA and VP excitotoxic lesions. It is hypothesized that MPOA acts to facilitate the active components of maternal behavior by inhibiting NA, which then releases VP from GABAergic inhibition, and such disinhibition of VP allows pup stimuli to trigger appropriate maternal responses.