Abstract

Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist VU0255035, significantly suppressed seizure severity and prevented the development of SE for about 40 min after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (BLA), a brain region that plays a key role in seizure initiation after nerve agent exposure, VU0255035 blocked the effects produced by bath application of paraoxon, namely, a brief barrage of spontaneous IPSCs, followed by a significant increase in the ratio of the total charge transferred by spontaneous EPSCs over that of the IPSCs. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ih in BLA principal cells‒which could be one of the mechanisms underlying the increased glutamatergic activity‒an effect that was also blocked in the presence of VU0255035. Thus, selective M1 antagonists may be an efficacious pretreatment in contexts where there is risk for exposure to OPs, as they will delay the development of SE long enough for medical assistance to arrive.