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 microM 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 microM or 10 microM 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 microM) were augmented and those induced by high concentrations of ACh (100-1000 microM) were inhibited by 10 microM 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 microM 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.
Zhao
X
X
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
Nagata
K
K
Marszalec
W
W
Yeh
J Z
JZ
Narahashi
T
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D010078:Oxazines / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013997:Time Factors
D007306:Insecticides; D010078:Oxazines; D011978:Receptors, Nicotinic; C401104:indoxacarb; D000109:Acetylcholine