Effects of the oxadiazine insecticide indoxacarb, DPX-MP062, on neuronal nicotinic acetylcholine receptors in mammalian neurons

The effects of the novel oxadiazine insecticide DPX-MP062 and its metabolite (DCJW) on neuronal nicotinic acetylcholine receptors (AChRs) were investigated using the whole-cell patch clamp technique in rat embryonic cerebral cortical neurons in primary culture. DPX-MP062, applied at concentrations of 1 and 10 μM to the bath, reduced the peak amplitude of ACh-induced, rapidly decaying currents to 46.8 ± 8.8% (n = 9) and 15.7 ± 5.0% (n = 4) of the control, respectively. The effect was irreversible after washing with drug-free solution. DCJW at either 1 μM or 10 μM had similar actions but the potency was much less than that of DPX-MP062. The slowly desensitizing currents induced by low concentrations of ACh (0.1-10 μM) were augmented and those induced by high concentrations of ACh (100-1000 μM) were inhibited by 10 μM DPX-MP062 with great acceleration of the current decay in a time-dependent manner. These effects were use independent and reversible after washing with drug-free solution. In contrast, DCJW at 10 μM did not show significant effects on peak amplitude and decay phase of the slowly desensitizing ACh-induced current in cortical neurons. These results indicate that the oxadiazine insecticide DPX-MP062 has potent modulating actions on neuronal nicotinic AChRs. The neuronal nicotinic AChR could be one of the primary target sites of the insecticide in mammals.