Drexler_2011_Toxicol.Lett_206_84

Patients suffering from organophosphorus intoxication are compromised by generalised seizures and respiratory insufficiency, either being potentially lethal. In these patients induction of general anaesthesia to allow artificial ventilation is an important therapeutic option. Previously, it has been demonstrated that cholinergic overstimulation impaired network depressing effects of etomidate and sevoflurane. In this study we tested the impact of cholinergic overstimulation on inhibitory effects of diazepam in organotypic slice cultures of cerebrocortical neurons. Effects of clinically relevant concentrations of diazepam on spontaneous action potential activity were assessed by extracellular action potential recordings under basal cholinergic tone as well as in the presence of acetylcholine (1 muM). Diazepam at anaesthetic concentrations (25-500 muM) impeded spontaneous network activity in a concentration dependent manner (EC(5)(0) 80.5+/-8.0 muM). In the presence of 1 muM acetylcholine the potency of diazepam was not significantly altered (EC(5)(0) 83.6+/-8.4 muM). The results demonstrate that the potency of diazepam to depress neocortical network-excitability is not significantly impaired by cholinergic overstimulation. Diazepam thereby differs from other anaesthetics like etomidate or sevoflurane whose potencies and efficacies were severely attenuated. Hence diazepam might be preferable for induction and maintenance of general anaesthesia in patients suffering from nerve agent intoxication.